scholarly journals Spatial, Temporal, and Functional Assessment of LC3-Dependent Autophagy inShigella flexneriDissemination

2018 ◽  
Vol 86 (8) ◽  
Author(s):  
Erin Weddle ◽  
Hervé Agaisse
Keyword(s):  
Colonic Mucosa ◽  
Defense Mechanism ◽  
Positive Impact ◽  
Shigella Flexneri ◽  
Wild Type ◽  
Content Type ◽  
Cell Defense ◽  
Membrane Protrusions ◽  
Cell Spread

ABSTRACTShigella flexneridisseminates within the colonic mucosa by displaying actin-based motility in the cytosol of epithelial cells. Motile bacteria form membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the bacteria escape, thereby achieving cell-to-cell spread. During dissemination,S. flexneriis targeted by LC3-dependent autophagy, a host cell defense mechanism against intracellular pathogens. TheS. flexneritype III secretion system effector protein IcsB was initially proposed to counteract the recruitment of the LC3-dependent autophagy machinery to cytosolic bacteria. However, a recent study proposed that LC3 was recruited to bacteria in DMVs formed during cell-to-cell spread. To resolve the controversy and clarify the role of autophagy inS. flexneriinfection, we tracked dissemination using live confocal microscopy and determined the spatial and temporal recruitment of LC3 to bacteria. This approach demonstrated that (i) LC3 was exclusively recruited to wild-type oricsBbacteria located in DMVs and (ii) theicsBmutant was defective in cell-to-cell spread due to failure to escape LC3-positive as well as LC3-negative DMVs. Failure ofS. flexnerito escape DMVs correlated with late LC3 recruitment, suggesting that LC3 recruitment is the consequence and not the cause of DMV escape failure. Inhibition of autophagy had no positive impact on the spreading of wild-type oricsBmutant bacteria. Our results unambiguously demonstrate that IcsB is required for DMV escape during cell-to-cell spread, regardless of LC3 recruitment, and do not support the previously proposed notion that autophagy countersS. flexneridissemination.

scholarly journals The Autotransporter IcsA PromotesShigella flexneriBiofilm Formation in the Presence of Bile Salts

2019 ◽  
Vol 87 (7) ◽  
Author(s):  
Volkan K. Köseoğlu ◽  
Chelsea P. Hall ◽  
Eric M. Rodríguez-López ◽  
Hervé Agaisse
Keyword(s):  
Biofilm Formation ◽  
Bile Salts ◽  
Colonic Mucosa ◽  
Shigella Flexneri ◽  
Bacterial Pathogen ◽  
Phenotypic Analysis ◽  
Content Type ◽  
Mutant Strains ◽  
Aggregative Growth

ABSTRACTShigella flexneriis an intracellular bacterial pathogen that invades epithelial cells in the colonic mucosa, leading to bloody diarrhea. A previous study showed thatS. flexneriforms biofilms in the presence of bile salts, through an unknown mechanism. Here, we investigated the potential role of adhesin-like autotransporter proteins inS. flexneribiofilm formation. BLAST search analysis revealed that theS. flexneri2457T genome harbors 4 genes,S1242,S1289,S2406, andicsA, encoding adhesin-like autotransporter proteins. Deletion mutants of theS1242,S1289,S2406andicsAgenes were generated and tested for biofilm formation. Phenotypic analysis of the mutant strains revealed that disruption oficsAabolished bile salt-induced biofilm formation. IcsA is an outer membrane protein secreted at the bacterial pole that is required forS. flexneriactin-based motility during intracellular infection. In extracellular biofilms, IcsA was also secreted at the bacterial pole and mediated bacterial cell-cell contacts and aggregative growth in the presence of bile salts. Dissecting individual roles of bile salts showed that deoxycholate is a robust biofilm inducer compared to cholate. The release of the extracellular domain of IcsA through IcsP-mediated cleavage was greater in the presence of cholate, suggesting that the robustness of biofilm formation was inversely correlated with IcsA processing. Accordingly, deletion oficsPabrogated IcsA processing in biofilms and enhanced biofilm formation.

scholarly journals The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 565
Author(s):  
Angela Toss ◽  
Claudia Piombino ◽  
Elena Tenedini ◽  
Alessandra Bologna ◽  
Elisa Gasparini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Positive Impact ◽  
Progression Free Survival ◽  
Molecular Testing ◽  
Wild Type ◽  
Brca Mutations ◽  
Multicenter Cohort Study ◽  
Advanced Stages ◽  
Predictive Role

Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.

Promoting strategic performance through strategic orientation and strategic renewal

2019 ◽  
Vol 58 (2) ◽  
pp. 376-392 ◽  
Author(s):  
Hassan Ahmed Shah ◽  
Muhammad Yasir ◽  
Abdul Majid ◽  
Muhammad Yasir ◽  
Asad Javed
Keyword(s):  
Positive Impact ◽  
Moderated Mediation ◽  
Strategic Orientation ◽  
Mediation Model ◽  
Content Type ◽  
Strategic Performance ◽  
Strategic Renewal ◽  
Mediating Role ◽  
Moderated Mediation Model

Purpose The purpose of this paper is to explore the ways in which strategic orientation (SO) and strategic renewal (SR) could create the possibility for improving strategic performance (SP). The indirect effect of SO was also tested in this study. Furthermore, by using the moderated mediation model, the authors also investigated the moderating role of organizational ambidexterity (OA). Design/methodology/approach The results of this cross-sectional study are based on a survey conducted on 1,430 owner/managers of SMEs. To analyze the relationship among variables, this study used descriptive, correlation and hierarchical multiple regression approach. Findings Results revealed that SO positively affects SR and SP in SMEs. Furthermore, the mediating role of SR between the relationships of SO and SP was also confirmed. Moreover, OA strengthens the connection between SO, SR and SP. Practical implications The current study provides new insights for strategic planning and management by focusing on SO along with its different dimensions. Therefore, it provides new guidelines and a roadmap that would be helpful in achieving the objectives of SP. Originality/value The study makes significant contributions to the extant literature by adding new knowledge about the positive impact of SO on SP. Moreover, with the analysis of mediating role of SR in this relationship, the study has made significant addition to the existing literature on SP. Furthermore, moderated mediation model adds value to the existing body of knowledge.

scholarly journals Spontaneous Gac Mutants of Pseudomonas Biological Control Strains: Cheaters or Mutualists?

2011 ◽  
Vol 77 (20) ◽  
pp. 7227-7235 ◽  
Author(s):  
William W. Driscoll ◽  
John W. Pepper ◽  
Leland S. Pierson ◽  
Elizabeth A. Pierson
Keyword(s):  
Alternative Hypothesis ◽  
Natural Populations ◽  
Regulatory System ◽  
Wild Type ◽  
Content Type ◽  
The Public ◽  
Extracellular Metabolites ◽  
Mutualistic Interaction ◽  
Alternative Hypotheses

ABSTRACTBacteria rely on a range of extracellular metabolites to suppress competitors, gain access to resources, and exploit plant or animal hosts. The GacS/GacA two-component regulatory system positively controls the expression of many of these beneficial external products in pseudomonad bacteria. Natural populations often contain variants with defective Gac systems that do not produce most external products. These mutants benefit from a decreased metabolic load but do not appear to displace the wild type in nature. How could natural selection maintain the wild type in the presence of a mutant with enhanced growth? One hypothesis is that Gac mutants are “cheaters” that do not contribute to the public good, favored within groups but selected against between groups, as groups containing more mutants lose access to ecologically important external products. An alternative hypothesis is that Gac mutants have a mutualistic interaction with the wild type, so that each variant benefits by the presence of the other. In the biocontrol bacteriumPseudomonas chlororaphisstrain 30-84, Gac mutants do not produce phenazines, which suppress competitor growth and are critical for biofilm formation. Here, we test the predictions of these alternative hypotheses by quantifying interactions between the wild type and the phenazine- and biofilm-deficient Gac mutant within growing biofilms. We find evidence that the wild type and Gac mutants interact mutualistically in the biofilm context, whereas a phenazine-defective structural mutant does not. Our results suggest that the persistence of alternative Gac phenotypes may be due to the stabilizing role of local mutualistic interactions.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

Paternity leave: stepchild of family-friendly policies. Moderating the role of traditional masculinity ideology

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Bhawana Maheshwari ◽  
Jatin Pandey ◽  
Aditya Billore
Keyword(s):  
Organizational Support ◽  
Positive Impact ◽  
Theory And Practice ◽  
Content Type ◽  
Masculinity Ideology ◽  
Moderated Mediation Model ◽  
Paternity Leave ◽  
Traditional Masculinity ◽  
The Relationship

PurposeThe purpose of this study is to demonstrate the importance and influence of paternity leave on individual level organizational outcomes. Drawing on signaling theory, the study examines the relationship between paid paternity leave entitlement (PPLE) and organizational attractiveness (OA) through a mediating path of anticipated organizational support (AOS). Furthermore, the study proposes that this mediated relationship would be conditional on traditional masculinity ideology (TMI) such that the relationship would be stronger for individuals who score low on TMI.Design/methodology/approachThe study analyzed a moderated mediation model using the data from a survey experiment. Data were collected from 264 professionals enrolled in an executive education course and will soon be looking for employment.FindingsThe findings supported the mediating role of AOS between PPLE and OA. As predicted, the positive impact of PPLE on AOS and OA is stronger for individuals scoring low on TMI.Originality/valueThis study takes a multidisciplinary approach to understand the underlying mechanisms that impact decisions related to employers. It is one of the few studies that study paternity leave in the Indian context and makes important contributions to theory and practice.

scholarly journals Genetic Mechanisms behind the Spread of Reduced Susceptibility to Azithromycin in Shigella Strains Isolated from Men Who Have Sex with Men in Québec, Canada

2018 ◽  
Vol 63 (2) ◽  
pp. e01679-18 ◽  
Author(s):  
Khadidja Yousfi ◽  
Christiane Gaudreau ◽  
Pierre A. Pilon ◽  
Brigitte Lefebvre ◽  
Matthew Walker ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Shigella Flexneri ◽  
Complete Sequence ◽  
Shigella Sonnei ◽  
Content Type ◽  
Genetic Mechanisms ◽  
Sex With Men

ABSTRACT We analyzed 254 Shigella species isolates collected in Québec, Canada, during 2013 and 2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%), or both genes (86.7%). Shigella strains with RSA were mostly isolated from men who have sex with men (68.8% or higher) from the Montreal region. A complete sequence analysis of six selected plasmids from Shigella sonnei and different serotypes of Shigella flexneri emphasized the role of IS26 in the dissemination of RSA.

scholarly journals Magnitude of Voriconazole Resistance in Clinical and Environmental Isolates of Aspergillus flavus and Investigation into the Role of Multidrug Efflux Pumps

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Raees A. Paul ◽  
Shivaprakash M. Rudramurthy ◽  
Manpreet Dhaliwal ◽  
Pankaj Singh ◽  
Anup K. Ghosh ◽  
...  
Keyword(s):  
Aspergillus Flavus ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Wild Type ◽  
Multidrug Efflux ◽  
Environmental Isolates ◽  
Content Type ◽  
Multidrug Efflux Pumps

ABSTRACT The magnitude of azole resistance in Aspergillus flavus and its underlying mechanism is obscure. We evaluated the frequency of azole resistance in a collection of clinical (n = 121) and environmental isolates (n = 68) of A. flavus by the broth microdilution method. Six (5%) clinical isolates displayed voriconazole MIC greater than the epidemiological cutoff value. Two of these isolates with non-wild-type MIC were isolated from same patient and were genetically distinct, which was confirmed by amplified fragment length polymorphism analysis. Mutations associated with azole resistance were not present in the lanosterol 14-α demethylase coding genes (cyp51A, cyp51B, and cyp51C). Basal and voriconazole-induced expression of cyp51A homologs and various efflux pump genes was analyzed in three each of non-wild-type and wild-type isolates. All of the efflux pump genes screened showed low basal expression irrespective of the azole susceptibility of the isolate. However, the non-wild-type isolates demonstrated heterogeneous overexpression of many efflux pumps and the target enzyme coding genes in response to induction with voriconazole (1 μg/ml). The most distinctive observation was approximately 8- to 9-fold voriconazole-induced overexpression of an ortholog of the Candida albicans ATP binding cassette (ABC) multidrug efflux transporter, Cdr1, in two non-wild-type isolates compared to those in the reference strain A. flavus ATCC 204304 and other wild-type strains. Although the dominant marker of azole resistance in A. flavus is still elusive, the current study proposes the possible role of multidrug efflux pumps, especially that of Cdr1B overexpression, in contributing azole resistance in A. flavus.

The relationship between training satisfaction, organisational citizenship behaviour, and turnover intention

2017 ◽  
Vol 4 (3) ◽  
pp. 267-290 ◽  
Author(s):  
Mumtaz Ali Memon ◽  
Rohani Sallaeh ◽  
Mohamed Noor Rosli Baharom ◽  
Shahrina Md Nordin ◽  
Hiram Ting
Keyword(s):  
Turnover Intention ◽  
Structural Equation ◽  
Oil And Gas ◽  
Positive Impact ◽  
Future Research ◽  
Content Type ◽  
Training Satisfaction ◽  
Negative Effect ◽  
Unexpected Findings

Purpose The purpose of this paper is to explore the role of training satisfaction as a predictor of organisational citizenship behaviour (OCB) and turnover intention. The study further examines the mediating role of OCB between training satisfaction and turnover intention. Design/methodology/approach Data were collected from 409 Malaysian oil and gas (O&G) sector employees. Partial least squares structural equation modelling (PLS-SEM) was used to test the hypotheses in the research model using SmartPLS 3.0. Findings This study highlights the significant positive impact of training satisfaction on OCB and the negative effect on turnover intention. Contrary to expectations, OCB proved to be neither a predictor of turnover intention nor a mediator in the model. Practical implications Although the main aim of this study was to test the theoretically driven hypotheses, the findings have a number of valuable implications for organisations. This study suggests that O&G organisations should focus on increasing employee satisfaction with training to maximise desired workplace attitudes and behaviours. Originality/value This is the first study to explore the causal links between training satisfaction, OCB and turnover intention. Although it has been observed in the past that training does not directly influence turnover intention, the present study indicates that training satisfaction significantly influences turnover intention. Further, this study unexpectedly found no direct relationship between OCB and turnover intention. Also, OCB was not a significant mediator in the present study. These unexpected findings open new avenues for future research, thus representing an important contribution of the present study.

scholarly journals Causal Role of Single Nucleotide Polymorphisms within themprFGene of Staphylococcus aureus in Daptomycin Resistance

2013 ◽  
Vol 57 (11) ◽  
pp. 5658-5664 ◽  
Author(s):  
Soo-Jin Yang ◽  
Nagendra N. Mishra ◽  
Aileen Rubio ◽  
Arnold S. Bayer
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Point Mutations ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Content Type ◽  
Reading Frame ◽  
A Charge

ABSTRACTSingle nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been commonly observed in daptomycin-resistant (DAPr)Staphylococcus aureusstrains. Such SNPs are usually associated with a gain-in-function phenotype, in terms of either increased synthesis or enhanced translocation (flipping) of lysyl-phosphatidylglycerol (L-PG). However, it is unclear if suchmprFSNPs are causal in DAPrstrains or are merely a biomarker for this phenotype. In this study, we used an isogenic set ofS. aureusstrains: (i) Newman, (ii) its isogenic ΔmprFmutant, and (iii) several intransplasmid complementation constructs, expressing either a wild-type or point-mutated form of themprFORF cloned from two isogenic DAP-susceptible (DAPs)-DAPrstrain pairs (616-701 and MRSA11/11-REF2145). Complementation of the ΔmprFstrain with singly point-mutatedmprFgenes (mprFS295LormprFT345A) revealed that (i) individual and distinct point mutations within themprFORF can recapitulate phenotypes observed in donor strains (i.e., changes in DAP MICs, positive surface charge, and cell membrane phospholipid profiles) and (ii) these gain-in-function SNPs (i.e., enhanced L-PG synthesis) likely promote reduced DAP binding toS. aureusby a charge repulsion mechanism. Thus, for these two DAPrstrains, the definedmprFSNPs appear to be causally related to this phenotype.

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