scholarly journals Mutations within embCAB Are Associated with Variable Level of Ethambutol Resistance in Mycobacterium tuberculosis Isolates from China

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Qing Sun ◽  
Tong-yang Xiao ◽  
Hai-can Liu ◽  
Xiu-qin Zhao ◽  
Zhi-guang Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multivariate Regression ◽  
Upstream Region ◽  
Multivariate Regression Model ◽  
Resistance Level ◽  
Content Type ◽  
Variable Level ◽  
High Level ◽  
Different Levels

ABSTRACT The EmbCAB proteins have been considered a target for ethambutol (EMB). Mutations in embCAB are known to confer most EMB resistance. However, the knowledge about the effects of embCAB mutations on the EMB resistance level and about the role of mutation-mutation interactions is limited in China. Here, we sequenced embCAB among 125 Mycobacterium tuberculosis isolates from China and quantified their EMB MICs by testing growth at 10 concentrations. Furthermore, a multivariate regression model was established to assess the effects of both individual mutations and multiple mutations. Our results revealed that in China, 82.6% of EMB-resistant isolates (71/86 isolates) harbored at least one mutation within embCAB. Most of the mutations were located in the embB and embA upstream region. Several individual mutations and multiple mutations within this region contributed to the different levels of EMB resistance. Their effects were statistically significant. Additionally, there was an association between high-level EMB resistance and multiple mutations.

scholarly journals An Upstream Truncation of thefurA-katGOperon Confers High-Level Isoniazid Resistance in a Mycobacterium tuberculosis Clinical Isolate with No Known Resistance-Associated Mutations

2014 ◽  
Vol 58 (10) ◽  
pp. 6093-6100 ◽  
Author(s):  
Gilman Kit Hang Siu ◽  
Wing Cheong Yam ◽  
Ying Zhang ◽  
Richard Y. T. Kao
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Isolate ◽  
Intergenic Region ◽  
Catalase Activity ◽  
Significant Proportion ◽  
Northern Blotting ◽  
Upstream Region ◽  
Sequencing Analysis ◽  
Content Type ◽  
High Level

ABSTRACTAlthough the major causes of isoniazid (INH) resistance inMycobacterium tuberculosisare confined to structural mutations inkatGand promoter mutations in themabA-inhAoperon, a significant proportion of INH-resistant strains have unknown resistance mechanisms. Recently, we identified a high-level INH-resistantM. tuberculosisclinical isolate, GB005, with no known resistance-associated mutations. A comprehensive study was performed to investigate the molecular basis of drug resistance in this strain. Although no mutations were found throughout thekatGandfurA-katGintergenic region, thekatGexpression and the catalase activity were greatly diminished compared to those in H37Rv (P< 0.01). Northern blotting revealed that thekatGtranscript from the isolate was smaller than that of H37Rv. Sequencing analysis offurAand upstream genes discovered a 7.2-kb truncation extended from the 96th base preceding the initiation codon ofkatG. Complementation of theM. tuberculosisΔ(furA-katG) strain withkatGand different portions of the truncated region identified a 134-bp upstream fragment offurAthat was essential for full catalase activity and INH susceptibility inM. tuberculosis. The promoter activity of this fragment was also shown to be stronger than that of thefurA-katGintergenic region (P< 0.01). Collectively, these findings demonstrate that deletion of the 134-bpfurAupstream fragment is responsible for the reduction inkatGexpression, resulting in INH resistance in GB005. To our knowledge, this is the first report showing that deletion of the upstream region preceding thefurA-katGoperon causes high-level INH resistance in a clinical isolate ofM. tuberculosis.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Spo0A Suppresses sin Locus Expression in Clostridioides difficile

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Babita Adhikari Dhungel ◽  
Revathi Govind
Keyword(s):  
Diarrheal Disease ◽  
Toxin Production ◽  
The United States ◽  
Upstream Region ◽  
Pcr Analysis ◽  
Bacterial Cells ◽  
Master Regulator ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile is the leading cause of nosocomial infection and is the causative agent of antibiotic-associated diarrhea. The severity of the disease is directly associated with toxin production, and spores are responsible for the transmission and persistence of the organism. Previously, we characterized sin locus regulators SinR and SinR′ (we renamed it SinI), where SinR is the regulator of toxin production and sporulation. The SinI regulator acts as its antagonist. In Bacillus subtilis, Spo0A, the master regulator of sporulation, controls SinR by regulating the expression of its antagonist, sinI. However, the role of Spo0A in the expression of sinR and sinI in C. difficile had not yet been reported. In this study, we tested spo0A mutants in three different C. difficile strains, R20291, UK1, and JIR8094, to understand the role of Spo0A in sin locus expression. Western blot analysis revealed that spo0A mutants had increased SinR levels. Quantitative reverse transcription-PCR (qRT-PCR) analysis of its expression further supported these data. By carrying out genetic and biochemical assays, we show that Spo0A can bind to the upstream region of this locus to regulates its expression. This study provides vital information that Spo0A regulates the sin locus, which controls critical pathogenic traits such as sporulation, toxin production, and motility in C. difficile. IMPORTANCE Clostridioides difficile is the leading cause of antibiotic-associated diarrheal disease in the United States. During infection, C. difficile spores germinate, and the vegetative bacterial cells produce toxins that damage host tissue. In C. difficile, the sin locus is known to regulate both sporulation and toxin production. In this study, we show that Spo0A, the master regulator of sporulation, controls sin locus expression. Results from our study suggest that Spo0A directly regulates the expression of this locus by binding to its upstream DNA region. This observation adds new detail to the gene regulatory network that connects sporulation and toxin production in this pathogen.

scholarly journals Mutation ofRv2887, amarR-Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

2015 ◽  
Vol 59 (11) ◽  
pp. 6873-6881 ◽  
Author(s):  
Kathryn Winglee ◽  
Shichun Lun ◽  
Marco Pieroni ◽  
Alan Kozikowski ◽  
William Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Efflux Pump ◽  
Transcriptional Regulator ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Strong Activity ◽  
Content Type ◽  
Novel Drug

ABSTRACTDrug resistance is a major problem inMycobacterium tuberculosiscontrol, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity againstM. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independentM. tuberculosismutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations inRv2887were common to all three MP-III-71-resistant mutants, and we confirmed the role ofRv2887as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified inEscherichia colito negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation ofRv2887abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations ofRv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance ofM. tuberculosisRv2887mutants may involve efflux pump upregulation and also drug methylation.

Comparing predictive performance of general regression neural network (GRNN) and hedonic regression model for factors affecting housing prices in “Pune-India”

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Abhijat Arun Abhyankar ◽  
Harish Kumar Singla
Keyword(s):  
Neural Network ◽  
Regression Model ◽  
Multivariate Regression ◽  
Housing Prices ◽  
Predictive Performance ◽  
General Regression Neural Network ◽  
Multivariate Regression Model ◽  
Data Set ◽  
Content Type ◽  
General Regression

Purpose The purpose of this study is to compare the predictive performance of the hedonic multivariate regression model with the probabilistic neural network (PNN)-based general regression neural network (GRNN) model of housing prices in “Pune-India.” Design/methodology/approach Data on 211 properties across “Pune city-India” is collected. The price per square feet is considered as a dependent variable whereas distances from important landmarks such as railway station, fort, university, airport, hospital, temple, parks, solid waste site and stadium are considered as independent variables along with a dummy for amenities. The data is analyzed using a hedonic type multivariate regression model and GRNN. The GRNN divides the entire data set into two sets, namely, training set and testing set and establishes a functional relationship between the dependent and target variables based on the probability density function of the training data (Alomair and Garrouch, 2016). Findings While comparing the performance of the hedonic multivariate regression model and PNN-based GRNN, the study finds that the output variable (i.e. price) has been accurately predicted by the GRNN model. All the 42 observations of the testing set are correctly classified giving an accuracy rate of 100%. According to Cortez (2015), a value close to 100% indicates that the model can correctly classify the test data set. Further, the root mean square error (RMSE) value for the final testing for the GRNN model is 0.089 compared to 0.146 for the hedonic multivariate regression model. A lesser value of RMSE indicates that the model contains smaller errors and is a better fit. Therefore, it is concluded that GRNN is a better model to predict the housing price functions. The distance from the solid waste site has the highest degree of variable senstivity impact on the housing prices (22.59%) followed by distance from university (17.78%) and fort (17.73%). Research limitations/implications The study being a “case” is restricted to a particular geographic location hence, the findings of the study cannot be generalized. Further, as the objective of the study is restricted to just to compare the predictive performance of two models, it is felt appropriate to restrict the scope of work by focusing only on “location specific hedonic factors,” as determinants of housing prices. Practical implications The study opens up a new dimension for scholars working in the field of housing prices/valuation. Authors do not rule out the use of traditional statistical techniques such as ordinary least square regression but strongly recommend that it is high time scholars use advanced statistical methods to develop the domain. The application of GRNN, artificial intelligence or other techniques such as auto regressive integrated moving average and vector auto regression modeling helps analyze the data in a much more sophisticated manner and help come up with more robust and conclusive evidence. Originality/value To the best of the author’s knowledge, it is the first case study that compares the predictive performance of the hedonic multivariate regression model with the PNN-based GRNN model for housing prices in India.

Promoting authenticity through celebrity brands

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Amanda Kennedy ◽  
Stacey M. Baxter ◽  
Alicia Kulczynski
Keyword(s):  
Design Methodology ◽  
Consumer Attitudes ◽  
Purchase Intentions ◽  
Consumer Perceptions ◽  
Positive Outcomes ◽  
Content Type ◽  
Monetary Compensation ◽  
High Level ◽  
Practical Implications

Purpose This paper aims to examine the importance of celebrity brands in influencing consumer perceptions of celebrity authenticity, which drives positive consumer attitudes and intentions. In addition, the notion of low-celebrity investment is investigated as a factor that diminishes the positive outcomes associated with celebrity brands. Design/methodology/approach Study 1 examines the effect of brand situation (endorsement versus celebrity brand) on consumer attitudes and intentions. Studies 2 and 3 investigate the role of celebrity authenticity in explaining the effects observed in Study 1. Study 4 examines celebrity investment as a bound of the phenomenon. Findings Study 1 demonstrates that consumers report heightened attitudes and intentions towards celebrity brands when compared to endorsements. Studies 2 and 3 provide evidence that authenticity explains the effects observed in Study 1. Results of Study 4 show that when consumers are aware of low-celebrity investment, the celebrity is viewed as inauthentic regardless of brand situation. Research limitations/implications This research is limited as it focuses only on known celebrity endorsers who were matched with products that had a high level of fit. In addition, purchase intentions were measured as opposed to the study of actual purchase behaviour. Practical implications This research has important implications for the development of endorsements and celebrity brands by demonstrating that consumers view celebrities as authentic when they are involved with brands for reasons other than monetary compensation. Originality/value This research shows that consumers have heightened attitudes and intentions towards celebrity brands compared to endorsements. This research identifies celebrity authenticity as the process underlying the observed phenomenon. However, celebrity investment is identified as a boundary condition demonstrating that knowledge of low investment results in a celebrity being viewed as inauthentic.

Customer centricity and guanxi prevalence as social capital: a study of international business relationships

2018 ◽  
Vol 33 (8) ◽  
pp. 1209-1220 ◽  
Author(s):  
Angeline Close Scheinbaum ◽  
Stephen W. Wang
Keyword(s):  
Structural Equation ◽  
Equation Modeling ◽  
Global Business ◽  
Global Marketing ◽  
Logistics Industry ◽  
Content Type ◽  
Global Logistics ◽  
High Level ◽  
Customer Centricity

Purpose This research blends perspectives of the Eastern phenomenon of guanxi with the more Western perspectives of relationship marketing and customer centricity. Extending scholarship on guanxi in marketing (e.g. Park and Luo, 2001; Sheu and Hu, 2009; Luo et al., 2008; Fowler and Reisenwitz, 2014), the objective is to highlight the indirect role of customer centricity (i.e. how visible or central it is for the business partner to communicate with/have information sharing with), for firms in regions with a prevalence of guanxi. Design/methodology/approach The empirical model is tested in context of global marketing in the business-to-business (B2B) logistics industry (n = 508). A total of 508 global logistics employees and managers with experience in global business participated in the survey in Taiwan. Structural equation modeling was used for data analysis with multi-group analyses. Findings Customer centricity intensifies positive outcomes of guanxi prevalence. Specifically, a high level of customer centricity strengthens established associations among guanxi prevalence, trust, relationship commitment and firm performance. Originality/value While most work on guanxi has a focus in China, this research focuses on Taiwan. While building on a wealth of literature, relatively less work has focused on customer centricity.

Does transformational leadership always matter in frontline service roles?

2018 ◽  
Vol 28 (6) ◽  
pp. 733-751 ◽  
Author(s):  
Keo Mony Sok ◽  
Phyra Sok ◽  
Lan Snell ◽  
Pingping Qiu
Keyword(s):  
Customer Service ◽  
Service Performance ◽  
Hierarchical Regression ◽  
Content Type ◽  
Service Employees ◽  
High Level ◽  
Frontline Service Employees ◽  
The Relationship ◽  
Frontline Service

Purpose The purpose of this paper is to examine the role of frontline service employees (FSEs) motivation (enjoyment of work and driven to work) and ability (customer service ability) in the relationship between TFL and employee service performance. Design/methodology/approach This is a survey-based study which involves 534 FSEs and 135 supervisors in a hair salon setting. Hierarchical regression analysis was used to test the proposed hypotheses. Findings Results show that TFL is significantly related to employee service performance; this relationship is enhanced with the presence of driven to work; yet, it is neutralized with the presence of enjoyment of work. Further, the three-way interaction of TFL, enjoyment of work and customer service ability as well as TFL driven to work, and customer service ability are negatively associated with employee service performance. Practical implications The results advance service managers’ understanding of the importance of FSEs motivation and ability if they are to fully reap the benefits from their FSEs. The role of leader is not always effective in all situations. FSEs with high level of enjoyment of work and customer service ability would least rely on the guidance and support from the supervisors. Originality/value This research is one of the first to examine the role of subordinate’s characteristics (motivation – enjoyment of work and driven to work and ability – customer service ability) as the key moderators in the relationship between TFL and employee service performance.

scholarly journals Extending the Definition of the GyrB Quinolone Resistance-Determining Region in Mycobacterium tuberculosis DNA Gyrase for Assessing Fluoroquinolone Resistance in M. tuberculosis

2012 ◽  
Vol 56 (4) ◽  
pp. 1990-1996 ◽  
Author(s):  
Alix Pantel ◽  
Stéphanie Petrella ◽  
Nicolas Veziris ◽  
Florence Brossier ◽  
Sylvaine Bastian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hot Spot ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Content Type ◽  
Highly Active ◽  
Definition Of

ABSTRACTFluoroquinolone (FQ) resistance is emerging inMycobacterium tuberculosis. The main mechanism of FQ resistance is amino acid substitution within the quinolone resistance-determining region (QRDR) of the GyrA subunit of DNA gyrase, the sole FQ target inM. tuberculosis. However, substitutions in GyrB whose implication in FQ resistance is unknown are increasingly being reported. The present study clarified the role of four GyrB substitutions identified inM. tuberculosisclinical strains, two located in the QRDR (D500A and N538T) and two outside the QRDR (T539P and E540V), in FQ resistance. We measured FQ MICs and also DNA gyrase inhibition by FQs in order to unequivocally clarify the role of these mutations in FQ resistance. Wild-type GyrA, wild-type GyrB, and mutant GyrB subunits produced from engineeredgyrBalleles by mutagenesis were overexpressed inEscherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. MICs and DNA gyrase inhibition were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. All these substitutions are clearly implicated in FQ resistance, underlining the presence of a hot spot region housing most of the GyrB substitutions implicated in FQ resistance (residues NTE, 538 to 540). These findings help us to refine the definition of GyrB QRDR, which is extended to positions 500 to 540.

scholarly journals Servitization strategies from customers’ perspective: the moderating role of co-creation

2019 ◽  
Vol 34 (3) ◽  
pp. 628-642 ◽  
Author(s):  
José L. Ruiz-Alba ◽  
Anabela Soares ◽  
Miguel A. Rodríguez-Molina ◽  
Dolores M. Frías-Jamilena
Keyword(s):  
Structural Equation ◽  
Business Models ◽  
Service Providers ◽  
Moderating Effect ◽  
Mediating Effect ◽  
Content Type ◽  
The Impact ◽  
Moderating Role ◽  
Different Levels

Purpose This paper aims to investigate the moderating role of co-creation in the implementation of servitization strategies in the pharmaceutical industry in a business-to-business (B-to-B) context. More specifically, this investigation explores the impact of different levels of services (base, intermediate and advanced) on servitization and on performance by using co-creation as a moderating factor. Design/methodology/approach A research framework was developed and empirically tested in the pharmaceutical sector. Data collection was conducted through the online distribution of questionnaires. The final sample included 219 pharmacy stores, and the data were analysed using structural equation modelling. Findings Main findings suggest that when the level of co-creation of the design of services is high, there are significant effects of servitization on firm performance. The moderating effect of co-creation is illustrated in regard to intermediate and advanced services, but results referring to the impact of intermediate services on servitization appear non-significant with a low degree of co-creation. No significant effects could be found for the impact of base services on performance and servitization for both high and low degrees of co-creation. Findings show an impact of advanced services on performance through the mediating effect of servitization when the degree of co-creation is high. Originality/value Most research concerning servitization has been done from the perspective of manufacturers and service providers. This study adds value to the literature because it was designed from a customer’s perspective. Moreover, it contributes towards the conceptualization of the servitization research strategy and business models in a B2B context. This is accomplished through the investigation of the moderating effect of co-creation on the impact of the different levels of services on servitization and on performance.

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