WorldWideScience

Sample records for resistance mechanisms exist

  1. Rhythms of Resistance and Existence

    DEFF Research Database (Denmark)

    Chaudhary, Nandita; Hviid, Pernille; Marsico, Giuseppina

    2017-01-01

    and, when it is, resistance is most often considered counter-productive. Simple evaluations of resistance as positive or negative are avoided in this volume; instead it is conceptualised as a vital process for human development and well-being. While resistance is usually treated as an extraordinary...... occurrence, the focus here is on everyday resistance as an intentional process where new meaning constructions emerge in thinking, feeling, acting or simply living with others. Resistance is thus conceived as a meaning-making activity that operates at the intersection of personal and collective systems...

  2. On existence of resistive magnetohydrodynamic equilibria

    Energy Technology Data Exchange (ETDEWEB)

    Tasso, H.; Throumoulopoulos, G. N.

    2007-07-01

    A necessary condition for existence of general dissipative magnetohydrodynamic equi- libria is derived. The ingredients of the derivation are Ohms law and the existence of magnetic surfaces, only in the sense of KAM theorem. All other equations describing the system matter exclusively for the evaluation of the condition in a concrete case. (Author)

  3. Mechanisms of Antibiotic Resistance

    Science.gov (United States)

    Munita, Jose M.; Arias, Cesar A.

    2015-01-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens. PMID:27227291

  4. Driving Forces of Mechanisms Regulating Oxacillin-Resistance Phenotypes of MRSA : Truly Oxacillin-Susceptible mecA-Positive Staphylococcus aureus Clinical Isolates also Exist

    NARCIS (Netherlands)

    Pournaras, Spyros; Sabat, Artur J.; Grundmann, Hajo; Hendrix, Ron; Tsakris, Athanasios; Friedrich, Alexander W.

    2015-01-01

    As MRSA are considered Staphylococcus aureus isolates with oxacillin minimum inhibitory concentration (MIC) of ≥4 mg/L or harboring the mecA gene. However, the presence of mecA does not necessarily lead to oxacillin resistance and mecA gene-carrying isolates may have oxacillin MIC within the

  5. Mechanisms of ouabain resistance

    International Nuclear Information System (INIS)

    Schulz, J.T. III.

    1987-01-01

    Experiments were designed to investigate the mechanism of ouabain resistance in two distinct types of transfected cells derived from ouabain-sensitive CV-1 cell parents. The first type of transfectant is the recipient of a gene encoding the alpha subunit of the rodent renal Na,K-ATPase (R-alphal gene); the second type of transfectant is the recipient of the mouse ouabain resistance gene. Measurements of 86 Rb + uptake and Na,K=ATPase activity in R-alphal gene transfectant cells and CV-1 parent cells indicate that the ouabain-resistant phenotype of the transfectants is due to expression of a relatively ouabain-insensitive Na,K=ATPase. CV-1 parent cells express one component of ouabain sensitive 86 Rb + uptake and one component of ouabain-sensitive Na, K-ATPase activity. R-alpha 1 gene transfectants express the parental forms of ouabain-sensitive 86 Rb + uptake and Na,K-ATPase activity, but in addition express new,relatively ouabain-insensitive forms of 86 Rb + uptake activity and Na,K-ATPase activity

  6. Mechanisms of Drug Resistance: Daptomycin Resistance

    Science.gov (United States)

    Tran, Truc T.; Munita, Jose M.; Arias, Cesar A.

    2016-01-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction in clinical practice in 2003, DAP has become an important key front-line antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP-resistance (R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp, and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP resistance are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have offered novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID:26495887

  7. Mechanisms of insulin resistance in obesity

    Science.gov (United States)

    Ye, Jianping

    2014-01-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

  8. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

  9. Mechanisms of antidepressant resistance

    Directory of Open Access Journals (Sweden)

    Wissam eEl Hage

    2013-11-01

    Full Text Available Depression is one of the most frequent and severe mental disorder. Since the discovery of antidepressant properties of the imipramine and then after of other tricyclic compounds, several classes of psychotropic drugs have shown be effective in treating major depressive disorder. However, there is a wide range of variability in response to antidepressants that might lead to non response or partial response or in increased rate of relapse or recurrence. The mechanisms of response to antidepressant therapy are poorly understood, and few biomarkers are available than can predict response to pharmacotherapy. Here, we will first review markers that can be used to predict response to pharmacotherapy, such as markers of drug metabolism or blood-brain barrier function, the activity of specific brain areas or neurotransmitter systems, hormonal dysregulations or plasticity, and related molecular targets. We will describe both clinical and preclinical studies and describe factors that might affect the expression of these markers, including environmental or genetic factors and comorbidities. This information will permit us to suggest practical recommendations and innovative treatment strategies to improve therapeutic outcomes.

  10. Pathophysiological mechanisms of insulin resistance

    NARCIS (Netherlands)

    Brands, M.

    2013-01-01

    In this thesis we studied pathophysiological mechanisms of insulin resistance in different conditions in humans, i.e. in obesity, during lipid infusions, after hypercaloric feeding, and glucocorticoid treatment. We focused on 3 important hypotheses that are suggested to be implicated in the

  11. Antimicrobial resistance mechanisms among Campylobacter.

    Science.gov (United States)

    Wieczorek, Kinga; Osek, Jacek

    2013-01-01

    Campylobacter jejuni and Campylobacter coli are recognized as the most common causative agents of bacterial gastroenteritis in the world. Humans most often become infected by ingesting contaminated food, especially undercooked chicken, but also other sources of bacteria have been described. Campylobacteriosis is normally a self-limiting disease. Antimicrobial treatment is needed only in patients with more severe disease and in those who are immunologically compromised. The most common antimicrobial agents used in the treatment of Campylobacter infections are macrolides, such as erythromycin, and fluoroquinolones, such as ciprofloxacin. Tetracyclines have been suggested as an alternative choice in the treatment of clinical campylobacteriosis but in practice are not often used. However, during the past few decades an increasing number of resistant Campylobacter isolates have developed resistance to fluoroquinolones and other antimicrobials such as macrolides, aminoglycosides, and beta-lactams. Trends in antimicrobial resistance have shown a clear correlation between use of antibiotics in the veterinary medicine and animal production and resistant isolates of Campylobacter in humans. In this review, the patterns of emerging resistance to the antimicrobial agents useful in treatment of the disease are presented and the mechanisms of resistance to these drugs in Campylobacter are discussed.

  12. Antimicrobial Resistance Mechanisms among Campylobacter

    Science.gov (United States)

    2013-01-01

    Campylobacter jejuni and Campylobacter coli are recognized as the most common causative agents of bacterial gastroenteritis in the world. Humans most often become infected by ingesting contaminated food, especially undercooked chicken, but also other sources of bacteria have been described. Campylobacteriosis is normally a self-limiting disease. Antimicrobial treatment is needed only in patients with more severe disease and in those who are immunologically compromised. The most common antimicrobial agents used in the treatment of Campylobacter infections are macrolides, such as erythromycin, and fluoroquinolones, such as ciprofloxacin. Tetracyclines have been suggested as an alternative choice in the treatment of clinical campylobacteriosis but in practice are not often used. However, during the past few decades an increasing number of resistant Campylobacter isolates have developed resistance to fluoroquinolones and other antimicrobials such as macrolides, aminoglycosides, and beta-lactams. Trends in antimicrobial resistance have shown a clear correlation between use of antibiotics in the veterinary medicine and animal production and resistant isolates of Campylobacter in humans. In this review, the patterns of emerging resistance to the antimicrobial agents useful in treatment of the disease are presented and the mechanisms of resistance to these drugs in Campylobacter are discussed. PMID:23865047

  13. Resistance mechanisms in Campylobacter jejuni

    Science.gov (United States)

    Iovine, Nicole M.

    2013-01-01

    Campylobacter jejuni is a major cause of food-borne gastroenteritis worldwide. While mortality is low, morbidity imparted by post-infectious sequelae such as Guillain-Barré syndrome, Reiter syndrome/reactive arthritis and irritable bowel syndrome is significant. In addition, the economic cost is high due to lost productivity. Food animals, particularly poultry, are the main reservoirs of C. jejuni. The over-use of antibiotics in the human population and in animal husbandry has led to an increase in antibiotic-resistant infections, particularly with fluoroquinolones. This is problematic because C. jejuni gastroenteritis is clinically indistinguishable from that caused by other bacterial pathogens, and such illnesses are usually treated empirically with fluoroquinolones. Since C. jejuni is naturally transformable, acquisition of additional genes imparting antibiotic resistance is likely. Therefore, an understanding of the antibiotic resistance mechanisms in C. jejuni is needed to provide proper therapy both to the veterinary and human populations. PMID:23406779

  14. Mechanisms of buffer therapy resistance.

    Science.gov (United States)

    Bailey, Kate M; Wojtkowiak, Jonathan W; Cornnell, Heather H; Ribeiro, Maria C; Balagurunathan, Yoganand; Hashim, Arig Ibrahim; Gillies, Robert J

    2014-04-01

    Many studies have shown that the acidity of solid tumors contributes to local invasion and metastasis. Oral pH buffers can specifically neutralize the acidic pH of tumors and reduce the incidence of local invasion and metastatic formation in multiple murine models. However, this effect is not universal as we have previously observed that metastasis is not inhibited by buffers in some tumor models, regardless of buffer used. B16-F10 (murine melanoma), LL/2 (murine lung) and HCT116 (human colon) tumors are resistant to treatment with lysine buffer therapy, whereas metastasis is potently inhibited by lysine buffers in MDA-MB-231 (human breast) and PC3M (human prostate) tumors. In the current work, we confirmed that sensitive cells utilized a pH-dependent mechanism for successful metastasis supported by a highly glycolytic phenotype that acidifies the local tumor microenvironment resulting in morphological changes. In contrast, buffer-resistant cell lines exhibited a pH-independent metastatic mechanism involving constitutive secretion of matrix degrading proteases without elevated glycolysis. These results have identified two distinct mechanisms of experimental metastasis, one of which is pH-dependent (buffer therapy sensitive cells) and one which is pH-independent (buffer therapy resistant cells). Further characterization of these models has potential for therapeutic benefit. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

  15. Axes of resistance for tooth movement: does the center of resistance exist in 3-dimensional space?

    Science.gov (United States)

    Viecilli, Rodrigo F; Budiman, Amanda; Burstone, Charles J

    2013-02-01

    The center of resistance is considered the most important reference point for tooth movement. It is often stated that forces through this point will result in tooth translation. The purpose of this article is to report the results of numeric experiments testing the hypothesis that centers of resistance do not exist in space as 3-dimensional points, primarily because of the geometric asymmetry of the periodontal ligament. As an alternative theory, we propose that, for an arbitrary tooth, translation references can be determined by 2-dimensional projection intersections of 3-dimensional axes of resistance. Finite element analyses were conducted on a maxillary first molar model to determine the position of the axes of rotation generated by 3-dimensional couples. Translation tests were performed to compare tooth movement by using different combinations of axes of resistance as references. The couple-generated axes of rotation did not intersect in 3 dimensions; therefore, they do not determine a 3-dimensional center of resistance. Translation was obtained by using projection intersections of the 2 axes of resistance perpendicular to the force direction. Three-dimensional axes of resistance, or their 2-dimensional projection intersections, should be used to plan movement of an arbitrary tooth. Clinical approximations to a small 3-dimensional "center of resistance volume" might be adequate in nearly symmetric periodontal ligament cases. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  16. Mechanism of ciprofloxacin resistance in Shigella dysenteriae ...

    African Journals Online (AJOL)

    Bacterial resistance to quinolones has emerged rapidly and such resistance has traditionally been attributed to the chromosomally mediated mechanisms that alter the quinolone targets and/or overproduce multidrug resistance efflux pumps. In the present investigation possible mechanism of ciprofloxacin (Cp) resistance in ...

  17. Intrinsic and acquired resistance mechanisms in enterococcus

    Science.gov (United States)

    Hollenbeck, Brian L.; Rice, Louis B.

    2012-01-01

    Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options. PMID:23076243

  18. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies. We provide an overview of ...

  19. First resistance mechanisms characterization in glyphosate-resistant Leptochloa virgata.

    Directory of Open Access Journals (Sweden)

    Ricardo Alcántara-de la Cruz

    2016-11-01

    Full Text Available Leptochloa virgata (L. P. Beauv. is an annual weed common in citrus groves in the states of Puebla and Veracruz, Mexico limiting their production. Since 2010, several L. virgata populations were identified as being resistant to glyphosate, but studies of their resistance mechanisms developed by this species have been conducted. In this work, three glyphosate-resistant populations (R8, R14 and R15 collected in citrus orchards from Mexico, were used to study their resistance mechanisms comparing them to one susceptible population (S. Dose-response and shikimic acid accumulation assays confirmed the glyphosate resistance of the three resistant populations. Higher doses of up to 720 g ae ha-1 (field dose were needed to control by 50% plants of resistant populations. The S population absorbed between 7 and 13% more 14C-glyphosate than resistant ones, and translocated up to 32.2% of 14C-glyphosate to the roots at 96 h after treatment (HAT. The R8, R14 and R15 populations translocated only 24.5, 26.5 and 21.9%, respectively. The enzyme activity of 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS was not different in the S, R8 and R14 populations. The R15 Population exhibited 165.9 times greater EPSPS activity. Additionally, this population showed a higher EPSPS basal activity and a substitution in the codon 106 from Proline to Serine in the EPSPS protein sequence. EPSPS gene expression in the R15 population was similar to that of S population. In conclusion, the three resistant L. virgata populations show reduced absorption and translocation of 14C-glyphosate. Moreover, a mutation and an enhanced EPSPS basal activity at target-site level confers higher resistance to glyphosate. These results describe for the first time the glyphosate resistance mechanisms developed by resistant L. virgata populations of citrus orchards from Mexico.

  20. Bedaquiline resistance: Its emergence, mechanism and prevention.

    Science.gov (United States)

    Nguyen, Thi Van Anh; Anthony, Richard M; Bañuls, Anne-Laure; Vu, Dinh Hoa; Alffenaar, Jan-Willem C

    2017-11-08

    Bedaquiline, a new anti-tuberculosis drug, has already been used in more than 50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This paper aims to review currently identified mechanisms of resistance, the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from the compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance. Currently known mechanisms of resistance include mutations within the atpE, Rv0678 and pepQ genes. The development of standardized drug susceptibility testing (DST) for bedaquiline is urgently needed.Understanding any target and non-target based mechanisms is essential to minimize the resistance development and treatment failure, help to develop appropriate DST for bedaquiline and genetic based resistance screening. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  1. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    PRAKASH

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However ... PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene ... i.e. muscle, liver and fat, is extremely high (Brunetti et al 2001). However, there ...

  2. Molecular mechanisms of insulin resistance

    African Journals Online (AJOL)

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

  3. Bedaquiline resistance: Its emergence, mechanism and prevention.

    NARCIS (Netherlands)

    Nguyen, Thi Van Anh; Anthony, Richard M; Bañuls, Anne-Laure; Vu, Dinh Hoa; Alffenaar, Jan-Willem C

    2017-01-01

    Bedaquiline, a new anti-tuberculosis drug, has already been used in more than 50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This paper aims to review currently identified mechanisms of resistance, the emergence of bedaquiline

  4. [Resistance mechanisms and cross-resistance of phoxim-resistant Frankliniella occidentalis Pergande population].

    Science.gov (United States)

    Wang, Sheng-Yin; Zhou, Xian-Hong; Zhang, An-Sheng; Li, Li-Li; Men, Xing-Yuan; Zhang, Si-Cong; Liu, Yong-Jie; Yu, Yi

    2012-07-01

    To understand the resistance risks of Frankliniella occidentalis Pergande against phoxim, this paper studied the resistance mechanisms of phoxim-resistant F. occidentalis population against phoxim and the cross-resistance of the population against other insecticides. The phoxim-resistant population had medium level cross-resistance to chlorpyrifos, lambda-cyhalothrin, and methomyl, low level cross-resistance to chlorfenapyr, imidacloprid, emamectin-benzoate, and spinosad, but no cross-resistance to acetamiprid and abamectin. The synergists piperonyl butoxide (PBO), s, s, s-tributyl phosphorotrithioate (DEF), and triphenyl phosphate (TPP) had significant synergism (P occidentalis could play an important role in the resistance of the plant against phoxim.

  5. Mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis.

    Science.gov (United States)

    Zhang, Yu-jiao; Li, Xiao-jing; Mi, Kai-xia

    2016-10-20

    Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is one of the world's deadliest bacterial infectious disease. It is still a global-health threat, particularly because of the drug-resistant forms. Fluoroquinolones, with target of gyrase, are among the drugs used to treat tuberculosis. However, their widespread use has led to bacterial resistance. The molecular mechanisms of fluoroquinolone resistance in mycobacterium tuberculosis have been reported, such as DNA gyrase mutations, drug efflux pumps system, bacterial cell wall thickness and pentapeptide proteins (MfpA) mediated regulation of gyrase. Mutations in gyrase conferring quinolone resistance play important roles and have been extensively studied. Recent studies have shown that the regulation of DNA gyrase affects mycobacterial drug resistance, but the mechanisms, especially by post-translational modification and regulatory proteins, are poorly understood. In this review, we summarize the fluoroquinolone drug development, and the molecular genetics of fluoroquinolone resistance in mycobacteria. Comprehensive understanding of the mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis will open a new view on understanding drug resistance in mycobacteria and lead to novel strategies to develop new accurate diagnosis methods.

  6. Mechanisms of antibiotic resistance in enterococci

    Science.gov (United States)

    Miller, William R; Munita, Jose M; Arias, Cesar A

    2015-01-01

    Multidrug-resistant (MDR) enterococci are important nosocomial pathogens and a growing clinical challenge. These organisms have developed resistance to virtually all antimicrobials currently used in clinical practice using a diverse number of genetic strategies. Due to this ability to recruit antibiotic resistance determinants, MDR enterococci display a wide repertoire of antibiotic resistance mechanisms including modification of drug targets, inactivation of therapeutic agents, overexpression of efflux pumps and a sophisticated cell envelope adaptive response that promotes survival in the human host and the nosocomial environment. MDR enterococci are well adapted to survive in the gastrointestinal tract and can become the dominant flora under antibiotic pressure, predisposing the severely ill and immunocompromised patient to invasive infections. A thorough understanding of the mechanisms underlying antibiotic resistance in enterococci is the first step for devising strategies to control the spread of these organisms and potentially establish novel therapeutic approaches. PMID:25199988

  7. Mechanisms of Candida biofilm drug resistance

    Science.gov (United States)

    Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

    2013-01-01

    Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

  8. Correlation of molecular resistance mechanisms and phenotypic resistance levels in streptomycin-resistant Mycobacterium tuberculosis.

    OpenAIRE

    Meier, A; Sander, P; Schaper, K J; Scholz, M; Böttger, E C

    1996-01-01

    Quantitative susceptibility testing of clinical isolates of streptomycin-resistant Mycobacterium tuberculosis demonstrated that there is a close correlation between the molecular resistance mechanism and the in vitro activity of streptomycin: mutations in rpsL were mainly associated with high-level resistance, mutations in rrs were associated with an intermediate level of resistance, and streptomycin-resistant isolates with wild-type rpsL and rrs exhibited a low-level resistance phenotype. In...

  9. Mechanisms of Resistance to Photodynamic Therapy

    Science.gov (United States)

    Casas, Adriana; Di Venosa, Gabriela; Hasan, Tayyaba; Batlle, Alcira

    2013-01-01

    Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by illumination with visible light, leading to generation of reactive oxygen species. The mechanisms of resistance to PDT ascribed to the PS may be shared with the general mechanisms of drug resistance, and are related to altered drug uptake and efflux rates or altered intracellular trafficking. As a second step, an increased inactivation of oxygen reactive species is also associated to PDT resistance via antioxidant detoxifying enzymes and activation of heat shock proteins. Induction of stress response genes also occurs after PDT, resulting in modulation of proliferation, cell detachment and inducing survival pathways among other multiple extracellular signalling events. In addition, an increased repair of induced damage to proteins, membranes and occasionally to DNA may happen. PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption may also contribute to the appearance of resistant cells. The structure of the PS is believed to be a key point in the development of resistance, being probably related to its particular subcellular localization. Although most of the features have already been described for chemoresistance, in many cases, no cross-resistance between PDT and chemotherapy has been reported. These findings are in line with the enhancement of PDT efficacy by combination with chemotherapy. The study of cross resistance in cells with developed resistance against a particular PS challenged against other PS is also highly complex and comprises different mechanisms. In this review we will classify the different features observed in PDT resistance, leading to a comparison with the mechanisms most commonly found in chemo resistant cells. PMID:21568910

  10. Mechanisms of bacterial resistance to antimicrobial agents.

    NARCIS (Netherlands)

    van Duijkeren, Engeline; Schink, Anne-Kathrin; Roberts, Marilyn C; Wang, Yang; Schwarz, Stefan

    During the past decades resistance to virtually all antimicrobial agents has been observed in bacteria of animal origin. This chapter describes in detail the mechanisms so far encountered for the various classes of antimicrobial agents. The main mechanisms include enzymatic inactivation by either

  11. Mechanisms of resistance to paraquat in plants.

    Science.gov (United States)

    Hawkes, Timothy R

    2014-09-01

    The aim of this brief review is to draw information from studies of the mechanism of evolved resistance in weeds, together with information from laboratory studies of paraquat tolerance in model plants. Plants having mutations that limit paraquat uptake into cytoplasm, that confer various stress tolerances or that have transgenes that co-express two or more of the chloroplast Halliwell-Asada cycle enzymes can all exhibit enhanced tolerance to paraquat. However, none of these mechanisms correspond to the high-level resistances that have evolved naturally in weeds. Most, but not all, of the evidence from studies of paraquat-resistant biotypes of weeds can reasonably be reconciled with the proposal of a single major gene mechanism that sequesters paraquat away from chloroplasts and into the vacuole. However, the molecular details of this putative mechanism remain ill-defined. © 2013 Society of Chemical Industry.

  12. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria

    Directory of Open Access Journals (Sweden)

    Abiola Olumuyiwa Olaitan

    2014-11-01

    Full Text Available Polymyxins are polycationic antimicrobial peptides that are currently the last-resort antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, develop resistance to polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp. and Burkholderia spp., are naturally resistant to these drugs. Reports of polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of polymyxins.Gram-negative bacteria employ several strategies to protect themselves from polymyxin antibiotics (polymyxin B and colistin, including a variety of lipopolysaccharide (LPS modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria.

  13. Antibiotic resistance mechanisms of Vibrio cholerae.

    Science.gov (United States)

    Kitaoka, Maya; Miyata, Sarah T; Unterweger, Daniel; Pukatzki, Stefan

    2011-04-01

    As the causative agent of cholera, the bacterium Vibrio cholerae represents an enormous public health burden, especially in developing countries around the world. Cholera is a self-limiting illness; however, antibiotics are commonly administered as part of the treatment regimen. Here we review the initial identification and subsequent evolution of antibiotic-resistant strains of V. cholerae. Antibiotic resistance mechanisms, including efflux pumps, spontaneous chromosomal mutation, conjugative plasmids, SXT elements and integrons, are also discussed. Numerous multidrug-resistant strains of V. cholerae have been isolated from both clinical and environmental settings, indicating that antibiotic use has to be restricted and alternative methods for treating cholera have to be implemented.

  14. Mechanisms of resistance to immune checkpoint inhibitors.

    Science.gov (United States)

    Jenkins, Russell W; Barbie, David A; Flaherty, Keith T

    2018-01-01

    Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors ('targeted therapies') largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.

  15. Mechanisms of hormonal therapy resistance in breast cancer.

    Science.gov (United States)

    Hayashi, Shin-ichi; Kimura, Mariko

    2015-04-01

    Whilst estrogen receptor (ER)-positive breast cancers are preferentially treated with hormone therapy, approximately one-third of them relapse. The mechanisms of refractoriness have been investigated by numerous studies but have not been fully clarified. Hormonal therapy resistance, particularly aromatase inhibitor (AI) resistance, may be related to the acquisition of alternative intracellular ER signaling. We have been investing the mechanisms using cancer specimens and cell lines by monitoring the transcription activity of ERs. AI refractory specimens showed diverse ER activity in the adenovirus estrogen receptor element-green fluorescent protein (ERE-GFP) assay and varied sensitivity to anti-estrogens, indicating the existence of multiple resistant mechanisms. We established six different types of cell lines mimicking AI resistance from ERE-GFP-introduced ER-positive cell lines. They revealed that multiple and alternative ER activating pathways were involved in the resistance, such as phosphorylation-dependent or androgen metabolite-dependent mechanisms. The response to fulvestrant and mammalian target of rapamycin inhibitor also varied among individual resistant cell lines. These results indicate that further subclassification of ER-positive breast cancer is extremely important to decide the therapeutic management of not only hormonal therapy but also new molecular target therapy.

  16. Mechanisms of resistance to alkylating agents

    OpenAIRE

    Damia, G.; D‘Incalci, M.

    1998-01-01

    Alkylating agents are the most widely used anticancer drugs whose main target is the DNA, although how exactly the DNA lesions cause cell death is still not clear. The emergence of resistance to this class of drugs as well as to other antitumor agents is one of the major causes of failure of cancer treatment. This paper reviews some of the best characterized mechanisms of resistance to alkylating agents. Pre- and post-target mechanisms are recognized, the former able to limit the formation of...

  17. Some resistance mechanisms to ultraviolet radiation

    International Nuclear Information System (INIS)

    Alcantara D, D.

    2002-12-01

    The cyclical exposure of bacterial cells to the ultraviolet light (UV) it has as consequence an increment in the resistance to the lethal effects of this type of radiation, increment that happens as a result of a selection process of favorable genetic mutations induced by the same UV light. With object to study the reproducibility of the genetic changes and the associate mechanisms to the resistance to UV in the bacteria Escherichia coli, was irradiated cyclically with UV light five different derived cultures of a single clone, being obtained five stumps with different resistance grades. The genetic mapping Hfr revealed that so much the mutation events like of selection that took place during the adaptation to the UV irradiation, happened of random manner, that is to say, each one of the resistant stumps it is the result of the unspecified selection of mutations arisen at random in different genes related with the repair and duplication of the DNA. (Author)

  18. Antibacterial Mechanisms of Polymyxin and Bacterial Resistance

    Directory of Open Access Journals (Sweden)

    Zhiliang Yu

    2015-01-01

    Full Text Available Multidrug resistance in pathogens is an increasingly significant threat for human health. Indeed, some strains are resistant to almost all currently available antibiotics, leaving very limited choices for antimicrobial clinical therapy. In many such cases, polymyxins are the last option available, although their use increases the risk of developing resistant strains. This review mainly aims to discuss advances in unraveling the mechanisms of antibacterial activity of polymyxins and bacterial tolerance together with the description of polymyxin structure, synthesis, and structural modification. These are expected to help researchers not only develop a series of new polymyxin derivatives necessary for future medical care, but also optimize the clinical use of polymyxins with minimal resistance development.

  19. Dominant mechanisms of primary resistance differ from dominant mechanisms of secondary resistance to targeted therapies.

    Science.gov (United States)

    Asić, Ksenija

    2016-01-01

    The effectiveness of targeted therapies is currently limited, as almost all patients eventually acquire resistance within year/year and a half from therapy initiation and a small subset of a patients fail to respond at all, demonstrating intrinsic resistance. The aim of this review was to determine the potential common features and differences between the mechanisms of intrinsic and acquired resistance to targeted therapies by analyzing established resistance-generating alterations for ten FDA-approved targeted drugs. The frequency of alterations underlying intrinsic and acquired resistance shows distinctive pattern, where dominant mechanisms of intrinsic resistance include aberrations of signals downstream or upstream of the targeted protein and dominant mechanisms of acquired resistance refer to lesions in the target itself or alterations of signals at target-level that can mimic or compensate for target function. It appears that during the evolution of acquired resistance, the tumor cell is inclined to preserve the same oncogene addiction on a targeted protein it had prior to drug administration. On the other hand, intrinsic resistance develops early in tumorogenesis and is based on randomly selected mutated signals between targeted and non-targeted signaling pathways, leading to the acquisition of cancer hallmarks. In general, there is an overlap between the mechanisms of intrinsic and acquired resistance, but the occurrence frequency and distribution of alterations underlying intrinsic and acquired resistance to targeted therapies are significantly different. Focus should be placed on different group of genes in pursuing predictive markers for intrinsic and acquired resistance to targeted therapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Glioblastoma Multiforme Therapy and Mechanisms of Resistance

    Directory of Open Access Journals (Sweden)

    Yulian P. Ramirez

    2013-11-01

    Full Text Available Glioblastoma multiforme (GBM is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy.

  1. Targeting Mechanisms of Resistance to Taxane-Based Chemotherapy

    National Research Council Canada - National Science Library

    Huang, Chung-Yung

    2006-01-01

    .... Further, current clinical, pathological and molecular markers poorly predict the response and resistance of chemotherapy, and the molecular mechanisms of chemotherapy resistance are largely unknown...

  2. Targeting Mechanisms of Resistance to Taxane-Based Chemotherapy

    National Research Council Canada - National Science Library

    Huang, Chung-Ying

    2007-01-01

    .... Further current clinical pathological and molecular markers poorly predict the response and resistance of chemotherapy and the molecular mechanisms of chemotherapy resistance are largely unknown...

  3. [Molecular Mechanisms of Insulin Resistance: An Update].

    Science.gov (United States)

    Gutiérrez-Rodelo, Citlaly; Roura-Guiberna, Adriana; Olivares-Reyes, Jesús Alberto

    The biological actions of insulin are initiated by activating its membrane receptor, which triggers multiple signaling pathways to mediate their biological actions. Due to the importance of metabolic regulation and promoting functions of cell growth and proliferation, insulin actions are highly regulated to promote proper metabolic functioning and energy balance. If these mechanisms are altered, this can lead to a condition known as insulin resistance, which is the consequence of a deficient insulin signaling caused by mutations or post-translational modifications of the receptor or effector molecules located downstream. Insulin resistance is one of the main characteristics of pathological manifestations associated with type 2 diabetes mellitus, one of the leading causes of death in Mexico and worldwide. In recent years, it has been found that conditions such as inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction promote insulin resistance. The aim of this review is to elucidate the molecular aspects of insulin resistance and the mechanisms involved in regulating its effects, with particular emphasis on the role of inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction.

  4. The mechanical effect of the existing cement mantle on the in-cement femoral revision.

    LENUS (Irish Health Repository)

    Keeling, Parnell

    2012-08-01

    Cement-in-cement revision hip arthroplasty is an increasingly popular technique to replace a loose femoral stem which retains much of the original cement mantle. However, some concern exists regarding the retention of the existing fatigued and aged cement in such cement-in-cement revisions. This study investigates whether leaving an existing fatigued and aged cement mantle degrades the mechanical performance of a cement-in-cement revision construct.

  5. Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE).

    Science.gov (United States)

    Goodman, K E; Simner, P J; Tamma, P D; Milstone, A M

    2016-01-01

    The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.

  6. Molecular Mechanisms of Intrinsic Streptomycin Resistance in Mycobacterium abscessus.

    Science.gov (United States)

    Dal Molin, Michael; Gut, Myriam; Rominski, Anna; Haldimann, Klara; Becker, Katja; Sander, Peter

    2018-01-01

    Streptomycin, the first drug used for the treatment of tuberculosis, shows limited activity against the highly resistant pathogen Mycobacterium abscessus We recently identified two aminoglycoside-acetylating genes [ aac(2') and eis2 ] which, however, do not affect susceptibility to streptomycin. This suggests the existence of a discrete mechanism of streptomycin resistance. M. abscessus BLASTP analysis identified MAB_2385 as a close homologue of the 3″- O -phosphotransferase [APH(3″)] from the opportunistic pathogen Mycobacterium fortuitum as a putative streptomycin resistance determinant. Heterologous expression of MAB_2385 in Mycobacterium smegmatis increased the streptomycin MIC, while the gene deletion mutant M. abscessus ΔMAB_2385 showed increased streptomycin susceptibility. The MICs of other aminoglycosides were not altered in M. abscessus ΔMAB_2385. This demonstrates that MAB_2385 encodes a specific and prime innate streptomycin resistance determinant in M. abscessus We further explored the feasibility of applying rpsL -based streptomycin counterselection to generate gene deletion mutants in M. abscessus Spontaneous streptomycin-resistant mutants of M. abscessus ΔMAB_2385 were selected, and we demonstrated that the wild-type rpsL is dominant over the mutated rpsL K43R in merodiploid strains. In a proof of concept study, we exploited this phenotype for construction of a targeted deletion mutant, thereby establishing an rpsL -based counterselection method in M. abscessus . Copyright © 2017 American Society for Microbiology.

  7. Dynamic escape of pre-existing raltegravir-resistant HIV-1 from raltegravir selection pressure.

    Science.gov (United States)

    Codoñer, Francisco M; Pou, Christian; Thielen, Alexander; García, Federico; Delgado, Rafael; Dalmau, David; Santos, José Ramon; Buzón, Maria José; Martínez-Picado, Javier; Alvarez-Tejado, Miguel; Clotet, Bonaventura; Ruiz, Lidia; Paredes, Roger

    2010-12-01

    Using quantitative deep HIV-1 sequencing in a subject who developed virological failure to deep salvage therapy with raltegravir, we found that most Q148R and N155H mutants detected at the time of virological failure originated from pre-existing minority Q148R and N155H variants through independent evolutionary clusters. Double 148R+N155H mutants were also detected in 1.7% of viruses at virological failure in association with E138K and/or G163R. Our findings illustrate the ability of HIV-1 to escape from suboptimal antiretroviral drug pressure through selection of pre-existing drug-resistant mutants, underscoring the importance of using fully active antiretroviral regimens to treat all HIV-1-infected subjects. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Analysis and modeling of resistive switching mechanisms oriented to resistive random-access memory

    International Nuclear Information System (INIS)

    Huang Da; Wu Jun-Jie; Tang Yu-Hua

    2013-01-01

    With the progress of the semiconductor industry, the resistive random-access memory (RAM) has drawn increasing attention. The discovery of the memristor has brought much attention to this study. Research has focused on the resistive switching characteristics of different materials and the analysis of resistive switching mechanisms. We discuss the resistive switching mechanisms of different materials in this paper and analyze the differences of those mechanisms from the view point of circuitry to establish their respective circuit models. Finally, simulations are presented. We give the prospect of using different materials in resistive RAM on account of their resistive switching mechanisms, which are applied to explain their resistive switchings

  9. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae.

    Science.gov (United States)

    Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman

    2011-10-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea.

  10. Antimicrobial Peptide Resistance Mechanisms of Gram-Positive Bacteria.

    Science.gov (United States)

    Nawrocki, Kathryn L; Crispell, Emily K; McBride, Shonna M

    2014-10-13

    Antimicrobial peptides, or AMPs, play a significant role in many environments as a tool to remove competing organisms. In response, many bacteria have evolved mechanisms to resist these peptides and prevent AMP-mediated killing. The development of AMP resistance mechanisms is driven by direct competition between bacterial species, as well as host and pathogen interactions. Akin to the number of different AMPs found in nature, resistance mechanisms that have evolved are just as varied and may confer broad-range resistance or specific resistance to AMPs. Specific mechanisms of AMP resistance prevent AMP-mediated killing against a single type of AMP, while broad resistance mechanisms often lead to a global change in the bacterial cell surface and protect the bacterium from a large group of AMPs that have similar characteristics. AMP resistance mechanisms can be found in many species of bacteria and can provide a competitive edge against other bacterial species or a host immune response. Gram-positive bacteria are one of the largest AMP producing groups, but characterization of Gram-positive AMP resistance mechanisms lags behind that of Gram-negative species. In this review we present a summary of the AMP resistance mechanisms that have been identified and characterized in Gram-positive bacteria. Understanding the mechanisms of AMP resistance in Gram-positive species can provide guidelines in developing and applying AMPs as therapeutics, and offer insight into the role of resistance in bacterial pathogenesis.

  11. On the impossibility of existence of an absolute, unambiguous interpretation of quantum mechanics and physical reality

    International Nuclear Information System (INIS)

    Pankovic, V.

    1991-01-01

    In this paper it has been shown that there does not exist a unique, a priori interpretation of quantum mechanics and physical reality and that different, relatively consistent and relatively complete interpretations, Copenhagen interpretation and the interpretations in terms (non-contextual) hidden variables (whose existence is also here proved), for example, can be considered meta-theoretically complementary in the sense of meta-epistemologically generalized Bohr's principle of complementarity. Meta-theoretical complementarity of physics and mathematics has also been discussed

  12. Molecular Mechanisms of Insulin Resistance Development

    Directory of Open Access Journals (Sweden)

    Vsevolod Arsen'evich Tkachuk

    2014-05-01

    Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

  13. Superconductivity and the existence of Nambu's three-dimensional phase space mechanics

    International Nuclear Information System (INIS)

    Angulo, R.; Gonzalez-Bernardo, C.A.; Rodriguez-Gomez, J.; Kalnay, A.J.; Perez-M, F.; Tello-Llanos, R.A.

    1984-01-01

    Nambu proposed a generalization of hamiltonian mechanics such that three-dimensional phase space is allowed. Thanks to a recent paper by Holm and Kupershmidt we are able to show the existence of such three-dimensional phase space systems in superconductivity. (orig.)

  14. Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers.

    Science.gov (United States)

    Yamamoto, Kimiyo N; Hirota, Kouji; Takeda, Shunichi; Haeno, Hiroshi

    2014-01-01

    Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a pre-existing drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.

  15. Resistance mechanisms to plant viruses: an overview

    NARCIS (Netherlands)

    Goldbach, R.W.; Bucher, E.C.; Prins, A.H.

    2003-01-01

    To obtain virus-resistant host plants, a range of operational strategies can be followed nowadays. While for decades plant breeders have been able to introduce natural resistance genes in susceptible genotypes without knowing precisely what these resistance traits were, currently a growing number of

  16. Action and resistance mechanisms of antibiotics: A guide for clinicians

    Directory of Open Access Journals (Sweden)

    Garima Kapoor

    2017-01-01

    Full Text Available Infections account for a major cause of death throughout the developing world. This is mainly due to the emergence of newer infectious agents and more specifically due to the appearance of antimicrobial resistance. With time, the bacteria have become smarter and along with it, massive imprudent usage of antibiotics in clinical practice has resulted in resistance of bacteria to antimicrobial agents. The antimicrobial resistance is recognized as a major problem in the treatment of microbial infections. The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Determination of bacterial resistance to antibiotics of all classes (phenotypes and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis are helpful. Better understanding of the mechanisms of antibiotic resistance will help clinicians regarding usage of antibiotics in different situations. This review discusses the mechanism of action and resistance development in commonly used antimicrobials.

  17. Mechanisms of lichen resistance to metallic pollution

    Energy Technology Data Exchange (ETDEWEB)

    Sarret, C.; Manceau, A.; Eybert-Berard, L. [Univ. of Grenoble and CNRS (France). Environmental Geochemistry Group; Cuny, D.; Haluwyn, C. van [Lab. de Botanique et de Cryptogamie, Lille (France); Deruelle, S. [Institut d`Ecologie, Paris (France); Hazemann, J.L.; Menthonnex, J.J. [Univ. of Grenoble and CNRS (France). Environmental Geochemistry Group]|[CNRS, Grenoble (France). Lab. de Cristallographie; Soldo, Y. [CNRS, Grenoble (France). Lab. de Cristallographie

    1998-11-01

    Some lichens have a unique ability to grow in heavily contaminated areas due to the development of adaptative mechanisms allowing a high tolerance to metals. Here the authors report on the chemical forms of Pb and Zn in the metal hyperaccumulator Diploschistes muscorum and of Pb in the metal tolerant lichen Xanthoria parietina. The speciation of Zn and Pb has been investigated by powder X-ray diffraction (XRD) and extended X-ray absorption fine structure (EXAFS) spectroscopy using the advanced third-generation synchrotron radiation source of the European synchrotron radiation facility (ESRF in Grenoble). This study reveals that in both lichens cells are protected from toxicity by complexation of heavy metals, but the strategies differ: in D. muscorum, Pb and Zn are accumulated through an enhanced synthesis of oxalate, which precipitates toxic elements as insoluble salts, whereas in X. parietina, Pb is complexed to carboxylic groups of the fungal cell walls. The authors conclude that hyperaccumulation of metals results from a reactive mechanism of organic acid production, whereas metallo-tolerance is achieved by a passive complexation to existing functional groups.

  18. A new detection method for a newly revealed mechanism of pyrethroid resistance development in Varroa destructor.

    Science.gov (United States)

    Strachecka, Aneta; Borsuk, Grzegorz; Olszewski, Krzysztof; Paleolog, Jerzy

    2015-11-01

    The Varroa destructor mite has recently displayed an ever increasing resistance to new drugs, contributing to CCD proliferation. This work was aimed at determining new viable methods for identifying the pyrethroid resistance of V. destructor and DNA methylation in resistant and sensitive mites. DNA was extracted from Varroa mites. Nucleotide changes in the DNA of pyrethroid-resistant, pyrethroid-sensitive, and control mites were identified with polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) in the case of five mitochondrial gene fragments. More bands were observed in the drug-resistant mites than in the other two groups. Sequencing confirmed these observations. Decreased global DNA methylation levels were observed in the pyrethroid-resistant mites. There exists a previously undescribed mechanism of pyrethroid resistance development in Varroa mites. The PCR-SSCP methods can be considered and further developed as useful tools for detecting V. destructor resistance.

  19. Mechanisms and circumvention of cellular resistance to cisplatin.

    NARCIS (Netherlands)

    Hospers, Geesiena Alberdina Petronella

    1989-01-01

    Cisplatin (CDDP) is an active cytostatic agent. A limitation to its effectiveness initially or appearing during cystatic treatment is the occurrence of resistance. This thesis describes mechanisms wich are responsible for acquired cellular CDDP resistance. To investigate cellular CDDP resistance, a

  20. Mechanisms of rhizobacteria-mediated induced systemic resistance

    NARCIS (Netherlands)

    Hase, S.; Pieterse, C.M.J.; Loon, L.C. van

    2001-01-01

    Some of non-pathogenic rhizosphere bacteria reduce disease by activating a resistance mechanism in the plant called rhizobacteria-mediated induced systemic resistance (ISR). Rhizobacteria-mediated ISR resembles classic pathogen-induced systemic acquired resistance (SAR) in that both types of

  1. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    Science.gov (United States)

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis.

  2. Antibiotic resistance trends and mechanisms in the foodborne pathogen, Campylobacter.

    Science.gov (United States)

    Tang, Yizhi; Fang, Liangxing; Xu, Changyun; Zhang, Qijing

    2017-11-23

    Campylobacter is a major foodborne pathogen and is commonly present in food producing animals. This pathogenic organism is highly adaptable and has become increasingly resistant to various antibiotics. Recently, both the Centers for Disease Control and Prevention and the World Health Organization have designated antibiotic-resistant Campylobacter as a serious threat to public health. For the past decade, multiple mechanisms conferring resistance to clinically important antibiotics have been described in Campylobacter, and new resistance mechanisms constantly emerge in the pathogen. Some of the recent examples include the erm(B) gene conferring macrolide resistance, the cfr(C) genes mediating resistance to florfenicol and other antimicrobials, and a functionally enhanced variant of the multidrug resistance efflux pump, CmeABC. The continued emergence of new resistance mechanisms illustrates the extraordinary adaptability of Campylobacter to antibiotic selection pressure and demonstrate the need for innovative strategies to control antibiotic-resistant Campylobacter. In this review, we will briefly summarize the trends of antibiotic resistance in Campylobacter and discuss the mechanisms of resistance to antibiotics used for animal production and important for clinical therapy in humans. A special emphasis will be given to the newly discovered antibiotic resistance.

  3. Genetic variation for growth rate, feed conversion efficiency, and disease resistance exists within a farmed population of rainbow trout

    DEFF Research Database (Denmark)

    Henryon, Mark; Jokumsen, Alfred; Berg, Peer

    2002-01-01

    The objective of this study was to test that additive genetic (co)variation for survival, growth rate, feed conversion efficiency, and resistance to viral haemorrhagic septicaemia (VHS) exists within a farmed population of rainbow trout. Thirty sires and 30 dams were mated by a partly factorial...... the predicted breeding values for VHS resistance and the predicted breeding values for the body weights, body length, and feed conversion efficiencies. These results demonstrate that additive genetic (co)variation for growth rate, feed conversion efficiency, and VHS resistance does exist within the farmed...

  4. Mechanisms Leading to Co-Existence of Gas Hydrate in Ocean Sediments [Part 2 of 2

    Energy Technology Data Exchange (ETDEWEB)

    Bryant, Steven; Juanes, Ruben

    2011-12-31

    In this project we have sought to explain the co-existence of gas and hydrate phases in sediments within the gas hydrate stability zone. We have focused on the gas/brine interface at the scale of individual grains in the sediment. The capillary forces associated with a gas/brine interface play a dominant role in many processes that occur in the pores of sediments and sedimentary rocks. The mechanical forces associated with the same interface can lead to fracture initiation and propagation in hydrate-bearing sediments. Thus the unifying theme of the research reported here is that pore scale phenomena are key to understanding large scale phenomena in hydrate-bearing sediments whenever a free gas phase is present. Our analysis of pore-scale phenomena in this project has delineated three regimes that govern processes in which the gas phase pressure is increasing: fracturing, capillary fingering and viscous fingering. These regimes are characterized by different morphology of the region invaded by the gas. On the other hand when the gas phase pressure is decreasing, the corresponding regimes are capillary fingering and compaction. In this project, we studied all these regimes except compaction. Many processes of interest in hydrate-bearing sediments can be better understood when placed in the context of the appropriate regime. For example, hydrate formation in sub-permafrost sediments falls in the capillary fingering regime, whereas gas invasion into ocean sediments is likely to fall into the fracturing regime. Our research provides insight into the mechanisms by which gas reservoirs are converted to hydrate as the base of the gas hydrate stability zone descends through the reservoir. If the reservoir was no longer being charged, then variation in grain size distribution within the reservoir explain hydrate saturation profiles such as that at Mt. Elbert, where sand-rich intervals containing little hydrate are interspersed between intervals containing large hydrate

  5. Mechanisms Leading to Co-Existence of Gas Hydrate in Ocean Sediments [Part 1 of 2

    Energy Technology Data Exchange (ETDEWEB)

    Bryant, Steven; Juanes, Ruben

    2011-12-31

    In this project we have sought to explain the co-existence of gas and hydrate phases in sediments within the gas hydrate stability zone. We have focused on the gas/brine interface at the scale of individual grains in the sediment. The capillary forces associated with a gas/brine interface play a dominant role in many processes that occur in the pores of sediments and sedimentary rocks. The mechanical forces associated with the same interface can lead to fracture initiation and propagation in hydrate-bearing sediments. Thus the unifying theme of the research reported here is that pore scale phenomena are key to understanding large scale phenomena in hydrate-bearing sediments whenever a free gas phase is present. Our analysis of pore-scale phenomena in this project has delineated three regimes that govern processes in which the gas phase pressure is increasing: fracturing, capillary fingering and viscous fingering. These regimes are characterized by different morphology of the region invaded by the gas. On the other hand when the gas phase pressure is decreasing, the corresponding regimes are capillary fingering and compaction. In this project, we studied all these regimes except compaction. Many processes of interest in hydrate-bearing sediments can be better understood when placed in the context of the appropriate regime. For example, hydrate formation in sub-permafrost sediments falls in the capillary fingering regime, whereas gas invasion into ocean sediments is likely to fall into the fracturing regime. Our research provides insight into the mechanisms by which gas reservoirs are converted to hydrate as the base of the gas hydrate stability zone descends through the reservoir. If the reservoir was no longer being charged, then variation in grain size distribution within the reservoir explain hydrate saturation profiles such as that at Mt. Elbert, where sand-rich intervals containing little hydrate are interspersed between intervals containing large hydrate

  6. Resistant mechanism study of benzalkonium chloride selected Salmonella Typhimurium mutants.

    Science.gov (United States)

    Guo, Wei; Cui, Shenghui; Xu, Xiao; Wang, Haoyan

    2014-02-01

    Benzalkonium chloride is one of the invaluable biocides that is extensively used in healthcare settings as well as in the food processing industry. After exposing wild-type Salmonella Typhimurium 14028s or its AcrAB inactivation mutant to gradually increasing levels of benzalkonium chloride, resistance mutants S-41, S-150, S-AB-23, S-AB-38, and S-AB-73 were selected and these mutants also showed a 2-64-fold stable minimum inhibitory concentration (MIC) increase to chloramphenicol, ciprofloxacin, nalidixic acid, and tetracycline. In S-41 and S-150, the expression of acrB was increased 2.7- and 7.6-fold, and ΔtolC or ΔacrAB mutants of S-41 and S-150 showed the same MICs to all tested antimicrobials as the equivalent Salmonella Typhimurium 14028s mutants. However, in S-AB-23, S-AB-38, and S-AB-73, the expression of acrF was increased 96-, 230-, and 267-fold, respectively, and ΔtolC or ΔacrEF mutants of S-AB-23, S-AB-38, and S-AB-73 showed the similar MICs to all tested antimicrobials as the ΔtolC mutant of Salmonella Typhimurium 14028s. Our data showed that constitutively over-expressed AcrAB working through TolC was the main resistance mechanism in ST14028s benzalkonium chloride resistance mutants. However, after AcrAB had been inactivated, benzalkonium chloride-resistant mutants could still be selected and constitutively over-expressed, AcrEF became the dominant efflux pump working through TolC and being responsible for the increasing antimicrobial resistance. These data indicated that different mechanisms existed for acrB and acrF constitutive over-expression. Since exposure to benzalkonium chloride may lead to Salmonella mutants with a decreased susceptibility to quinolones, which is currently one of the drugs of choice for the treatment of life-threatening salmonelosis, research into the pathogenesis and epidemiology of the benzalkonium chloride resistance mutants will be of increasing importance.

  7. Mechanisms of Antimicrobial Peptide Resistance in Gram-Negative Bacteria

    Directory of Open Access Journals (Sweden)

    Victor I. Band

    2014-12-01

    Full Text Available Cationic antimicrobial peptides (CAMPs are important innate immune defenses that inhibit colonization by pathogens and contribute to clearance of infections. Gram-negative bacterial pathogens are a major target, yet many of them have evolved mechanisms to resist these antimicrobials. These resistance mechanisms can be critical contributors to bacterial virulence and are often crucial for survival within the host. Here, we summarize methods used by Gram-negative bacteria to resist CAMPs. Understanding these mechanisms may lead to new therapeutic strategies against pathogens with extensive CAMP resistance.

  8. Effectiveness of Antipseudomonal Antibiotics and Mechanisms of Multidrug Resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    El ZOWALATYl, Mohamed E; Gyetvaii, Bpla

    2016-01-01

    Pseudomonas aeruginosa is a leading human pathogen that causes serious infections at various tissues and organs leading to life threatening health problems and possible deadly outcomes. Resistance patterns vary widely whether it is from hospitals or community acquired infections. Reporting resistance profiles to a certain antibiotics provide valuable information in a given setting, but may be extrapolated outside the sampling location. In the present study, P. aeruginosa isolates were screened to determine their susceptibilities against anti-pseudomonal antimicrobial agents and possible existing mechanisms of resistance were determined. Eighty-six isolates of P. aeruginosa were recovered. Isolates representing different resistance profiles were screened for the existence of three different resistance mechanisms including drug inactivation due to metallo-β-lactamases, drug impermeability by outer membrane proteins and drug efflux. All tested isolates showed uniform susceptibility (100%, n = 86/86) to piperacillin, meropenem, amikacin, and polymyxin B. A single isolate was found to be imipenem resistant (99%, n = 85/86). The possible mechanisms of resistance of P. aeruginosa to imipenem involve active drug efflux pumps, outer membrane impermeability as well as drug inactivating enzymes. These findings demonstrate the fundamental importance of the in vitro susceptibility testing of antibiotics prior to antipseudomonal therapy and highlight the need for a continuous antimicrobial resistance surveillance programs to monitor the changing resistance patterns so that clinicians and health care officials are updated as to the most effective therapeutic agents to combat the serious outcomes of P. aeruginosa infections.

  9. Mechanisms of hepatitis B virus resistance development.

    Science.gov (United States)

    Warner, Nadia; Locarnini, Stephen

    2014-01-01

    Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional 'right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA. The selection of resistance occurs at different rates for each NA, and is affected by the high mutational rate of HBV and the ability of the drug to suppress viral replication. Some mutations or combinations of mutations may be associated with multidrug resistance, limiting treatment options. In contrast to most other viruses, resistance in HBV is confounded by the overlapping surface gene, the major NA-resistant mutations also altering the surface proteins in most cases, potentially altering virus secretion and neutralization, which may pose a public health threat in the future. © 2014 S. Karger AG, Basel.

  10. Molecular mechanisms of bortezomib resistant adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Erika Suzuki

    Full Text Available Bortezomib (Velcade™ is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM. Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.

  11. Mechanism for detecting NAPL using electrical resistivity imaging

    Science.gov (United States)

    Halihan, Todd; Sefa, Valina; Sale, Tom; Lyverse, Mark

    2017-10-01

    The detection of non-aqueous phase liquid (NAPL) related impacts in freshwater environments by electrical resistivity imaging (ERI) has been clearly demonstrated in field conditions, but the mechanism generating the resistive signature is poorly understood. An electrical barrier mechanism which allows for detecting NAPLs with ERI is tested by developing a theoretical basis for the mechanism, testing the mechanism in a two-dimensional sand tank with ERI, and performing forward modeling of the laboratory experiment. The NAPL barrier theory assumes at low bulk soil NAPL concentrations, thin saturated NAPL barriers can block pore throats and generate a detectable electrically resistive signal. The sand tank experiment utilized a photographic technique to quantify petroleum saturation, and to help determine whether ERI can detect and quantify NAPL across the water table. This experiment demonstrates electrical imaging methods can detect small quantities of NAPL of sufficient thickness in formations. The bulk volume of NAPL is not the controlling variable for the amount of resistivity signal generated. The resistivity signal is primarily due to a zone of high resistivity separate phase liquid blocking current flow through the fully NAPL saturated pores spaces. For the conditions in this tank experiment, NAPL thicknesses of 3.3 cm and higher in the formation was the threshold for detectable changes in resistivity of 3% and greater. The maximum change in resistivity due to the presence of NAPL was an increase of 37%. Forward resistivity models of the experiment confirm the barrier mechanism theory for the tank experiment.

  12. Mechanisms Linking Inflammation to Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Li Chen

    2015-01-01

    Full Text Available Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

  13. The existence of a symmetric stress tensor in a non-local description of continuum mechanics

    Science.gov (United States)

    Schwarz, G.

    1993-12-01

    Among the foundations of continuum mechanics is the description of the constitutive forces in terms of a symmetric tensor. Noll showed that this is a consequence of the axiom of material frame indifference, what in turn means a local invariance of the system under the Euclidean group. Here we will prove, in order to obtain the same result, that the assumption of locality in this axiom is redundant. We model a non-local system by means of a virtual work principle. Under the global demand that the corresponding functional does not respond on rigid infinitesimal motions, we show the existence of a symmetric stress tensor as a local result.

  14. Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

    Science.gov (United States)

    Domínguez, M A; Liñares, J; Martín, R

    1997-09-01

    Methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most common nosocomial pathogens. The most significant mechanism of resistance to methicillin in this-species is the acquisition of a genetic determinant (mecA gene). However, resistance seems to have a more complex molecular basis, since additional chromosomal material is involved in such resistance. Besides, overproduction of penicillinase and/or alterations in the PBPs can contribute to the formation of resistance phenotypes. Genetic and environmental factors leading to MRSA are reviewed.

  15. Tumor cell heterogeneity: impact on mechanisms of therapeutic drug resistance

    International Nuclear Information System (INIS)

    Richardson, Mary E.; Siemann, Dietmar W.

    1997-01-01

    Purpose: The aim of these studies was to determine whether chemotherapy-resistant tumor cell sublines derived from a single starting cell population with identical treatment protocols, have the same mechanism of resistance. Methods and Materials: Twelve cyclophosphamide-resistant sublines were derived from KHT-iv murine sarcoma cells by repeated exposures to 2, 4, or 8 μg/ml doses of 4-hydroperoxycyclophosphamide (4-OOHCP). To investigate possible mechanisms of resistance, glutathione (GSH) levels, glutathione S-transferase (GST) activity, and aldehyde dehydrogenase (ALDH) activity were determined. In addition, studies with the GSH depletor buthionine sulfoximine (BSO) and the ALDH inhibitor diethylamino-benzaldehyde (DEAB) were undertaken. Results: Resistant factors to 4-OOHCP, assessed at 10% clonogenic cell survival, ranged from 1.5-7.0 for the various cell lines. Crossresistance to melphalan and adriamycin also were commonly observed. Increased GSH levels, GST activity and ALDH activity were detected in the sublines but not all exhibited the same pattern of biochemical alterations. The response to GSH and ALDH inhibitors also varied among the sublines; the resistance being reversible in some cell lines but not others. Conclusion: The present results indicate that when resistant sublines are derived simultaneously from the same starting cell population, the observed mechanisms of resistance may not be the same in each of the variants. These findings support the hypothesis that preexisting cellular heterogeneity may affect mechanisms of acquired resistance

  16. Mechanism of Resistance to Glyphosate in Lolium perenne from Argentina

    Directory of Open Access Journals (Sweden)

    Marcos Yanniccari

    2017-10-01

    Full Text Available In Argentina, glyphosate resistance was reported in a Lolium perenne population after 12 years of successful herbicide use. The aim of the current paper was to put in evidence for the mechanism of glyphosate resistance of this weed. Susceptible leaves treated with different doses of glyphosate and incubated in vitro showed an accumulation of shikimic acid of around three to five times the basal level, while no changes were detected in leaves of glyphosate-resistant plants. The resistance mechanism prevents shikimate accumulation in leaves, even under such tissue-isolation conditions. The activity of the glyphosate target enzyme (EPSPS: 5-enolpyruvylshikimate-3-phosphate synthase was quantified at different herbicide concentrations. EPSPS from resistant plants showed no difference in glyphosate-sensitivity compared to EPSPS from susceptible plants, and, accordingly, no amino acid substitution causing mutations associated with resistance were found. While the glyphosate target enzymes were equally sensitive, the basal EPSPS activity in glyphosate resistant plants was approximately 3-fold higher than the EPSPS activity in susceptible plants. This increased EPSPS activity in glyphosate resistant plants was associated with a 15-fold higher expression of EPSPS compared with susceptible plants. Therefore, the over-expression of EPSPS appears to be the main mechanism responsible for resistance to glyphosate. This mechanism has a constitutive character and has important effects on plant fitness, as recently reported.

  17. Structural instability and phase co-existence driven non-Gaussian resistance fluctuations in metal nanowires at low temperatures

    Science.gov (United States)

    Bid, Aveek; Raychaudhuri, A. K.

    2016-11-01

    We report a detailed experimental study of the resistance fluctuations measured at low temperatures in high quality metal nanowires ranging in diameter from 15-200 nm. The wires exhibit co-existing face-centered-cubic and 4H hcp phases of varying degrees as determined from the x-ray diffraction data. We observe the appearance of a large non-Gaussian noise for nanowires of diameter smaller than 50 nm over a certain temperature range around ≈30 K. The diameter range ˜30 nm, where the noise has maxima coincides with the maximum volume fraction of the co-existing 4H hcp phase thus establishing a strong link between the fluctuation and the phase co-existence. The resistance fluctuation in the same temperature range also shows a deviation of 1/f behavior at low frequency with appearance of single frequency Lorentzian type contribution in the spectral power density. The fluctuations are thermally activated with an activation energy {E}{{a}}˜ 35 meV, which is of same order as the activation energy of creation of stacking fault in FCC metals that leads to the co-existing crystallographic phases. Combining the results of crystallographic studies of the nanowires and analysis of the resistance fluctuations we could establish the correlation between the appearance of the large resistance noise and the onset of phase co-existence in these nanowires.

  18. Resistance Mechanisms in an In Vitro-Selected Amoxicillin-Resistant Strain of Helicobacter pylori▿

    OpenAIRE

    Co, Edgie-Mark A.; Schiller, Neal L.

    2006-01-01

    We investigated the β-lactam resistance mechanism(s) of an in vitro-selected amoxicillin-resistant Helicobacter pylori strain (AmoxR). Our results demonstrated that resistance is due to a combination of amino acid substitutions in penicillin binding protein 1 (PBP1), HopB, and HopC identified in AmoxR, resulting in decreased affinity of PBP1 for amoxicillin and decreased accumulation of penicillin.

  19. Why Organic Farming Should Embrace Co-Existence with Cisgenic Late Blight–Resistant Potato

    Directory of Open Access Journals (Sweden)

    Godelieve Gheysen

    2017-01-01

    Full Text Available The EU regulation on organic farming does not allow the use of genetically modified organisms (GMOs which are subject to Directive 2001/18/EC. Mutagenesis using irradiation or chemicals is genetic modification, but the organisms obtained through these techniques are not subject to the provisions of the GMO directive. Such mutants can therefore be used in organic agriculture. Derived from its basic principles, organic farming can only use natural substances to control disease and crops should be resilient, which, in the case of disease resistance, means that durable (horizontal resistance is preferred to vertical (single gene resistance. Cisgenesis can achieve such a durable resistance by introducing multiple resistance genes in one step. These multiple-resistant plants only contain natural genes that can also be introduced by breeding. In case cisgenic plants are not subject to the provisions of the GMO legislation, they can even be legally used in organic agriculture. In case they are not exempted from the GMO regulation, the question is: why obstruct a cisgenic potato crop that can hardly be distinguished from a potato crop that is the result of conventional breeding? Among the reasons why organic agriculture does not allow the use of GMOs it is mentioned that genetic engineering is unpredictable, it causes genome disruption and it is unnatural. However, our knowledge of plant genome evolution and breeding has increased dramatically. We now know that breeding is more unpredictable and causes more genome disruption than genetic engineering. Recent field trials have shown the efficacy of cisgenic late blight–resistant potatoes carrying multiple resistance genes. Large-scale growing of such durably resistant potatoes would not only be environmentally beneficial by it would strongly reducing the need for fungicide sprays in conventional potato cultivation and it would also reduce the disease pressure in organic potato cultivation.

  20. Physiological mechanism of resistance to anthracnose of different ...

    African Journals Online (AJOL)

    However, enzyme activity of resistant cultivars improved markedly after pathogen inoculation, while those of susceptible cultivars did not change. This study broadens the understanding of the mechanisms of disease resistance in Camellia. Keywords: Anthracnose, Camellia oleifera, phenylalanine ammonia lyase, ...

  1. Nucleus geometry and mechanical properties of resistance spot ...

    Indian Academy of Sciences (India)

    Abstract. In this study, mechanical properties of resistance spot welding of DP450 and DP600, galvanized and ungalvanized automotive sheets have been investigated. The specimens have been joined by resistance spot welding at different weld currents and times. Welded specimens have been examined for their ...

  2. Mechanisms of drought resistance in grain: II Stomatal regulation ...

    African Journals Online (AJOL)

    Earlier research works conducted to identify mechanisms of drought resistance in grain legumes under soil water stress of -0.6 MPa showed that drought resistance (maintenace of turgor) in chick pea was due to a significant decrease in osmotic potential (osmotic adjustment) while in common bean it was due to ...

  3. Biomarkers and mechanisms of natural disease resistance in dairy cows

    NARCIS (Netherlands)

    Altena, van S.E.C.

    2016-01-01

    The aim of this thesis was to define and test biomarkers for disease resistance in dairy cows and to determine the underlying mechanism in natural disease resistance. The health status of the cows is an important issue in dairy farming. Due to the mandatory reduction in the use of antibiotics,

  4. Adaptive Mechanisms Underlying Microbial Resistance to Disinfectants

    Science.gov (United States)

    2016-02-01

    ammonium compounds RTU SDS-PAGE ready-to- use sodium dodecyl (lauryl) sulfate-polyacrylamide gel electrophoresis SNP single nucleotide polymorphism TSB...resistance to Lysol, an all-purpose cleaner and disinfectant (U.S. Environmental Protection Agency regulation no. 777-89 [ready-to- use (RTU) 1:16...dilution]). A clinical surrogate, Escherichia coli, was used in these studies. E. coli cells were grown in the absence or presence of Lysol. The parent

  5. Mechanisms Linking Inflammation to Insulin Resistance

    OpenAIRE

    Chen, Li; Chen, Rui; Wang, Hua; Liang, Fengxia

    2015-01-01

    Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several sig...

  6. Conduction Mechanism of Valence Change Resistive Switching Memory: A Survey

    Directory of Open Access Journals (Sweden)

    Ee Wah Lim

    2015-09-01

    Full Text Available Resistive switching effect in transition metal oxide (TMO based material is often associated with the valence change mechanism (VCM. Typical modeling of valence change resistive switching memory consists of three closely related phenomena, i.e., conductive filament (CF geometry evolution, conduction mechanism and temperature dynamic evolution. It is widely agreed that the electrochemical reduction-oxidation (redox process and oxygen vacancies migration plays an essential role in the CF forming and rupture process. However, the conduction mechanism of resistive switching memory varies considerably depending on the material used in the dielectric layer and selection of electrodes. Among the popular observations are the Poole-Frenkel emission, Schottky emission, space-charge-limited conduction (SCLC, trap-assisted tunneling (TAT and hopping conduction. In this article, we will conduct a survey on several published valence change resistive switching memories with a particular interest in the I-V characteristic and the corresponding conduction mechanism.

  7. Chemotherapy resistance mechanisms in advanced skin cancer

    Directory of Open Access Journals (Sweden)

    Bhuvanesh Sukhlal Kalal

    2017-03-01

    Full Text Available Melanoma is a most dangerous and deadly type of skin cancer, and considered intrinsically resistant to both radiotherapy and chemotherapy. It has become a major public health concern as the incidence of melanoma has been rising steadily over recent decades with a 5-year survival remaining less than 5%. Detection of the disease in early stage may be curable, but late stage metastatic disease that has spread to other organs has an extremely poor prognosis with a median survival of less than 10 months. Since metastatic melanoma is unresponsive to therapy that is currently available, research is now focused on different treatment strategies such as combinations of surgery, chemotherapy and radiotherapy. The molecular basis of resistance to chemotherapy seen in melanoma is multifactorial; defective drug transport system, altered apoptotic pathway, deregulation of apoptosis and/or changes in enzymatic systems that mediate cellular metabolic machinery. Understanding of alterations in molecular processes involved in drug resistance may help in developing new therapeutic approaches to treatment of malignant melanoma.

  8. Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates

    Directory of Open Access Journals (Sweden)

    Meng Dong-Ya

    2014-01-01

    Full Text Available To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs of DNA gyrase (gyrA and gyrB and topoisomerase IV (parC and parE in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX, intermediate resistant to Levofloxacin (LVX and Sparfloxacin (SFX, and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

  9. Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates.

    Science.gov (United States)

    Meng, Dong-Ya; Sun, Chang-Jian; Yu, Jing-Bo; Ma, Jun; Xue, Wen-Cheng

    2014-01-01

    To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH) clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs) of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX), intermediate resistant to Levofloxacin (LVX) and Sparfloxacin (SFX), and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

  10. Testing and Modeling of Mechanical Characteristics of Resistance Welding Machines

    DEFF Research Database (Denmark)

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2003-01-01

    The dynamic mechanical response of resistance welding machine is very important to the weld quality in resistance welding especially in projection welding when collapse or deformation of work piece occurs. It is mainly governed by the mechanical parameters of machine. In this paper, a mathematical...... model for characterizing the dynamic mechanical responses of machine and a special test set-up called breaking test set-up are developed. Based on the model and the test results, the mechanical parameters of machine are determined, including the equivalent mass, damping coefficient, and stiffness...

  11. Genetic variation for growth rate, feed conversion efficiency, and disease resistance exists within a farmed population of rainbow trout

    DEFF Research Database (Denmark)

    Henryon, Mark; Jokumsen, Alfred; Berg, Peer

    2002-01-01

    The objective of this study was to test that additive genetic (co)variation for survival, growth rate, feed conversion efficiency, and resistance to viral haemorrhagic septicaemia (VHS) exists within a farmed population of rainbow trout. Thirty sires and 30 dams were mated by a partly factorial...... mating design. Each sire was mated to two dams, and each dam was mated to two sires, producing 50 viable full-sib families (29 sires, 25 dams). The fish from these families were reared for a 215-day growout period, and were assessed for survival between days 52 and 215, growth rate (i.e., body weight...... the predicted breeding values for VHS resistance and the predicted breeding values for the body weights, body length, and feed conversion efficiencies. These results demonstrate that additive genetic (co)variation for growth rate, feed conversion efficiency, and VHS resistance does exist within the farmed...

  12. Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing

    Science.gov (United States)

    Takeda, Haruhiko; Ueda, Yoshihide; Inuzuka, Tadashi; Yamashita, Yukitaka; Osaki, Yukio; Nasu, Akihiro; Umeda, Makoto; Takemura, Ryo; Seno, Hiroshi; Sekine, Akihiro; Marusawa, Hiroyuki

    2017-03-01

    Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.

  13. Targeting bacterial topoisomerases: how to counter mechanisms of resistance.

    Science.gov (United States)

    Tse-Dinh, Yuk-Ching

    2016-06-01

    DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in antibacterial therapy. Bacterial topoisomerase I is being explored as an alternative target that is not expected to show cross-resistance. Dual targeting or combination therapy could be strategies for circumventing the development of resistance to topoisomerase-targeting antibiotics. Bacterial topoisomerases are high-value bactericidal targets that could continue to be exploited for antibacterial therapy, if new tactics to counter resistance can be adopted.

  14. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    Science.gov (United States)

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  15. Volume Resistivity and Mechanical Behavior of Epoxy Nanocomposite Materials

    Directory of Open Access Journals (Sweden)

    M. F. Abdelkarim

    2015-04-01

    Full Text Available Electrical and mechanical properties of polymer composite materials are investigated through the determination of resistivity and hardness for composites samples. Epoxy composite samples have been prepared with different concentrations of certain inorganic fillers such as; Titanium dioxide (TiO2 and Silica (SiO2, of various size (micro, nano and hybrid to study the electrical and mechanical behavior. The volume resistivity reaches 3.23×1014 ohm.cm for the micro silica composite. Surface of composite material has been mechanically examined by hardness test. The results show that the resistivity of microcomposites and nanocmposites are increased with the decrease of filler concentration. But the resistivity of hybrid composites is increased with the increase of filler concentration. Maximum hardness value was obtained from hybrid silica composite with 0.1% filler concentration.

  16. Cross-resistance, inheritance and biochemical mechanisms of imidacloprid resistance in B-biotype Bemisia tabaci.

    Science.gov (United States)

    Wang, Zhenyu; Yao, Mingde; Wu, Yidong

    2009-11-01

    The B-type Bemisia tabaci (Gennadius) has become established in many regions in China, and neonicotinoids are extensively used to control this pest. Imidacloprid resistance in a laboratory-selected strain of B-type B. tabaci was characterised in order to provide the basis for recommending resistance management tactics. The NJ-Imi strain of B-type B. tabaci was selected from the NJ strain with imidacloprid for 30 generations. The NJ-Imi strain exhibited 490-fold resistance to imidacloprid, high levels of cross-resistance to three other neonicotinoids, low levels of cross-resistance to monosultap, cartap and spinosad, but no cross-resistance to abamectin and cypermethrin. Imidacloprid resistance in the NJ-Imi strain was autosomal and semi-dominant. It is shown that enhanced detoxification mediated by cytochrome-P450-dependent monooxygenases contributes to imidacloprid resistance to some extent in the NJ-Imi strain. Results from synergist bioassays and cross-resistance patterns indicated that target-site insensitivity may be involved in imidacloprid resistance in the NJ-Imi strain of B. tabaci. Although oxidative detoxification mediated by P450 monooxygenases is involved in imidacloprid resistance in the NJ-Imi strain of B-type B. tabaci, target-site modification as an additional resistance mechanism cannot be ruled out. Considering the high risk of cross-resistance, neonicotinoids should be regarded as a single group when implementing an insecticide rotation scheme in B. tabaci control. (c) 2009 Society of Chemical Industry.

  17. Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance.

    Science.gov (United States)

    Hooper, David C; Jacoby, George A

    2016-09-01

    Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis. Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity. Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens. Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes are commonly in a localized domain of the GyrA and ParC subunits of gyrase and topoisomerase IV, respectively, and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include other antimicrobials as well as quinolones. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is because of Qnr proteins that protect the target enzymes from quinolone action, a mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  18. [Investigation of molecular mechanisms of aminoglycoside resistance in Salmonella].

    Science.gov (United States)

    Zubritskiĭ, A V; Il'ina, E N; Strel'chenko, S A; Malakhova, M V; Lenev, S V; Skliarov, O D; Panin, A N; Govorun, V M

    2011-01-01

    The spread of aminoglycoside resistance phenotype and respective genetic resistance determinants was evaluated in 243 Salmonella strains isolated within 1948-2010 and stored in the Culture Collection of the Russian State Research Institute for Control, Standardization and Certification of Veterinary Preparations (Moscow). The Salmonella strains showed resistance to streptomycin and gentamicin in 3.7% (n = 9) and 0.8% (n = 2) of the isolates respectively. Intermediate resistance to streptomycin was recorded in 9.9% (n = 24) of the isolates. To detect the genes responsible for the aminoglycoside resistance, primers for aadA1, aadA2, aadB, aphA1, aphA3, sat, strA, strB, aphA, aacC, rmtB, armA and rpsL genes amplification and sequencing were designed. The strains with lower susceptibility to streptomycin harbored aadA1, aadA2, strA, strB resistance genes encoding enzymes for aminoglicoside modification and rpsL mutant allele (K42N, G91D). Genetic mechanisms able to explain the gentamicin resistance development were not detected. Some strains carried genetic markers of streptomycine resistance but had no clinically sufficient resistance to it. In this regard, genetic testing is essential for prevention of drug resistance spreading due to horizontal transfer of genes in microbial population.

  19. Fiber-optic demultiplexers with high mechanical resistance

    Directory of Open Access Journals (Sweden)

    Yakovlev M. Ya.

    2011-04-01

    Full Text Available The paper observes possibilities of fused fiber-optic multiplexer-demultiplexer creation with resistance to mechanical effect. Fabrication method and the equipment for their production are presented. Resonant frequency of weld area mechanical oscillations dependences from fused fiber-optic demultiplexer design characteristics are investigated.

  20. Identification of Mechanical parameters for Resistance Welding Machines

    DEFF Research Database (Denmark)

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2003-01-01

    Mechanical dynamic responses of resistance welding machine have a significant influence on weld quality and electrode service life, it must be considered when the real welding production is carried out or the welding process is simulated. The mathematical models for characterizing the mechanical ...

  1. Characterisation of glufosinate resistance mechanisms in Eleusine indica.

    Science.gov (United States)

    Jalaludin, Adam; Yu, Qin; Zoellner, Peter; Beffa, Roland; Powles, Stephen B

    2017-06-01

    An Eleusine indica population has evolved resistance to glufosinate, a major post-emergence herbicide of global agriculture. This population was analysed for target-site (glutamine synthetase) and non-target-site (glufosinate uptake, translocation and metabolism) resistance mechanisms. Glutamine synthetase (GS) activity extracted from susceptible (S) and resistant (R*) plants was equally sensitive to glufosinate inhibition, with IC 50 values of 0.85 mm and 0.99 mm, respectively. The extractable GS activity was also similar in S and R* samples. Foliar uptake of [ 14 C]-glufosinate did not differ in S and R* plants, nor did glufosinate net uptake in leaf discs. Translocation of [ 14 C]-glufosinate into untreated shoots and roots was also similar in both populations, with 44% to 47% of the herbicide translocated out from the treated leaf 24 h after treatment. The HPLC and LC-MS analysis of glufosinate metabolism revealed no major metabolites in S or R* leaf tissue. Glufosinate resistance in this resistant population is not due to an insensitive GS, or increased activity, or altered glufosinate uptake and translocation, or enhanced glufosinate metabolism. Thus, target-site resistance is likely excluded and the exact resistance mechanism(s) remain to be determined. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  2. Resistance Mechanisms of Anopheles stephensi (Diptera: Culicidae to Temephos

    Directory of Open Access Journals (Sweden)

    Aboozar Soltani

    2015-10-01

    Full Text Available Background: Anopheles stephensi is a sub-tropical species and has been considered as one of the most important vector of human malaria throughout the Middle East and South Asian region including the malarious areas of southern Iran. Current reports confirmed An. stephensi resistance to temephos in Oman and India. However, there is no comprehensive research on mechanisms of temephos resistance in An. stephensi in the literature. This study was designed in order to clarify the enzymatic and molecular mechanisms of temephos resistance in this species.Methods: Profile activities of α- and ß-esterases, mixed function oxidase (MFO, glutathione-S-transferase (GST, insensitive acetylcholinesterase, and para-nitrophenyl acetate (PNPA-esterase enzymes were tested for An. stephensi strain with resistance ratio of 15.82 to temephos in comparison with susceptible strain.Results: Results showed that the mean activity of α-EST, GST and AChE enzymes were classified as altered indicating metabolic mechanisms have considerable role in resistance of An. stephensi to temephos. Molecular study using PCR-RFLP method to trace the G119S mutation in ACE-1 gene showed lack of the mutation responsible for organophosphate insecticide resistance in the temephos-selected strain of An. stephensi.Conclusion: This study showed that the altered enzymes but not targets site insensitivity of ACE-1 are responsible for temephos resistance in An. stephensi in south of Iran.

  3. Mechanisms of antimicrobial resistance among hospital-associated pathogens.

    Science.gov (United States)

    Khan, Ayesha; Miller, William R; Arias, Cesar A

    2018-04-01

    The introduction of antibiotics revolutionized medicine in the 20th-century permitting the treatment of once incurable infections. Widespread use of antibiotics, however, has led to the development of resistant organisms, particularly in the healthcare setting. Today, the clinician is often faced with pathogens carrying a cadre of resistance determinants that severely limit therapeutic options. The genetic plasticity of microbes allows them to adapt to stressors via genetic mutations, acquisition or sharing of genetic material and modulation of genetic expression leading to resistance to virtually any antimicrobial used in clinical practice. Areas covered: This is a comprehensive review that outlines major mechanisms of resistance in the most common hospital-associated pathogens including bacteria and fungi. Expert commentary: Understanding the genetic and biochemical mechanisms of such antimicrobial adaptation is crucial to tackling the rapid spread of resistance, can expose unconventional therapeutic targets to combat multidrug resistant pathogens and lead to more accurate prediction of antimicrobial susceptibility using rapid molecular diagnostics. Clinicians making treatment decisions based on the molecular basis of resistance may design therapeutic strategies that include de-escalation of broad spectrum antimicrobial usage, more focused therapies or combination therapies. These strategies are likely to improve patient outcomes and decrease the risk of resistance in hospital settings.

  4. Different mechanisms of resistance modulate sulfite tolerance in wine yeasts.

    Science.gov (United States)

    Nadai, Chiara; Treu, Laura; Campanaro, Stefano; Giacomini, Alessio; Corich, Viviana

    2016-01-01

    From a technological point of view, yeast resistance to sulfite is of great interest and represents an important technological character for winemaking. Several mechanisms are involved, and strain-dependent strategies to obtain SO2 resistance can deeply influence wine quality, although this choice is less relevant in determining the technological performance of the strain during fermentation. In this study, to better understand the strain-specific mechanisms of resistance, 11 Saccharomyces cerevisiae strains, whose genomes have been previously sequenced, were selected. Their attitude towards sulfites, in terms of resistance and production, was evaluated, and RNA-sequencing of four selected strains was performed during fermentation process in synthetic grape must in the presence of SO2. Results demonstrated that at molecular level, the physical effect of SO2 triggered multiple stress responses in the cell and high tolerance to general enological stressing condition increased SO2 resistance. Adaptation mechanism due to high basal gene expression level rather than specific gene induction in the presence of sulfite seemed to be responsible in modulating strain resistance. This mechanism involved higher basal gene expression level of specific cell wall proteins, enzymes for lipid biosynthesis, and enzymes directly involved in SO2 assimilation pathway and efflux.

  5. Cationic antimicrobial peptide resistance mechanisms of streptococcal pathogens.

    Science.gov (United States)

    LaRock, Christopher N; Nizet, Victor

    2015-11-01

    Cationic antimicrobial peptides (CAMPs) are critical front line contributors to host defense against invasive bacterial infection. These immune factors have direct killing activity toward microbes, but many pathogens are able to resist their effects. Group A Streptococcus, group B Streptococcus and Streptococcus pneumoniae are among the most common pathogens of humans and display a variety of phenotypic adaptations to resist CAMPs. Common themes of CAMP resistance mechanisms among the pathogenic streptococci are repulsion, sequestration, export, and destruction. Each pathogen has a different array of CAMP-resistant mechanisms, with invasive disease potential reflecting the utilization of several mechanisms that may act in synergy. Here we discuss recent progress in identifying the sources of CAMP resistance in the medically important Streptococcus genus. Further study of these mechanisms can contribute to our understanding of streptococcal pathogenesis, and may provide new therapeutic targets for therapy and disease prevention. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Role of nutrient limitation and stationary-phase existence in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin.

    Science.gov (United States)

    Anderl, Jeff N; Zahller, Jeff; Roe, Frank; Stewart, Philip S

    2003-04-01

    Biofilms formed by Klebsiella pneumoniae resisted killing during prolonged exposure to ampicillin or ciprofloxacin even though these agents have been shown to penetrate bacterial aggregates. Bacteria dispersed from biofilms into medium quickly regained most of their susceptibility. Experiments with free-floating bacteria showed that stationary-phase bacteria were protected from killing by either antibiotic, especially when the test was performed in medium lacking carbon and nitrogen sources. These results suggested that the antibiotic tolerance of biofilm bacteria could be explained by nutrient limitation in the biofilm leading to stationary-phase existence of at least some of the cells in the biofilm. This mechanism was supported by experimental characterization of nutrient availability and growth status in biofilms. The average specific growth rate of bacteria in biofilms was only 0.032 h(-1) compared to the specific growth rate of planktonic bacteria of 0.59 h(-1) measured in the same medium. Glucose did not penetrate all the way through the biofilm, and oxygen was shown to penetrate only into the upper 100 micro m. The specific catalase activity was elevated in biofilm bacteria to a level similar to that of stationary-phase planktonic cells. Transmission electron microscopy revealed that bacteria were affected by ampicillin near the periphery of the biofilm but were not affected in the interior. Taken together, these results indicate that K. pneumoniae in this system experience nutrient limitation locally within the biofilm, leading to zones in which the bacteria enter stationary phase and are growing slowly or not at all. In these inactive regions, bacteria are less susceptible to killing by antibiotics.

  7. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  8. DEVELOPMENT OF DUAL ANCHORED SHEET PILE WALL METHOD TO INCREASE FRONT WATER DEPTH AND SEISMIC RESISTANCE OF EXISTING QUAY

    Science.gov (United States)

    Nakamura, Yasushi; Sato, Masakatsu; Kikuchi, Yoshiaki; Sugano, Takahiro; Morikawa, Yoshiyuki; Hoshino, Masami; Miki, Kenichi

    Recently the dual anchored sheet pile wall method has been developed to increase a front water depth and seismic resistance of existing quay walls by providing an additional anchor in the lower level of them to reduce a flexural moment of the sheet piles and a tension of the anchors. The existing technical information is not enough to evaluate the seismic behavior and the retrofit of the quay walls with anchors at two different levels. Therefore the experiments with a scale model set on the vibration table of the centrifugal apparatus as well as two dimensional effective stress analyses have been mobilized to investigate the seismic retrofit of the dual anchored sheet pile wall. The experiments and analyses demonstrate the increase the earthquake resistance of quay walls, because they showed the additional anchor can reduce the stress of the sheet walls to one half.

  9. Multidrug resistance in cancer: its mechanism and its modulation.

    Science.gov (United States)

    Pauwels, Ernest K J; Erba, Paula; Mariani, Giuliano; Gomes, Célia M F

    2007-01-01

    One of the major problems related with the curative treatment of cancer patients is resistance against anticancer drugs. This resistance, which may occur from the beginning or is evident only later as an acquired phenomenon, is due to the action of drug transporters. These transmembrane proteins belong to the ATP-binding cassette (ABC) transporters which reduce bioavailability of drugs, but also determine the elimination of xenobiotics into bile, urine and feces. The present review summarizes recent knowledge in this area, highlighting the mechanism of action of these transporters, its clinical significance and its possible modulation. Novel approaches to overcome multidrug resistance include agents which inhibit or circumvent this efflux mechanism. For the latter category developments in nanomedicine may be of consequence. However, in spite of considerable progress in research regarding multidrug resistance, the phase of efficacious clinical use of this knowledge has not been reached yet. (c) 2007 Prous Science. All rights reserved.

  10. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Al-Saeedi M

    2017-10-01

    Full Text Available Mashael Al-Saeedi, Sahal Al-Hajoj Department of Infection and Immunity, Mycobacteriology Research Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Abstract: Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis. Keywords: Mycobacterium tuberculosis, antibiotic resistance, compensatory evolution, epistasis, efflux pumps, fitness cost

  11. Treatment Resistance Mechanisms of Malignant Glioma Tumor Stem Cells

    International Nuclear Information System (INIS)

    Schmalz, Philip G.R.; Shen, Michael J.; Park, John K.

    2011-01-01

    Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their counterpart differentiated tumor cells and may underlie the persistence and recurrence of tumors following treatment. The various mechanisms by which tumor stem cells avoid or repair the damaging effects of cancer therapies are discussed

  12. An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance.

    Science.gov (United States)

    Xu, Yongchang; Wei, Wenhui; Lei, Sheng; Lin, Jingxia; Srinivas, Swaminath; Feng, Youjun

    2018-04-10

    Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA , the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli , Salmonella enterica , Klebsiella pneumoniae , etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and p hospho e thanol a mine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens. IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and

  13. Pathophysiological mechanisms of death resistance in colorectal carcinoma.

    Science.gov (United States)

    Huang, Ching-Ying; Yu, Linda Chia-Hui

    2015-11-07

    Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

  14. Vip3A resistance alleles exist at high levels in Australian targets before release of cotton expressing this toxin.

    Directory of Open Access Journals (Sweden)

    Rod J Mahon

    Full Text Available Crops engineered to produce insecticidal crystal (Cry proteins from the soil bacterium Bacillus thuringiensis (Bt have revolutionised pest control in agriculture. However field-level resistance to Bt has developed in some targets. Utilising novel vegetative insecticidal proteins (Vips, also derived from Bt but genetically distinct from Cry toxins, is a possible solution that biotechnical companies intend to employ. Using data collected over two seasons we determined that, before deployment of Vip-expressing plants in Australia, resistance alleles exist in key targets as polymorphisms at frequencies of 0.027 (n = 273 lines, 95% CI = 0.019-0.038 in H. armigera and 0.008 (n = 248 lines, 0.004-0.015 in H. punctigera. These frequencies are above mutation rates normally encountered. Homozygous resistant neonates survived doses of Vip3A higher than those estimated in field-grown plants. Fortunately the resistance is largely, if not completely, recessive and does not confer resistance to the Bt toxins Cry1Ac or Cry2Ab already deployed in cotton crops. These later characteristics are favourable for resistance management; however the robustness of Vip3A inclusive varieties will depend on resistance frequencies to the Cry toxins when it is released (anticipated 2016 and the efficacy of Vip3A throughout the season. It is appropriate to pre-emptively screen key targets of Bt crops elsewhere, especially those such as H. zea in the USA, which is not only closely related to H. armigera but also will be exposed to Vip in several varieties of cotton and corn.

  15. Nonoclusive thrombosis of mechanical mitral valve prosthesis caused by inadequate treatment of anticoagulant therapy resistance

    Directory of Open Access Journals (Sweden)

    Ivanović Branislava

    2008-01-01

    Full Text Available Background. Oral anticoagulants have been used in the prevention of thromboembolic complications for over six decades. A rare, but possible problem in the application of these medications could be resistance to them. Case report. We presented a patient with nonocclusive thrombosis of the mechanical mitral prosthesis due to inadequately treated resistance to peroral anticoagulant therapy. Resistance to oral anticoagulant medications was proven by an increased dosage of warfarin up to 20 mg and, after that, acenokumarol to 15 mg over ten days which did not lead to an increase in the international normalized ratio (INR value over 1.2. On the basis of information that she did not take food rich in vitamin K or medications which could reduce effects of oral anticoagulants, and that she did not have additional illnesses and conditions that could cause an inadequate response to anticoagulant therapy, it was circumstantially concluded that this was a hereditary form of resistance. Because of the existing mechanical prosthetics on the mitral position, low molecular heparin has been introduced into the therapy. The patient reduced it on her own initiative, leading to nonocclusive valvular thrombosis. Conclusion. When associated complications like absolute arrhithmia does not exist, the finding of resistance to oral anticoagulant agents is an indication for the replacement of a mechanical prosthetic with a biological one which has been done in this patients.

  16. Mechanisms of resistance to decitabine in the myelodysplastic syndrome.

    Directory of Open Access Journals (Sweden)

    Taichun Qin

    Full Text Available The DNA methylation inhibitor 5-aza-2'-deoxycytidine (DAC is approved for the treatment of myelodysplastic syndromes (MDS, but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance. We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM analysis of global methylation in secondary resistance.Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05, suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05. On average, the methylation of 10 genes was lower at relapse (16.1% compared to diagnosis (18.1% (P<.05. MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%-9.7% of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment.

  17. Microbial Resistance Mechanisms to the Antibiotic and Phytotoxin Fusaric Acid.

    Science.gov (United States)

    Crutcher, Frankie K; Puckhaber, Lorraine S; Stipanovic, Robert D; Bell, Alois A; Nichols, Robert L; Lawrence, Katheryn S; Liu, Jinggao

    2017-10-01

    Fusaric acid (FA) produced by Fusarium oxysporum plays an important role in disease development in plants, including cotton. This non-specific toxin also has antibiotic effects on microorganisms. Thus, one expects a potential pool of diverse detoxification mechanisms of FA in nature. Bacteria and fungi from soils infested with Fusarium and from laboratory sources were evaluated for their ability to grow in the presence of FA and to alter the structure of FA into less toxic compounds. None of the bacterial strains were able to chemically modify FA. Highly FA-resistant strains were found only in Gram-negative bacteria, mainly in the genus of Pseudomonas. The FA resistance of the Gram-negative bacteria was positively correlated with the number of predicted genes for FA efflux pumps present in the genome. Phylogenetic analysis of predicted FA resistance proteins (FUSC, an inner membrane transporter component of the efflux pump) revealed that FUSC proteins having high sequence identities with the functionally characterized FA resistance protein FusC or Fdt might be the major contributors of FA resistance. In contrast, most fungi converted FA to less toxic compounds regardless of the level of FA resistance they exhibited. Five derivatives were detected, and the detoxification of FA involved either oxidative reactions on the butyl side chain or reductive reactions on the carboxylic acid group. The production of these metabolites from widely different phyla indicates that resistance to FA by altering its structure is highly conserved. A few FA resistant saprophytic or biocontrol strains of fungi were incapable of altering FA, indicating a possible involvement of efflux transporters. Deployment of both efflux and derivatization mechanisms may be a common feature of fungal FA resistance.

  18. Distinguishing Antimicrobial Models with Different Resistance Mechanisms via Population Pharmacodynamic Modeling.

    Directory of Open Access Journals (Sweden)

    Matthieu Jacobs

    2016-03-01

    Full Text Available Semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD modeling is increasingly used for antimicrobial drug development and optimization of dosage regimens, but systematic simulation-estimation studies to distinguish between competing PD models are lacking. This study compared the ability of static and dynamic in vitro infection models to distinguish between models with different resistance mechanisms and support accurate and precise parameter estimation. Monte Carlo simulations (MCS were performed for models with one susceptible bacterial population without (M1 or with a resting stage (M2, a one population model with adaptive resistance (M5, models with pre-existing susceptible and resistant populations without (M3 or with (M4 inter-conversion, and a model with two pre-existing populations with adaptive resistance (M6. For each model, 200 datasets of the total bacterial population were simulated over 24h using static antibiotic concentrations (256-fold concentration range or over 48h under dynamic conditions (dosing every 12h; elimination half-life: 1h. Twelve-hundred random datasets (each containing 20 curves for static or four curves for dynamic conditions were generated by bootstrapping. Each dataset was estimated by all six models via population PD modeling to compare bias and precision. For M1 and M3, most parameter estimates were unbiased (<10% and had good imprecision (<30%. However, parameters for adaptive resistance and inter-conversion for M2, M4, M5 and M6 had poor bias and large imprecision under static and dynamic conditions. For datasets that only contained viable counts of the total population, common statistical criteria and diagnostic plots did not support sound identification of the true resistance mechanism. Therefore, it seems advisable to quantify resistant bacteria and characterize their MICs and resistance mechanisms to support extended simulations and translate from in vitro experiments to animal infection models and

  19. Resistance Status and Resistance Mechanisms in a Strain of Aedes aegypti (Diptera: Culicidae) From Puerto Rico.

    Science.gov (United States)

    Estep, Alden S; Sanscrainte, Neil D; Waits, Christy M; Louton, Jessica E; Becnel, James J

    2017-11-07

    Puerto Rico (PR) has a long history of vector-borne disease and insecticide-resistant Aedes aegypti (L.). Defining contributing mechanisms behind phenotypic resistance is critical for effective vector control intervention. However, previous studies from PR have each focused on only one mechanism of pyrethroid resistance. This study examines the contribution of P450-mediated enzymatic detoxification and sodium channel target site changes to the overall resistance phenotype of Ae. aegypti collected from San Juan, PR, in 2012. Screening of a panel of toxicants found broad resistance relative to the lab susceptible Orlando (ORL1952) strain. We identified significant resistance to representative Type I, Type II, and nonester pyrethroids, a sodium channel blocker, and a sodium channel blocking inhibitor, all of which interact with the sodium channel. Testing of fipronil, a chloride channel agonist, also showed low but significant levels of resistance. In contrast, the PR and ORL1952 strains were equally susceptible to chlorfenapyr, which has been suggested as an alternative public health insecticide. Molecular characterization of the strain indicated that two common sodium channel mutations were fixed in the population. Topical bioassay with piperonyl butoxide (PBO) indicated cytochrome P450-mediated detoxification accounts for approximately half of the resistance profile. Transcript expression screening of cytochrome P450s and glutathione-S-transferases identified the presence of overexpressed transcripts. This study of Puerto Rican Ae. aegypti with significant contributions from both genetic changes and enzymatic detoxification highlights the necessity of monitoring for resistance but also defining the multiple resistance mechanisms to inform effective mosquito control. Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by US Government employees and is in the public domain in the US.

  20. Mechanisms of Helicobacter pylori antibiotic resistance and molecular testing

    Directory of Open Access Journals (Sweden)

    Toshihiro eNishizawa

    2014-10-01

    Full Text Available Antibiotic resistance in Helicobacter pylori (H. pylori is the main factor affecting the efficacy of current treatment methods against infection caused by this organism. The traditional culture methods for testing bacterial susceptibility to antibiotics are expensive and require 10 to 14 days. Since resistance to clarithromycin, fluoroquinolone, and tetracycline seems to be exclusively caused by specific mutations in a small region of the responsible gene, molecular methods offer an attractive alternative to the above-mentioned techniques. The technique of polymerase chain reaction (PCR is an accurate and rapid method for the detection of mutations that confer antibiotic resistance. This review highlights the mechanisms of antibiotic resistance in H. pylori and the molecular methods for antibiotic susceptibility testing.

  1. Mechanisms of resistance to HER2 target therapy.

    Science.gov (United States)

    Tortora, Giampaolo

    2011-01-01

    In the past years, several agents targeting signaling proteins critical for breast cancer growth and dissemination entered clinical evaluation. They include drugs directed against the HER/ErbB family of receptor tyrosine kinases, especially HER2; several downstream signal transducers; and proteins involved in tumor angiogenesis and dissemination. Unfortunately, resistance to targeted agents is a quite common feature, and understanding of the molecular mechanisms predicting response or failure has become a crucial issue to optimize treatment and select patients who are the best candidates to respond. The neoadjuvant setting offers unique opportunities allowing tumor sampling and search for molecular determinants of response. A variety of tumor and host factors may account for the onset of resistance. Major progress has been made in the understanding of the mechanisms involved in the primary and acquired resistance to targeted agents, especially the anti-HER2 drugs, which play a pivotal role in the weaponry against breast cancer.

  2. The operational mechanism of ferroelectric-driven organic resistive switches

    NARCIS (Netherlands)

    Kemerink, M.; Asadi, K.; Blom, P.W.M.; Leeuw, D.M. de

    2012-01-01

    The availability of a reliable memory element is crucial for the fabrication of 'plastic' logic circuits. We use numerical simulations to show that the switching mechanism of ferroelectric-driven organic resistive switches is the stray field of the polarized ferroelectric phase. The stray field

  3. mechanisms of drought resistance in grain ii:.stomatal regulation ...

    African Journals Online (AJOL)

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    ABSTRACT: Earlier research works conducted to identify mechanisms of drought resistance in grain legumes under soil ... maintenance of high plant water potential in common bean under stress was the function of stomatal regulation and/or root ..... available only for maintenance requirements of the plant. On the other ...

  4. The operational mechanism of ferroelectric-driven organic resistive switches

    NARCIS (Netherlands)

    Kemerink, Martijn; Asadi, Kamal; Blom, Paul W. M.; de Leeuw, Dago M.

    The availability of a reliable memory element is crucial for the fabrication of 'plastic' logic circuits. We use numerical simulations to show that the switching mechanism of ferroelectric-driven organic resistive switches is the stray field of the polarized ferroelectric phase. The stray field

  5. Plant resistance to cold stress: Mechanisms and environmental ...

    Indian Academy of Sciences (India)

    Unknown

    temperature was an even more effective signal than day-length. [Beck E H, Heim R and Hansen J 2004 Plant resistance to cold stress: Mechanisms and environmental signals triggering frost hardening and dehardening; J. Biosci. 29 449–459]. 1. Introduction. 1.1 Ecophysiological aspects of plant cold stress and acclimation.

  6. Mechanical and electrical properties of resistance welds at cryogenic temperatures

    Energy Technology Data Exchange (ETDEWEB)

    Wang, S T; Kim, S H; Kim, N S; Ludwig, H

    1979-01-01

    The mechanical and electrical properties of resistance welds at cryogenic temperatures for the large superconducting magnet such as the superconducting MHD Dipole system for the National Coal-Fired Flow Facility (CFFF SCMS) at the U. of Tennessee Space Institute are reported.

  7. Cross-resistance of bisultap resistant strain of Nilaparvata lugens and its biochemical mechanism.

    Science.gov (United States)

    Ling, Shanfeng; Zhang, Runjie

    2011-02-01

    The resistant (R) strain of the planthopper Nilaparvata lugens (Stål) selected for bisultap resistance displayed 7.7-fold resistance to bisultap and also had cross-resistance to nereistoxin (monosultap, thiocyclam, and cartap), chlorpyrifos, dimethoate, and malathion but no cross-resistance to buprofezin, imidacloprid, and fipronil. To find out the biochemical mechanism of resistance to bisultap, biochemical assay was done. The results showed that cytochrome P450 monooxygenases (P450) activity in R strain was 2.71-fold that in susceptible strain (S strain), in which the changed activity for general esterase (EST) was 1.91 and for glutathione S-transferases only 1.32. Piperonyl butoxide (PBO) could significantly inhibit P450 activity (percentage of inhibition [PI]: 37.31%) in the R strain, with ESTs PI = 16.04% by triphenyl phosphate (TPP). The results also demonstrated that diethyl maleate had no synergism with bisultap. However, PBO displayed significant synergism in three different strains, and the synergism increased with resistance (S strain 1.42, Lab strain, 2.24 and R strain, 3.23). TPP also showed synergism for three strains, especially in R strain (synergistic ratio = 2.47). An in vitro biochemical study and in vivo synergistic study indicated that P450 might be play important role in the biochemical mechanism of bisultap resistance and that esterase might be the important factor of bisultap resistance. Acetylcholinesterase (AChE) insensitivity play important role in bisultap resistance. We suggest that buprofezin, imidacloprid, and fipronil could be used in resistance management programs for N. lugens via alternation and rotation with bisultap.

  8. Using pre-existing microarray datasets to increase experimental power: application to insulin resistance.

    Directory of Open Access Journals (Sweden)

    Bernie J Daigle

    2010-03-01

    Full Text Available Although they have become a widely used experimental technique for identifying differentially expressed (DE genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources; thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT, a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes' expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58% of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a

  9. Effect of the existing form of Cu element on the mechanical properties, bio-corrosion and antibacterial properties of Ti-Cu alloys for biomedical application.

    Science.gov (United States)

    Zhang, Erlin; Wang, Xiaoyan; Chen, Mian; Hou, Bing

    2016-12-01

    Ti-Cu alloys have exhibited strong antibacterial ability, but Ti-Cu alloys prepared by different processes showed different antibacterial ability. In order to reveal the controlling mechanism, Ti-Cu alloys with different existing forms of Cu element were prepared in this paper. The effects of the Cu existing form on the microstructure, mechanical, corrosion and antibacterial properties of Ti-Cu alloys have been systematically investigated. Results have shown that the as-cast Ti-Cu alloys showed a higher hardness and mechanical strength as well as a higher antibacterial rate (51-64%) but a relatively lower corrosion resistance than pure titanium. Treatment at 900°C/2h (T4) significantly increased the hardness and the strength, improved the corrosion resistance but had little effect on the antibacterial property. Treatment at 900°C/2h+400°C/12h (T6) increased further the hardness and the mechanical strength, improved the corrosion resistance and but also enhanced the antibacterial rate (>90%) significantly. It was demonstrated that the Cu element in solid solution state showed high strengthening ability but low antibacterial property while Cu element in Ti2Cu phase exhibited strong strengthening ability and strong antibacterial property. Ti2Cu phase played a key role in the antibacterial mechanism. The antibacterial ability of Ti-Cu alloy was strongly proportional to the Cu content and the surface area of Ti2Cu phase. High Cu content and fine Ti2Cu phase would contribute to a high strength and a strong antibacterial ability. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

    Science.gov (United States)

    Andersson, D I; Hughes, D; Kubicek-Sutherland, J Z

    2016-05-01

    Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Cryogenic Ice Penetration Mechanics for Investigating the Existence of Life on the Jupiter Moon Europa Project

    Data.gov (United States)

    National Aeronautics and Space Administration — A key challenge is that ice properties at the temperatures that exist on Europa are not well characterized. Our previous studies have shown that hardness as well as...

  12. Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans.

    Science.gov (United States)

    Teelucksingh, Surujpal; Jaimungal, Sarada; Pinto Pereira, Lexley; Seemungal, Terence; Nayak, Shivananda

    2012-03-30

    The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance. Using acanthosis nigricans (AN) and skin vasoconstrictor (SVC) response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32), with those without AN (n = 68) while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109) with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12). In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P glucocorticoid action in vascular tissue.

  13. Research on Service Life of Flame Resistant Materials in the Exhibition Hall by the Use of Mechanical Method of the Meso Damage Mechanics

    OpenAIRE

    Zhang Junzhu

    2015-01-01

    The population in the exhibition hall is relatively dense, and fire incidents often occur, so the existence of flame resistant materials is very important. The flame resistant materials are used to analyze the museums, art galleries, science and technology museums and other exhibition halls. Taking two kinds of flame resistant materials, namely, Mg(OH)2 and Al(OH)3 as an example, this paper establishes a model of meso damage mechanics by the use of mechanical method of the meso damage mechani...

  14. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    LENUS (Irish Health Repository)

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  15. Characterisation of Dynamic Mechanical Properties of Resistance Welding Machines

    DEFF Research Database (Denmark)

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2005-01-01

    characterizing the dynamic mechanical characteristics of resistance welding machines is suggested, and a test set-up is designed determining the basic, independent machine parameters required in the model. The model is verified by performing a series of mechanical tests as well as real projection welds.......The dynamic mechanical properties of a resistance welding machine have significant influence on weld quality, which must be considered when simulating the welding process numerically. However, due to the complexity of the machine structure and the mutual coupling of components of the machine system......, it is very difficult to measure or calculate the basic, independent machine parameters required in a mathematical model of the machine dynamics, and no test method has so far been presented in literature, which can be applied directly in an industrial environment. In this paper, a mathematical model...

  16. Mechanisms of resistance to antimicrobial peptides in staphylococci.

    Science.gov (United States)

    Joo, Hwang-Soo; Otto, Michael

    2015-11-01

    Staphylococci are commensal bacteria living on the epithelial surfaces of humans and other mammals. Many staphylococci, including the dangerous pathogen Staphylococcus aureus, can cause severe disease when they breach the epithelial barrier. Both during their commensal life and during infection, staphylococci need to evade mechanisms of innate host defense, of which antimicrobial peptides (AMPs) play a key role in particular on the skin. Mechanisms that staphylococci have developed to evade the bactericidal activity of AMPs are manifold, comprising repulsion of AMPs via alteration of cell wall and membrane surface charges, proteolytic inactivation, sequestration, and secretion. Furthermore, many staphylococci form biofilms, which represents an additional way of protection from antimicrobial agents, including AMPs. Finally, staphylococci can sense the presence of AMPs by sensor/regulator systems that control many of those resistance mechanisms. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. Published by Elsevier B.V.

  17. The Current State of Macrolide Resistance in Campylobacter spp.: Trends and Impacts of Resistance Mechanisms.

    Science.gov (United States)

    Bolinger, Hannah; Kathariou, Sophia

    2017-06-15

    Campylobacter spp., especially Campylobacter jejuni and C. coli , are leading bacterial foodborne pathogens worldwide. In the United States, an estimated 0.8 million cases of campylobacteriosis occur annually, mostly involving C. jejuni Campylobacteriosis is generally self-limiting, but in severe cases, treatment with antibiotics may be mandated. The increasing incidence of fluoroquinolone resistance in Campylobacter has rendered macrolides such as erythromycin and azithromycin the drugs of choice for human campylobacteriosis. The prevalence of macrolide resistance in C. jejuni remains low, but macrolide resistance can be common in C. coli Substitutions in the 23S rRNA gene, specifically A2075G, and less frequently A2074C/G, remain the most common mechanism for high-level resistance to macrolides. In C. jejuni , resistance mediated by such substitutions is accompanied by a reduced ability to colonize chickens and other fitness costs, potentially contributing to the low incidence of macrolide resistance. Interestingly, similar fitness impacts have not been noted in C. coli Also noteworthy is a novel mechanism first reported in 2014 for a C. coli isolate from China and mediated by erm (B) harbored on multidrug resistance genomic islands. The incidence of erm (B) appears to reflect clonal expansion of certain strains, and whole-genome sequencing has been critical to the elucidation of erm (B)-associated macrolide resistance in Campylobacter spp. With the exception of one report from Spain, erm (B)-mediated macrolide resistance has been restricted to Campylobacter spp., mostly C. coli , of animal and human origin from China. If erm (B)-mediated macrolide resistance does not confer fitness costs in C. jejuni , the range of this gene may expand in C. jejuni , threatening to compromise treatment effectiveness for severe campylobacteriosis cases. Copyright © 2017 American Society for Microbiology.

  18. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Eveline Snelders

    2008-11-01

    Full Text Available BACKGROUND: Resistance to triazoles was recently reported in Aspergillus fumigatus isolates cultured from patients with invasive aspergillosis. The prevalence of azole resistance in A. fumigatus is unknown. We investigated the prevalence and spread of azole resistance using our culture collection that contained A. fumigatus isolates collected between 1994 and 2007. METHODS AND FINDINGS: We investigated the prevalence of itraconazole (ITZ resistance in 1,912 clinical A. fumigatus isolates collected from 1,219 patients in our University Medical Centre over a 14-y period. The spread of resistance was investigated by analyzing 147 A. fumigatus isolates from 101 patients, from 28 other medical centres in The Netherlands and 317 isolates from six other countries. The isolates were characterized using phenotypic and molecular methods. The electronic patient files were used to determine the underlying conditions of the patients and the presence of invasive aspergillosis. ITZ-resistant isolates were found in 32 of 1,219 patients. All cases were observed after 1999 with an annual prevalence of 1.7% to 6%. The ITZ-resistant isolates also showed elevated minimum inhibitory concentrations of voriconazole, ravuconazole, and posaconazole. A substitution of leucine 98 for histidine in the cyp51A gene, together with two copies of a 34-bp sequence in tandem in the gene promoter (TR/L98H, was found to be the dominant resistance mechanism. Microsatellite analysis indicated that the ITZ-resistant isolates were genetically distinct but clustered. The ITZ-sensitive isolates were not more likely to be responsible for invasive aspergillosis than the ITZ-resistant isolates. ITZ resistance was found in isolates from 13 patients (12.8% from nine other medical centres in The Netherlands, of which 69% harboured the TR/L98H substitution, and in six isolates originating from four other countries. CONCLUSIONS: Azole resistance has emerged in A. fumigatus and might be more

  19. [Mechanisms underlying glucocorticoid resistance in chronic rhinosinusitis with nasal polyps].

    Science.gov (United States)

    Zhang, Y Y; Lou, H F; Wang, C S; Zhang, L

    2018-02-07

    Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease that occurs in the nasal and sinus mucosa, which is a common disease in otorhinolaryngology. At present, CRSwNP can be effectively treated by glucocorticoids (GC). GC binds to GC receptors in the nasal mucosa, affects the expression of inflammatory genes, inhibits the activation and action of eosinophils, T cell-associated inflammatory responses in nasal polyps, as well as tissue remodeling. However, there are some patients fall reponse to GC, so called GC resistance. The study suggests that the possible mechanism of CRSwNP GC resistance is mainly related to GC receptor abnormal, the role of cytokines and transcription factors, such as Th cells and IL-8. In addition, MAPK-related kinases and histone deacetylase in the GC signaling pathway also play important roles in the GC resistance process. This paper reviews the mechanism of GC treatment of CRSwNP, the mechanism of GC resistance and alternative treatment of GC.

  20. Dissemination and Mechanism for the MCR-1 Colistin Resistance.

    Directory of Open Access Journals (Sweden)

    Rongsui Gao

    2016-11-01

    Full Text Available Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens. Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-borne mobile colistin resistance gene (mcr-1. However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood. Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr-1 gene. Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance. The soluble form of the membrane protein MCR-1 was successfully prepared and verified. Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA potentially implies parallel evolutionary paths for the two genes. In conclusion, our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.

  1. Molecular mechanisms of cisplatin resistance in cervical cancer

    Science.gov (United States)

    Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

    2016-01-01

    Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. PMID:27354763

  2. Quinolone Resistance Mechanisms Among Salmonella enterica in Malaysia.

    Science.gov (United States)

    Thong, Kwai Lin; Ngoi, Soo Tein; Chai, Lay Ching; Teh, Cindy Shuan Ju

    2016-06-01

    The prevalence of quinolone-resistant Salmonella enterica is on the rise worldwide. Salmonella enterica is one of the major foodborne pathogens in Malaysia. Therefore, we aim to investigate the occurrence and mechanisms of quinolone resistance among Salmonella strains isolated in Malaysia. A total of 283 Salmonella strains isolated from food, humans, and animals were studied. The disk diffusion method was used to examine the quinolone susceptibility of the strains, and the minimum inhibitory concentration (MIC) values of nalidixic acid and ciprofloxacin were also determined. DNA sequencing of the quinolone resistance-determining regions (QRDRs) of gyrase and topoisomerase IV genes and the plasmid-borne qnr genes was performed. The transfer of the qnr gene was examined through transconjugation experiment. A total of 101 nalidixic acid-resistant Salmonella strains were identified. In general, all strains were highly resistant to nalidixic acid (average MICNAL, 170 μg/ml). Resistance to ciprofloxacin was observed in 30.7% of the strains (1 ≤ MICCIP ≤ 2 μg/ml). Majority of the strains contained missense mutations in the QRDR of gyrA (69.3%). Silent mutations were frequently detected in gyrB (75.2%), parC (27.7%), and parE (51.5%) within and beyond the QRDRs. Novel mutations were detected in parC and parE. The plasmid-borne qnrS1 variant was found in 36.6% of the strains, and two strains were found to be able to transfer the qnrS1 gene. Overall, mutations in gyrA and the presence of qnrS1 genes might have contributed to the high level of quinolone resistance among the strains. Our study provided a better understanding on the status of quinolone resistance among Salmonella strains circulating in Malaysia.

  3. Mechanisms and evolution of plant resistance to aphids.

    Science.gov (United States)

    Züst, Tobias; Agrawal, Anurag A

    2016-01-06

    Aphids are important herbivores of both wild and cultivated plants. Plants rely on unique mechanisms of recognition, signalling and defence to cope with the specialized mode of phloem feeding by aphids. Aspects of the molecular mechanisms underlying aphid-plant interactions are beginning to be understood. Recent advances include the identification of aphid salivary proteins involved in host plant manipulation, and plant receptors involved in aphid recognition. However, a complete picture of aphid-plant interactions requires consideration of the ecological outcome of these mechanisms in nature, and the evolutionary processes that shaped them. Here we identify general patterns of resistance, with a special focus on recognition, phytohormonal signalling, secondary metabolites and induction of plant resistance. We discuss how host specialization can enable aphids to co-opt both the phytohormonal responses and defensive compounds of plants for their own benefit at a local scale. In response, systemically induced resistance in plants is common and often involves targeted responses to specific aphid species or even genotypes. As co-evolutionary adaptation between plants and aphids is ongoing, the stealthy nature of aphid feeding makes both the mechanisms and outcomes of these interactions highly distinct from those of other herbivore-plant interactions.

  4. Mechanisms and improvement of acid resistance in lactic acid bacteria.

    Science.gov (United States)

    Wang, Chao; Cui, Yanhua; Qu, Xiaojun

    2018-03-01

    Lactic acid bacteria (LAB) can take advantage of fermentable carbohydrates to produce lactic acid. They are proverbially applied in industry, agricultural production, animal husbandry, food enterprise, pharmaceutical engineering and some other important fields, which are closely related to human life. For performing the probiotic functions, LAB have to face the low pH environment of the gastrointestinal tract. Therefore, acid resistance of LAB is of great importance not only for their own growth, but also for fermentation and preparation of probiotic products. Recent research studies on acid resistance mechanisms of LAB are mainly focused on neutralization process, biofilm and cell density, proton pump, protection of macromolecules, pre-adaptation and cross-protection, and effect of solutes. In this context, biotechnological strategies such as synthetic biology, genome shuffling, high pressure homogenization and adaptive laboratory evolution were also used to improve the acid resistance of LAB to respond to constantly changing low pH environment.

  5. Mechanisms of resistance to daptomycin in Staphylococcus aureus.

    Science.gov (United States)

    Gómez Casanova, N; Siller Ruiz, M; Muñoz Bellido, J L

    2017-12-01

    Daptomycin is a cyclic lipopeptide active against multidrug-resistant Gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus with reduced susceptibility to vancomycin. It is 4-8 fold as active as vancomycin against methicillin-susceptible S. aureus (MSSA) and MRSA, and retains most of this activity against S. aureus with reduced susceptibility to vancomycin. The mechanism of action of daptomycin is not fully understood. Daptomycin binds to the bacterial cytoplasmic membrane, leading to depolarization due to the loss of potassium ions from the cytoplasm. Daptomycin non-susceptibility is unusual in the clinical setting. Different mechanisms have been proposed to explain daptomycin-resistance, most of them associated to changes in composition, charge and fluidity of the cell wall. The mprF mutations, which lead to an increase in the lysyl-phosphatidyl glycerol production, and rpoB and rpoC mutations (rpo genes encode for bacterial RNA polymerase subunits) have been proposed as associated to daptomycin-resistance, but a number of mutations in other genes ( walK, cls, ggrA…) have been proposed.

  6. Degradation of sulfonamides as a microbial resistance mechanism.

    Science.gov (United States)

    Vila-Costa, Maria; Gioia, Rosalinda; Aceña, Jaume; Pérez, Sandra; Casamayor, Emilio O; Dachs, Jordi

    2017-05-15

    Two of the main mechanisms of bacterial resistance to sulfonamides in aquatic systems, spread of antibiotic resistance genes (ARG) among the microbial community and in-situ bacterial sulfonamide degradation, were studied in mesocosms experiments using water and cobble biofilms from upstream (pristine waters) and downstream (polluted waters) from the Llobregat river, NE Iberian Peninsula. Mesocosms were prepared at two different concentrations (5000 ng/L and 1000 ng/L) of sulfonamides antibiotics (sulfamethazine and sulfamethoxazole). Concentrations of ARG, nutrients, sulfonamides and their degradation products were measured during the time course of the experiments. Sulfonamides were efficiently degraded by the biofilms during the first four weeks of the experiment. The abundance of ARG in biofilms sharply decreased after addition of high concentrations of sulfonamides, but this was not observed in the mesocosms treated with low concentrations of sulfonamides. Sulfonamide degradation was faster in polluted waters and at high concentrations of sulfonamide (and lower ARG abundances), suggesting that both degradation and ARG are two complementary resistance strategies employed by the microbial community. This study shows that microbial degradation of antibiotics is an efficient resistance mechanism coupled with the presence of ARG, and suggests that in situ degradation prevails at high concentrations of antibiotics whereas physiological adaptation by ARG spread would be more important under relatively lower concentrations of antibiotics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Molecular epidemiological survey of bacteremia by multidrug resistant Pseudomonas aeruginosa: the relevance of intrinsic resistance mechanisms.

    Directory of Open Access Journals (Sweden)

    Raquel Cristina Cavalcanti Dantas

    Full Text Available The bacterial factors associated with bacteremia by multidrug-resistant and extensively drug-resistant P. aeruginosa, including overexpression of efflux pumps, AmpC overproduction, and loss/alteration of the OprD porin in isolates that are non-Metallo-β-Lactamase producing were analyzed in a retrospective study. Molecular analyses included strain typing by Pulsed Field Gel Electrophoresis and identification of key genes via qualitative and quantitative PCR-based assays. Previous use of carbapenems and tracheostomy was independently associated with the development of bacteremia by extensively drug-resistant and multidrug-resistant strains of P. aeruginosa. A high consumption of antimicrobials was observed, and 75.0% of the isolates contained amplicons with the blaSPM-1 and blaVIM genes. Of the 47 non-Metallo-β-Lactamase isolates, none had another type of carbapenemase. However, the isolates exhibited high rates of hyperproduction of AmpC, loss of the OprD porin (71.4% and the presence of MexABOprM (57.1% and MexXY (64.3%. This study suggests that in non-Metallo-β-Lactamase isolates, the association of intrinsic resistance mechanisms could contributes to the expression of multidrug-resistant/extensively drug-resistant phenotypes.

  8. [Molecular characterization of resistance mechanisms: methicillin resistance Staphylococcus aureus, extended spectrum β-lactamases and carbapenemases].

    Science.gov (United States)

    Oteo, Jesús; Belén Aracil, María

    2015-07-01

    Multi-drug resistance in bacterial pathogens increases morbidity and mortality in infected patients and it is a threat to public health concern by their high capacity to spread. For both reasons, the rapid detection of multi-drug resistant bacteria is critical. Standard microbiological procedures require 48-72 h to provide the antimicrobial susceptibility results, thus there is emerging interest in the development of rapid detection techniques. In recent years, the use of selective and differential culture-based methods has widely spread. However, the capacity for detecting antibiotic resistance genes and their low turnaround times has made molecular methods a reference for diagnosis of multidrug resistance. This review focusses on the molecular methods for detecting some mechanisms of antibiotic resistance with a high clinical and epidemiological impact: a) Enzymatic resistance to broad spectrum β-lactam antibiotics in Enterobacteriaceae, mainly extended spectrum β-lactamases (ESBL) and carbapenemases; and b) methicillin resistance in Staphylococcus aureus. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  9. Fluoroquinolone resistance mechanisms in multidrug-resistant Escherichia coli isolated from extraintestinal infections in dogs.

    Science.gov (United States)

    Gibson, Justine S; Cobbold, Rowland N; Kyaw-Tanner, Myat T; Heisig, Peter; Trott, Darren J

    2010-11-20

    Fluoroquinolone resistance is an emerging problem in companion animal practice. The present study aimed to determine comparative fluoroquinolone minimum inhibitory concentrations (MICs) for enrofloxacin, marbofloxacin and pradofloxacin and identify plasmid-mediated quinolone resistance (PMQR) mechanisms in 41 multidrug-resistant (MDR) Escherichia coli isolates representing three main clonal groups (CGs) cultured from extraintestinal infections in dogs. All isolates were resistant to fluoroquinolones and the PMQR genes qnrA1, qnrB2, qnrS1 and qepA were identified in isolates from each CG. For a subset of 13 representative isolates, fluoroquinolone chromosomal resistance mechanisms were characterized. CG1 isolates had three mutations in the quinolone resistance determining region (QRDR), two in gyrA (Ser TCG-83→Leu TTG and Asp GAC-87→Asn AAC) and one in parC (Ser AGC-80→Ile ATT), whilst CG2 and CG3 isolates also possessed an additional mutation in parC (Glu GAA-84→Gly GGA) which was reflected in higher fluoroquinolone MICs compared to CG1. Organic solvent tolerance was demonstrated in 8 of the 13 isolates, and all 13 isolates demonstrated enhanced efflux on the basis of a 4-fold decrease or greater in the MIC of enrofloxacin when incubated with an efflux pump inhibitor. A mutation in acrR which can cause overexpression of the AcrAB multidrug efflux pump was detected in CG1 strains. These findings indicate that fluoroquinolone resistance in MDR E. coli isolated from extraintestinal infections in dogs is associated with a combination of target mutations in the QRDRs, transferable PMQR mechanisms and enhanced efflux. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Towards the Understanding of Resistance Mechanisms in Clinically Isolated Trimethoprim-resistant, Methicillin-resistant Staphylococcus aureus Dihydrofolate Reductase

    Energy Technology Data Exchange (ETDEWEB)

    Frey, K.; Lombardo, M; Wright, D; Anderson, A

    2010-01-01

    Resistance to therapeutics such as trimethoprim-sulfamethoxazole has become an increasing problem in strains of methicillin-resistant Staphylococcus aureus (MRSA). Clinically isolated trimethoprim-resistant strains reveal a double mutation, H30N/F98Y, in dihydrofolate reductase (DHFR). In order to develop novel and effective therapeutics against these resistant strains, we evaluated a series of propargyl-linked antifolate lead compounds for inhibition of the mutant enzyme. For the propargyl-linked antifolates, the F98Y mutation generates minimal (between 1.2- and 6-fold) losses of affinity and the H30N mutation generates greater losses (between 2.4- and 48-fold). Conversely, trimethoprim affinity is largely diminished by the F98Y mutation (36-fold) and is not affected by the H30N mutation. In order to elucidate a mechanism of resistance, we determined a crystal structure of a complex of this double mutant with a lead propargyl-linked antifolate. This structure suggests a resistance mechanism consistent both for the propargyl-linked class of antifolates and for trimethoprim that is based on the loss of a conserved water-mediated hydrogen bond.

  11. [Mechanisms of microorganism resistance to beta-lactam antibiotics].

    Science.gov (United States)

    D'iachkova, V S; Bazhukova, T A

    2014-01-01

    Literature data on molecular mechanisms of resistance to beta-lactam antibiotics have been summarized. The following mechanisms are examined: appearance ofpenicillin-binding proteins (PBP) with lower affinity to beta-lactam antibiotics; production by microorganisms of enzymes (beta-lactamases) that hydrolyze beta-lactam ring; disruption of microbial cell outer membrane permeability and active secretion of antibiotics from the microbial cell (effiux-effect). Characterization of extended spectrum beta-lactamases (ESBL) as well as data on structure of SCCmec element of MRSA and bacterial efflux system (RND) is presented.

  12. Collapse mechanisms and the existence of equilibrium solutions for masonry bodies

    Czech Academy of Sciences Publication Activity Database

    Šilhavý, Miroslav

    2014-01-01

    Roč. 19, č. 7 (2014), s. 821-831 ISSN 1081-2865 Institutional support: RVO:67985840 Keywords : equilibrium of masonry bodies * collapse mechanism * coercivity Subject RIV: BA - General Mathematics Impact factor: 1.298, year: 2014 http://mms.sagepub.com/content/19/7/821

  13. Collapse mechanisms and the existence of equilibrium solutions for masonry bodies

    Czech Academy of Sciences Publication Activity Database

    Šilhavý, Miroslav

    2014-01-01

    Roč. 19, č. 7 (2014), s. 821-831 ISSN 1081-2865 Institutional support: RVO:67985840 Keywords : equilibrium of masonry bodies * collapse mechanism * coercivity Subject RIV: BA - General Mathematics Impact factor: 1.298, year: 2014 http:// mms .sagepub.com/content/19/7/821

  14. Embryo mechanics: balancing force production with elastic resistance during morphogenesis.

    Science.gov (United States)

    Davidson, Lance A

    2011-01-01

    Morphogenesis requires the spatial and temporal control of embryo mechanics, including force production and mechanical resistance to those forces, to coordinate tissue deformation and large-scale movements. Thus, biomechanical processes play a key role in directly shaping the embryo. Additional roles for embryo mechanics during development may include the patterning of positional information and to provide feedback to ensure the success of morphogenetic movements in shaping the larval body and organs. To understand the multiple roles of mechanics during development requires familiarity with engineering principles of the mechanics of structures, the viscoelastic properties of biomaterials, and the integration of force and stress within embryonic structures as morphogenesis progresses. In this chapter, we review the basic engineering principles of biomechanics as they relate to morphogenesis, introduce methods for quantifying embryo mechanics and the limitations of these methods, and outline a formalism for investigating the role of embryo mechanics in birth defects. We encourage the nascent field of embryo mechanics to adopt standard engineering terms and test methods so that studies of diverse organisms can be compared and universal biomechanical principles can be revealed. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Exacerbation of pre-existing diabetes insipidus during pregnancy, mechanisms and management.

    Science.gov (United States)

    Tack, Lloyd J W; T'Sjoen, Guy; Lapauw, Bruno

    2017-06-01

    During pregnancy, physiological changes in osmotic homeostasis cause water retention. If excessive, this can cause gestational diabetes insipidus (DI), particularly in patients with already impaired vasopressin secretion. We present the case of a 34-year-old patient with pre-existing hypopituitarism who experienced a transient exacerbation of her DI during a twin pregnancy. In contrast to typical gestational DI, polyuria and polydipsia occurred during the first trimester and remained stable thereafter. This case highlights a challenging clinical entity of which pathophysiology, diagnostic approach and treatment will be discussed.

  16. Ciprofloxacin-resistant Escherichia coli in Central Greece: mechanisms of resistance and molecular identification

    Directory of Open Access Journals (Sweden)

    Mavroidi Angeliki

    2012-12-01

    Full Text Available Abstract Background Fluoroquinolone resistant E. coli isolates, that are also resistant to other classes of antibiotics, is a significant challenge to antibiotic treatment and infection control policies. In Central Greece a significant increase of ciprofloxacin-resistant Escherichia coli has occurred during 2011, indicating the need for further analysis. Methods A total of 106 ciprofloxacin-resistant out of 505 E. coli isolates consecutively collected during an eight months period in a tertiary Greek hospital of Central Greece were studied. Antimicrobial susceptibility patterns and mechanisms of resistance to quinolones were assessed, whereas selected isolates were further characterized by multilocus sequence typing and β-lactamase content. Results Sequence analysis of the quinolone-resistance determining region of the gyrA and parC genes has revealed that 63% of the ciprofloxacin-resistant E. coli harbored a distinct amino acid substitution pattern (GyrA:S83L + D87N; ParC:S80I + E84V, while 34% and 3% carried the patterns GyrA:S83L + D87N; ParC:S80I and GyrA:S83L + D87N; ParC:S80I + E84G respectively. The aac (6’-1b-cr plasmid-mediated quinolone resistance determinant was also detected; none of the isolates was found to carry the qnrA, qnrB and qnrS. Genotyping of a subset of 35 selected ciprofloxacin-resistant E. coli by multilocus sequence typing has revealed the presence of nine sequence types; ST131 and ST410 were the most prevalent and were exclusively correlated with hospital and health care associated infections, while strains belonging to STs 393, 361 and 162 were associated with community acquired infections. The GyrA:S83L + D87N; ParC:S80I + E84V substitution pattern was found exclusively among ST131 ciprofloxacin-resistant E. coli. Extended-spectrum β-lactamase-positive ST131 ciprofloxacin-resistant isolates produced CTX-M-type enzymes; eight the CTX-M-15 and one the CTX-M-3 variant. CTX-M-1 like and KPC-2 enzymes were detected

  17. Existence and asymptotic estimates of periodic solutions of El Niño mechanism of atmospheric physics

    International Nuclear Information System (INIS)

    Xiao-Jing, Li

    2010-01-01

    This paper is devoted to studying the El Niño mechanism of atmospheric physics. The existence and asymptotic estimates of periodic solutions for its model are obtained by employing the technique of upper and lower solution, and using the continuation theorem of coincidence degree theory. (general)

  18. Characterization of multidrug‑resistant osteosarcoma sublines and the molecular mechanisms of resistance.

    Science.gov (United States)

    Yang, Jian-Zeng; Ma, Shu-Rong; Rong, Xiao-Li; Zhu, Mei-Ju; Ji, Qiu-Ye; Meng, Ling-Jie; Gao, Yi-Yao; Yang, Yu-Dan; Wang, Yan

    2016-10-01

    Multidrug resistance (MDR) is a challenge for the treatment of cancer and the underlying molecular mechanisms remain elusive. The current study exposed MG63 osteosarcoma cells to increasing concentrations of vincristine (VCR) to establish four VCR‑resistant MG63/VCR cell sublines (MG63/VCR1, 2, 3 and 4). The drug resistance indices (RI) of these sublines was detected with the CCK‑8 assay and determined to be163, 476, 1,247, and 2,707‑fold higher than that of parental cells, respectively. These sublines also exhibited cross‑resistance to doxorubicin, paclitaxel and pirarubicin. With increased RI, the proliferative capacity of these sublines was gradually reduced and cell morphology was also altered, characterized by increased formation of pseudopodia and long cytoplasmic processes at opposite poles. However, the migration capacity and expression of certain drug resistance‑associated genes were not in accordance with the increased RI; multidrug resistance protein 1 (MDR1) expression was significantly increased in these sublines compared with parental cells. However, in the highly resistant MG63/VCR3 and MG63/VCR4 cells, MDR‑associated protein 1, topoisomerase II and LIM domain kinase 1 levels were significantly reduced compared with the moderately resistant MG63/VCR2 cells. Expression of glutathione S‑transferase‑π mRNA was determined using reverse transcription‑quantitative polymerase chain reaction and determined that it was not changed between MG63 and MG63/VCR cells. The data of the present study demonstrated that the molecular alterations of drug resistance may change with the degree of drug resistance. Taking cell morphology into consideration, the intratumor clonal and phenotypic heterogeneity may be responsible for drug resistance. These MG63/VCR sublines may be a valuable tool to assess drug resistance and the underlying mechanisms, and to identify novel drug resistance‑associated genes or strategies to overcome MDR in human

  19. Studies on Acinetobacter baumannii involving multiple mechanisms of carbapenem resistance.

    Science.gov (United States)

    Sen, B; Joshi, S G

    2016-03-01

    Characterize the genetic type and resistance mechanisms of 16 carbapenem-resistant Acinetobacter baumannii (CRAB) isolates recovered between January 2010 and March 2011 from US tertiary-care hospital. A modified Hodge test demonstrated the presence of carbapenemases, but meropenem and ethylenediaminetetraacetic acid (EDTA) double-disc synergy tests and PCR for metallo-β-lactamase (MBL) genes were negative. The genes of ampC β-lactamase and efflux pump of adeABC and adeIJK were detected. The presence of oxacillinase (OXA)-like genes, blaOXA-51-like , blaOXA-23-like and blaOXA-40-like genes, and insertion sequence ISAba1 in promoter region of blaOXA-51-like and blaOXA-23-like genes were detected; and confirmed by RT-PCR analyses. The sequencing of blaOXA-51-like genes revealed two major alleles, blaOXA-66-like (blaOXA-82 ) and blaOXA-113 from 31·2 to 68·8% of isolates respectively. The blaOXA-23 and blaOXA-72 genes showed high expression and found co-harbouring blaOXA-51-like gene preceded by ISAba-1. All CRAB isolates revealed significant reduction in carO transcription, indicated downregulation of CarO porin system, a potentially independent mechanism of carbapenam resistance. Sequencing of carO gene from representative isolates showed no ISAba1 insertional inactivation. Pulsed-field gel electrophoresis revealed a clonal relationship. CRAB exhibited diversity of mechanisms of carbapenem resistance, and clonal relationship. Studies on distinct outbreaks of CRAB are alarming situation for clinicians. © 2015 The Society for Applied Microbiology.

  20. Antimicrobial Resistance of Hypervirulent Klebsiella pneumoniae: Epidemiology, Hypervirulence-Associated Determinants, and Resistance Mechanisms

    Directory of Open Access Journals (Sweden)

    Chang-Ro Lee

    2017-11-01

    Full Text Available Klebsiella pneumoniae is one of the most clinically relevant species in immunocompromised individuals responsible for community-acquired and nosocomial infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Since the mid-1980s, hypervirulent K. pneumoniae, generally associated with the hypermucoviscosity phenotype, has emerged as a clinically significant pathogen responsible for serious disseminated infections, such as pyogenic liver abscesses, osteomyelitis, and endophthalmitis, in a generally younger and healthier population. Hypervirulent K. pneumoniae infections were primarily found in East Asia and now are increasingly being reported worldwide. Although most hypervirulent K. pneumoniae isolates are antibiotic-susceptible, some isolates with combined virulence and resistance, such as the carbapenem-resistant hypervirulent K. pneumoniae isolates, are increasingly being detected. The combination of multidrug resistance and enhanced virulence has the potential to cause the next clinical crisis. To better understand the basic biology of hypervirulent K. pneumoniae, this review will provide a summarization and discussion focused on epidemiology, hypervirulence-associated factors, and antibiotic resistance mechanisms of such hypervirulent strains. Epidemiological analysis of recent clinical isolates in China warns the global dissemination of hypervirulent K. pneumoniae strains with extensive antibiotic resistance in the near future. Therefore, an immediate response to recognize the global dissemination of this hypervirulent strain with resistance determinants is an urgent priority.

  1. Antimicrobial Resistance of Hypervirulent Klebsiella pneumoniae: Epidemiology, Hypervirulence-Associated Determinants, and Resistance Mechanisms

    Science.gov (United States)

    Lee, Chang-Ro; Lee, Jung Hun; Park, Kwang Seung; Jeon, Jeong Ho; Kim, Young Bae; Cha, Chang-Jun; Jeong, Byeong Chul; Lee, Sang Hee

    2017-01-01

    Klebsiella pneumoniae is one of the most clinically relevant species in immunocompromised individuals responsible for community-acquired and nosocomial infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Since the mid-1980s, hypervirulent K. pneumoniae, generally associated with the hypermucoviscosity phenotype, has emerged as a clinically significant pathogen responsible for serious disseminated infections, such as pyogenic liver abscesses, osteomyelitis, and endophthalmitis, in a generally younger and healthier population. Hypervirulent K. pneumoniae infections were primarily found in East Asia and now are increasingly being reported worldwide. Although most hypervirulent K. pneumoniae isolates are antibiotic-susceptible, some isolates with combined virulence and resistance, such as the carbapenem-resistant hypervirulent K. pneumoniae isolates, are increasingly being detected. The combination of multidrug resistance and enhanced virulence has the potential to cause the next clinical crisis. To better understand the basic biology of hypervirulent K. pneumoniae, this review will provide a summarization and discussion focused on epidemiology, hypervirulence-associated factors, and antibiotic resistance mechanisms of such hypervirulent strains. Epidemiological analysis of recent clinical isolates in China warns the global dissemination of hypervirulent K. pneumoniae strains with extensive antibiotic resistance in the near future. Therefore, an immediate response to recognize the global dissemination of this hypervirulent strain with resistance determinants is an urgent priority. PMID:29209595

  2. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    Science.gov (United States)

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function.

  3. Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy

    Directory of Open Access Journals (Sweden)

    Mohamed El-Tanani

    2016-03-01

    Full Text Available Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1, and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review.

  4. Mechanisms Underlying the Antidepressant Response and Treatment Resistance

    Directory of Open Access Journals (Sweden)

    Marjorie Rose Levinstein

    2014-06-01

    Full Text Available Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance.

  5. [Ecology and mechanisms of bacterial resistance to antibiotics in peritonitis].

    Science.gov (United States)

    Edern, Anita; Fines-Guyon, Marguerite; Castrale, Cindy; Ficheux, Maxence; Ryckelynck, Jean-Philippe; Lobbedez, Thierry

    2012-11-01

    Peritonitis remains a common complication of peritoneal dialysis. The aim of our study is to describe the mechanisms of antibiotic resistance in bacteria isolated during peritonitis in peritoneal dialysis, to determine whether antibiotic therapy proposed by the International Society for Peritoneal Dialysis (ISPD) is adapted to the mechanisms of resistance. All causative microorganisms of peritonitis, isolated in 106 dialysis patients and reported 170 episodes of peritonitis, during the study period (01/01/2005 to 31/12/2010) were reviewed. According to the usual classification, twelve groups of microorganism were created. An interpretive reading of antibiograms was performed in each group to identify resistance phenotypes. The species most frequently isolated are coagulase-negative staphylococci (n=73) of which 46 had PBP2a (penicillin-binding protein). Many Enterobacteriaceae were also isolated (n=45), they are susceptible to third generation cephalosporins with the exception of Enterobacteriaceae producing an extended spectrum β-lactamase (ESBL) or a cephalosporinase. Except for staphylococci, probabilistic antibiotic therapy recommended by the ISPD to treat peritonitis is effective. Indeed, many staphylococci producing a PBP2a, a first-generation cephalosporin cannot be administered in all cases. It is therefore necessary to identify patients with a strain of staphylococcus producing a PBP2a, it must be treated by vancomycin. Copyright © 2012 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

  6. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  7. Molecular mechanism of free fatty acids-induced insulin resistance

    Directory of Open Access Journals (Sweden)

    Hui-zhe CAO

    2017-02-01

    Full Text Available Insulin resistance (IR is a complex metabolic disorder related to several diseases including type 2 diabetes (T2DM, hypertension and dyslipidemia. These diseases are all independent risk factors for cardiovascular disease. Lipid metabolism disorder has toxic effects on cells and may cause or aggravate IR in performance of elevated plasma levels of triglyceride (TG and free fatty acids (FFA, the last one is an independent risk factor for IR. It has been clear that FFA may induce IR by endoplasmic reticulum (ER stress, oxidative stress, apoptosis and inflammation, although the specific mechanisms remained unknown. The present paper summarizes the related molecules involved in the pathogenic process of IR and its mechanism, might provide a theoretical basis for the molecular mechanism of IR caused by FFA, and therapeutic reference for clinical treatment of IR and prevention of T2DM. DOI: 10.11855/j.issn.0577-7402.2017.01.16

  8. Mechanisms of resistance in nontyphoidal Salmonella enterica strains exhibiting a nonclassical quinolone resistance phenotype.

    Science.gov (United States)

    Gunell, Marianne; Webber, Mark A; Kotilainen, Pirkko; Lilly, Andrew J; Caddick, Jonathan M; Jalava, Jari; Huovinen, Pentti; Siitonen, Anja; Hakanen, Antti J; Piddock, Laura J V

    2009-09-01

    Nontyphoidal Salmonella enterica strains with a nonclassical quinolone resistance phenotype were isolated from patients returning from Thailand or Malaysia to Finland. A total of 10 isolates of seven serovars were studied in detail, all of which had reduced susceptibility (MIC > or = 0.125 microg/ml) to ciprofloxacin but were either susceptible or showed only low-level resistance (MIC resistance-determining regions (QRDR) of gyrA, gyrB, parC, and parE by PCR and denaturing high-pressure liquid chromatography and the amplification of plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, qnrS, qnrD, aac(6')-Ib-cr, and qepA by PCR. PMQR was confirmed by plasmid analysis, Southern hybridization, and plasmid transfer. No mutations in the QRDRs of gyrA, gyrB, parC, or parE were detected with the exception of a Thr57-Ser substitution within ParC seen in all but the S. enterica serovar Typhimurium strains. The qnrA and qnrS genes were the only PMQR determinants detected. Plasmids carrying qnr alleles were transferable in vitro, and the resistance phenotype was reproducible in Escherichia coli DH5alpha transformants. These data demonstrate the emergence of a highly mobile qnr genotype that, in the absence of mutation within topoisomerase genes, confers the nontypical quinolone resistance phenotype in S. enterica isolates. The qnr resistance mechanism enables bacteria to survive elevated quinolone concentrations, and therefore, strains carrying qnr alleles may be able to expand during fluoroquinolone treatment. This is of concern since nonclassical quinolone resistance is plasmid mediated and therefore mobilizable.

  9. Numerical simulation of high-temperature thermal contact resistance and its reduction mechanism

    Science.gov (United States)

    Zhang, Jing

    2018-01-01

    High-temperature thermal contact resistance (TCR) plays an important role in heat-pipe-cooled thermal protection structures due to the existence of contact interface between the embedded heat pipe and the heat resistive structure, and the reduction mechanism of thermal contact resistance is of special interests in the design of such structures. The present paper proposed a finite element model of the high-temperature thermal contact resistance based on the multi-point contact model with the consideration of temperature-dependent material properties, heat radiation through the cavities at the interface and the effect of thermal interface material (TIM), and the geometry parameters of the finite element model are determined by simple surface roughness test and experimental data fitting. The experimental results of high-temperature thermal contact resistance between superalloy GH600 and C/C composite material are employed to validate the present finite element model. The effect of the crucial parameters on the thermal contact resistance with and without TIM are also investigated with the proposed finite element model. PMID:29547651

  10. Mathematics anxiety and working memory: support for the existence of a deficient inhibition mechanism.

    Science.gov (United States)

    Hopko, D R; Ashcraft, M H; Gute, J; Ruggiero, K J; Lewis, C

    1998-01-01

    A current theory of anxiety effects in cognition claims that anxiety disrupts normal processing within the working memory system. We examined this theory in the context of a reading task, for participants who were high or low in assessed mathematics anxiety. The task was designed to measure the ability to inhibit attention to distracting information and the effects of this ability on explicit memory performance. The results suggested that math-anxious individuals have a deficient inhibition mechanism whereby working memory resources are consumed by task-irrelevant distracters. A consequence of this deficiency was that explicit memory performance was poorer for high-anxious individuals. Based on these results, the recommendation is made that Eysenck and Calvo's (1992) processing efficiency theory be integrated with Connelly, Hasher, and Zack's (1991) inhibition theory to portray more comprehensively the relation between anxiety and performance.

  11. On the existence of and mechanism for microwave-specific reaction rate enhancement.

    Science.gov (United States)

    Dudley, Gregory B; Richert, Ranko; Stiegman, A E

    2015-04-01

    The use of microwave radiation to drive chemical reactions has become ubiquitous in almost all fields of chemistry. In all of these areas it is principally due to rapid and convenient heating resulting in significantly higher rates of reaction, with other advantages including enhanced product selectivity and control of materials properties. Although microwave heating continues to grow as an enabling technology, fundamental research into the nature of microwave heating has not grown at the same rate. In the case of chemical reactions run in homogeneous solution, particularly synthetic organic reactions, there is considerable controversy over the origins of rate enhancement, with a fundamental question being whether there exist microwave-specific effects, distinct from what can be attained under conventional convective heating, that can accelerate a reaction rate. In this Perspective, we discuss unique aspects of microwave heating of molecules in solution and discuss the origin and nature of microwave-specific effects arising from the process of "selective heating" of reactants in solution. Integral to this discussion is work from the field of dielectric relaxation spectroscopy, which provides a model for selective heating by Debye relaxation processes. The Perspective also includes a critical discussion of hypotheses of non-thermal effects (alternatively classified here as resonant processes) and an outline of specific reaction parameters for chemical systems in which microwave-specific Debye relaxation processes can result in observable reaction rate enhancement.

  12. Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans

    Directory of Open Access Journals (Sweden)

    Teelucksingh Surujpal

    2012-03-01

    Full Text Available Abstract Background The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance. Results Using acanthosis nigricans (AN and skin vasoconstrictor (SVC response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32, with those without AN (n = 68 while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109 with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12. Findings In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P Conclusion An absent SVC response represents a new biomarker for the metabolic syndrome and the exaggerated inflammatory response, which characterizes the metabolic syndrome, may be an outcome of deficient glucocorticoid action in vascular tissue.

  13. Mycoplasma bovis: mechanisms of resistance and trends in antimicrobial susceptibility

    Directory of Open Access Journals (Sweden)

    Inna eLysnyansky

    2016-04-01

    Full Text Available Mycoplasma bovis is a cell-wall-less bacterium and belongs to the class Mollicutes. It is the most important etiological agent of bovine mycoplasmoses in North America and Europe, causing respiratory disease, mastitis, otitis media, arthritis, and reproductive disease. Clinical disease associated with M. bovis is often chronic, debilitating, and poorly responsive to antimicrobial therapy, resulting in significant economic loss, the full extent of which is difficult to estimate. Until M. bovis vaccines are universally available, sanitary control measures and antimicrobial treatment are the only approaches that can be used in attempts to control M. bovis infections. However, in vitro studies show that many of the current M. bovis isolates circulating in Europe have high minimum inhibitory concentrations (MIC for many of the commercially available antimicrobials. In this review we summarize the current MIC trends indicating the development of antimicrobial resistance in M. bovis as well as the known molecular mechanisms by which resistance is acquired.

  14. Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance.

    Science.gov (United States)

    Zeng, Daina; Debabov, Dmitri; Hartsell, Theresa L; Cano, Raul J; Adams, Stacy; Schuyler, Jessica A; McMillan, Ronald; Pace, John L

    2016-12-01

    The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  15. Mechanisms of reef coral resistance to future climate change.

    Science.gov (United States)

    Palumbi, Stephen R; Barshis, Daniel J; Traylor-Knowles, Nikki; Bay, Rachael A

    2014-05-23

    Reef corals are highly sensitive to heat, yet populations resistant to climate change have recently been identified. To determine the mechanisms of temperature tolerance, we reciprocally transplanted corals between reef sites experiencing distinct temperature regimes and tested subsequent physiological and gene expression profiles. Local acclimatization and fixed effects, such as adaptation, contributed about equally to heat tolerance and are reflected in patterns of gene expression. In less than 2 years, acclimatization achieves the same heat tolerance that we would expect from strong natural selection over many generations for these long-lived organisms. Our results show both short-term acclimatory and longer-term adaptive acquisition of climate resistance. Adding these adaptive abilities to ecosystem models is likely to slow predictions of demise for coral reef ecosystems. Copyright © 2014, American Association for the Advancement of Science.

  16. Mycoplasma bovis: Mechanisms of Resistance and Trends in Antimicrobial Susceptibility.

    Science.gov (United States)

    Lysnyansky, Inna; Ayling, Roger D

    2016-01-01

    Mycoplasma bovis is a cell-wall-less bacterium and belongs to the class Mollicutes. It is the most important etiological agent of bovine mycoplasmoses in North America and Europe, causing respiratory disease, mastitis, otitis media, arthritis, and reproductive disease. Clinical disease associated with M. bovis is often chronic, debilitating, and poorly responsive to antimicrobial therapy, resulting in significant economic loss, the full extent of which is difficult to estimate. Until M. bovis vaccines are universally available, sanitary control measures and antimicrobial treatment are the only approaches that can be used in attempts to control M. bovis infections. However, in vitro studies show that many of the current M. bovis isolates circulating in Europe have high minimum inhibitory concentrations (MIC) for many of the commercially available antimicrobials. In this review we summarize the current MIC trends indicating the development of antimicrobial resistance in M. bovis as well as the known molecular mechanisms by which resistance is acquired.

  17. Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms.

    Science.gov (United States)

    Viñuelas-Bayón, Jesús; Vitoria, María Asunción; Samper, Sofía

    2017-10-01

    Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment. Copyright © 2017 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  18. Mechanisms accounting for fluoroquinolone resistance in Escherichia coli clinical isolates.

    Science.gov (United States)

    Morgan-Linnell, Sonia K; Becnel Boyd, Lauren; Steffen, David; Zechiedrich, Lynn

    2009-01-01

    Fluoroquinolone MICs are increased through the acquisition of chromosomal mutations in the genes encoding gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE), increased levels of the multidrug efflux pump AcrAB, and the plasmid-borne genes aac(6')-Ib-cr and the qnr variants in Escherichia coli. In the accompanying report, we found that ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant E. coli clinical isolates were very high and widely varied (L. Becnel Boyd, M. J. Maynard, S. K. Morgan-Linnell, L. B. Horton, R. Sucgang, R. J. Hamill, J. Rojo Jimenez, J. Versalovic, D. Steffen, and L. Zechiedrich, Antimicrob. Agents Chemother. 53:229-234, 2009). Here, we sequenced gyrA, gyrB, parC, and parE; screened for aac(6')-Ib-cr and qnrA; and quantified AcrA levels in E. coli isolates for which patient sex, age, location, and site of infection were known. We found that (i) all fluoroquinolone-resistant isolates had gyrA mutations; (ii) approximately 85% of gyrA mutants also had parC mutations; (iii) the ciprofloxacin and norfloxacin MICs for isolates harboring aac(6')-Ib-cr ( approximately 23%) were significantly higher, but the gatifloxacin and levofloxacin MICs were not; (iv) no isolate had qnrA; and (v) approximately 33% of the fluoroquinolone-resistant isolates had increased AcrA levels. Increased AcrA correlated with nonsusceptibility to the fluoroquinolones but did not correlate with nonsusceptibility to any other antimicrobial agents reported from hospital antibiograms. Known mechanisms accounted for the fluoroquinolone MICs of 50 to 70% of the isolates; the remaining included isolates for which the MICs were up to 1,500-fold higher than expected. Thus, additional, unknown fluoroquinolone resistance mechanisms must be present in some clinical isolates.

  19. Mechanisms Accounting for Fluoroquinolone Resistance in Escherichia coli Clinical Isolates▿

    Science.gov (United States)

    Morgan-Linnell, Sonia K.; Becnel Boyd, Lauren; Steffen, David; Zechiedrich, Lynn

    2009-01-01

    Fluoroquinolone MICs are increased through the acquisition of chromosomal mutations in the genes encoding gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE), increased levels of the multidrug efflux pump AcrAB, and the plasmid-borne genes aac(6′)-Ib-cr and the qnr variants in Escherichia coli. In the accompanying report, we found that ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant E. coli clinical isolates were very high and widely varied (L. Becnel Boyd, M. J. Maynard, S. K. Morgan-Linnell, L. B. Horton, R. Sucgang, R. J. Hamill, J. Rojo Jimenez, J. Versalovic, D. Steffen, and L. Zechiedrich, Antimicrob. Agents Chemother. 53:229-234, 2009). Here, we sequenced gyrA, gyrB, parC, and parE; screened for aac(6′)-Ib-cr and qnrA; and quantified AcrA levels in E. coli isolates for which patient sex, age, location, and site of infection were known. We found that (i) all fluoroquinolone-resistant isolates had gyrA mutations; (ii) ∼85% of gyrA mutants also had parC mutations; (iii) the ciprofloxacin and norfloxacin MICs for isolates harboring aac(6′)-Ib-cr (∼23%) were significantly higher, but the gatifloxacin and levofloxacin MICs were not; (iv) no isolate had qnrA; and (v) ∼33% of the fluoroquinolone-resistant isolates had increased AcrA levels. Increased AcrA correlated with nonsusceptibility to the fluoroquinolones but did not correlate with nonsusceptibility to any other antimicrobial agents reported from hospital antibiograms. Known mechanisms accounted for the fluoroquinolone MICs of 50 to 70% of the isolates; the remaining included isolates for which the MICs were up to 1,500-fold higher than expected. Thus, additional, unknown fluoroquinolone resistance mechanisms must be present in some clinical isolates. PMID:18838592

  20. Nanoparticle mechanics: deformation detection via nanopore resistive pulse sensing

    Science.gov (United States)

    Darvish, Armin; Goyal, Gaurav; Aneja, Rachna; Sundaram, Ramalingam V. K.; Lee, Kidan; Ahn, Chi Won; Kim, Ki-Bum; Vlahovska, Petia M.; Kim, Min Jun

    2016-07-01

    Solid-state nanopores have been widely used in the past for single-particle analysis of nanoparticles, liposomes, exosomes and viruses. The shape of soft particles, particularly liposomes with a bilayer membrane, can greatly differ inside the nanopore compared to bulk solution as the electric field inside the nanopores can cause liposome electrodeformation. Such deformations can compromise size measurement and characterization of particles, but are often neglected in nanopore resistive pulse sensing. In this paper, we investigated the deformation of various liposomes inside nanopores. We observed a significant difference in resistive pulse characteristics between soft liposomes and rigid polystyrene nanoparticles especially at higher applied voltages. We used theoretical simulations to demonstrate that the difference can be explained by shape deformation of liposomes as they translocate through the nanopores. Comparing our results with the findings from electrodeformation experiments, we demonstrated that the rigidity of liposomes can be qualitatively compared using resistive pulse characteristics. This application of nanopores can provide new opportunities to study the mechanics at the nanoscale, to investigate properties of great value in fundamental biophysics and cellular mechanobiology, such as virus deformability and fusogenicity, and in applied sciences for designing novel drug/gene delivery systems.Solid-state nanopores have been widely used in the past for single-particle analysis of nanoparticles, liposomes, exosomes and viruses. The shape of soft particles, particularly liposomes with a bilayer membrane, can greatly differ inside the nanopore compared to bulk solution as the electric field inside the nanopores can cause liposome electrodeformation. Such deformations can compromise size measurement and characterization of particles, but are often neglected in nanopore resistive pulse sensing. In this paper, we investigated the deformation of various

  1. Antimicrobial Combinations against Pan-Resistant Acinetobacter baumannii Isolates with Different Resistance Mechanisms.

    Directory of Open Access Journals (Sweden)

    Gleice Cristina Leite

    Full Text Available The study investigated the effect of antibiotic combinations against 20 clinical isolates of A. baumannii (seven colistin-resistant and 13 colistin-susceptible with different resistance mechanisms. Clinical data, treatment, and patient mortality were evaluated. The following methods were used: MIC, PCRs, and outer membrane protein (OMP analysis. Synergy was investigated using the checkerboard and time-kill methods. Clonality was evaluated by PFGE. Based on clonality, the whole genome sequence of six A. baumannii isolates was analyzed. All isolates were resistant to meropenem, rifampicin, and fosfomycin. OXA-23 and OXA-143 were the most frequent carbapenemases found. Four isolates showed loss of a 43kDa OMP. The colistin-susceptible isolates belonged to different clones and showed the highest synergistic effect with fosfomycin-amikacin. Among colistin-resistant isolates, the highest synergistic effect was observed with the combinations of colistin-rifampicin followed by colistin-vancomycin. All colistin-resistant isolates harbored blaOXA-23-like and belonged to CC113. Clinical and demographic data were available for 18 of 20 patients. Fourteen received treatment and eight patients died during treatment. The most frequent site of infection was the blood in 13 of 14 patients. Seven patients received vancomycin plus an active drug against A. baumannii; however, mortality did not differ in this group. The synergistic effect was similar for colistin-susceptible isolates of distinct clonal origin presenting with the same resistance mechanism. Overall mortality and death during treatment was high, and despite the high synergism in vitro with vancomycin, death did not differ comparing the use or not of vancomycin plus an active drug against A. baumannii.

  2. Corrosion resistance of zirconium: general mechanisms, behaviour in nitric acid

    International Nuclear Information System (INIS)

    Pinard Legry, G.

    1990-01-01

    Corrosion resistance of zirconium results from the strong affinity of this metal for oxygen; as a result a thin protective oxide film is spontaneously formed in air or aqueous media, its thickness and properties depending on the physicochemical conditions at the interface. This film passivates the underlying metal but obviously if the passive film is partially or completely removed, localised or generalised corrosion phenomena will occur. In nitric acid, this depassivation may be chemical (fluorides) or mechanical (straining, creep, fretting). In these cases it is useful to determine the physicochemical conditions (concentration, temperature, potential, stress) which will have to be observed to use safely zirconium and its alloys in nitric acid solutions [fr

  3. Indoor air quality in mechanically ventilated residential dwellings/low-rise buildings: A review of existing information

    DEFF Research Database (Denmark)

    Aganovic, Amar; Hamon, Mathieu; Kolarik, Jakub

    Mechanical ventilation has become a mandatory requirement in multiple European standards addressing indoor air quality (IAQ) and ventilation in residential dwellings (single family houses and low-rise apartment buildings). This article presents the state of the art study through a review...... of the existing literature, to establish a link between ventilation rate and key indoor air pollutants. Design characteristics of a mechanical ventilation system such as supply/exhaustairflow, system and design of supply and exhaust outlets were considered. The performance of various ventilation solutionswas......-house ventilation rate was reported below 0.5h-1 or 14 l/s·person in bedrooms, the concentrations of the pollutants elevated above minimum threshold limits (CO2>1350 ppm; TVOC >3000 μg/m3) defined by the standard. Insufficient or non-existent supply of air was related to significantly higher pollutant...

  4. Implementation of partnership management model of SMK (Vocational High School) with existing industries in mechanical engineering expertise in Central Java

    Science.gov (United States)

    Sumbodo, Wirawan; Pardjono, Samsudi, Rahadjo, Winarno Dwi

    2018-03-01

    This study aims to determine the existing conditions of implementation of partnership management model of SMK with the industry on the mechanical engineering expertise in Central Java. The method used is descriptive analysis. The research result shows that the implementation of partnership management model of SMK based on new existing industry produces ready graduates of 62.5% which belongs to low category, although the partnership program of SMK with the industry is done well with the average score of 3.17. As many as 37.5% of SMK graduates of Mechanical Engineering Expertise Program choose to continue their studies or to be an entrepreneur. It is expected that the partnership model of SMK with the industry can be developed into a reference for government policy in developing SMK that is able to produce graduates who are ready to work according to the needs of partner industry.

  5. Mechanism of corrosion resistance for C + W dual implanted steel

    International Nuclear Information System (INIS)

    Zhang Tonghe; Wu Yuguang; Liu Andong; Zhang Xu; Wang Xiaoyan

    2003-01-01

    The properties of corrosion resistance for C and W dual-implanted H13 steel were studied using multi-sweep cyclic voltammetry. The corrosion morphologies were investigated by scanning electron microscopy (SEM). The results show that after corrosion for 30 voltage scanning-loops, serious corrosion morphology appears on the surface of H13 steel: dense corrosion pits are distributed on the surface. Both shape and distribution morphology of these pits indicate the crystal properties: some pits are triangle or rectangle, and the pits are located along grain boundaries. But after corrosion of the W and C dual implanted steel samples, surface corrosion pits are shallow and small. Shallow corrosion pits are dislocated random, their shape and distribution are not provided with crystal properties. When the fluence is increased and after corrosion for 88 voltage scanning-loops, the surface corrosion pits are still shallow and small, showing the corrosion resistance to be enhanced further. Finally the mechanism of corrosion resistance was discussed

  6. Mechanisms of Brain Glucocorticoid Resistance in Stress-Induced Psychopathologies.

    Science.gov (United States)

    Merkulov, V M; Merkulova, T I; Bondar, N P

    2017-03-01

    Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stress- and GR-induced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.

  7. The molecular mechanism linking muscle fat accumulation to insulin resistance.

    Science.gov (United States)

    Hulver, Matthew W; Dohm, G Lynis

    2004-05-01

    Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.

  8. Resistance to coumaphos and diazinon in Boophilus microplus (Acari: Ixodidae) and evidence for the involvement of an oxidative detoxification mechanism.

    Science.gov (United States)

    Li, Andrew Y; Davey, Ronald B; Miller, Robert J; George, John E

    2003-07-01

    The levels of resistance to two organophosphate acaricides, coumaphos and diazinon, in several Mexican strains of Boophilus microplus (Canestrini) were evaluated using the FAO larval packet test. Regression analysis of LC50 data revealed a significant cross-resistance pattern between those two acaricides. Metabolic mechanisms of resistance were investigated with synergist bioassays. Piperonyl butoxide (PBO) reduced coumaphos toxicity in susceptible strains, but synergized coumaphos toxicity in resistant strains. There was a significant correlation between PBO synergism ratios and the coumaphos resistance ratios. The results suggest that an enhanced cytochrome P450 monooxygenase (cytP450)-mediated detoxification mechanism may exist in the resistant strains, in addition to the cytP450-mediated metabolic pathway that activates coumaphos. PBO failed to synergize diazinon toxicity in resistant strains, suggesting the cytP450 involved in detoxification were specific. Triphenylphosphate (TPP) synergized toxicity of both acaricides in both susceptible and resistant strains, and there was no correlation between TPP synergism ratios and the LC50 estimates for either acaricide. Esterases may not play a major role in resistance to coumaphos and diazinon in those strains. Bioassays with diethyl maleate (DEM) revealed a significant correlation between DEM synergism ratios and LC50 estimates for diazinon, suggesting a possible role for glutathione S-transferases in diazinon detoxification. Resistance to coumaphos in the Mexican strains of B. microplus was likely to be conferred by both a cytP450-mediated detoxification mechanism described here and the mechanism of insensitive acetylcholinesterases reported elsewhere. The results of this study also underscore the potential risk of coumaphos resistance in B. microplus from Mexico to the U.S. cattle fever tick eradication program.

  9. Systemic acquired resistance in moss: further evidence for conserved defense mechanisms in plants.

    Science.gov (United States)

    Winter, Peter S; Bowman, Collin E; Villani, Philip J; Dolan, Thomas E; Hauck, Nathanael R

    2014-01-01

    Vascular plants possess multiple mechanisms for defending themselves against pathogens. One well-characterized defense mechanism is systemic acquired resistance (SAR). In SAR, a plant detects the presence of a pathogen and transmits a signal throughout the plant, inducing changes in the expression of various pathogenesis-related (PR) genes. Once SAR is established, the plant is capable of mounting rapid responses to subsequent pathogen attacks. SAR has been characterized in numerous angiosperm and gymnosperm species; however, despite several pieces of evidence suggesting SAR may also exist in non-vascular plants6-8, its presence in non-vascular plants has not been conclusively demonstrated, in part due to the lack of an appropriate culture system. Here, we describe and use a novel culture system to demonstrate that the moss species Amblystegium serpens does initiate a SAR-like reaction upon inoculation with Pythium irregulare, a common soil-borne oomycete. Infection of A. serpens gametophores by P. irregulare is characterized by localized cytoplasmic shrinkage within 34 h and chlorosis and necrosis within 7 d of inoculation. Within 24 h of a primary inoculation (induction), moss gametophores grown in culture became highly resistant to infection following subsequent inoculation (challenge) by the same pathogen. This increased resistance was a response to the pathogen itself and not to physical wounding. Treatment with β-1,3 glucan, a structural component of oomycete cell walls, was equally effective at triggering SAR. Our results demonstrate, for the first time, that this important defense mechanism exists in a non-vascular plant, and, together with previous studies, suggest that SAR arose prior to the divergence of vascular and non-vascular plants. In addition, this novel moss - pathogen culture system will be valuable for future characterization of the mechanism of SAR in moss, which is necessary for a better understanding of the evolutionary history of SAR in

  10. Systemic acquired resistance in moss: further evidence for conserved defense mechanisms in plants.

    Directory of Open Access Journals (Sweden)

    Peter S Winter

    Full Text Available Vascular plants possess multiple mechanisms for defending themselves against pathogens. One well-characterized defense mechanism is systemic acquired resistance (SAR. In SAR, a plant detects the presence of a pathogen and transmits a signal throughout the plant, inducing changes in the expression of various pathogenesis-related (PR genes. Once SAR is established, the plant is capable of mounting rapid responses to subsequent pathogen attacks. SAR has been characterized in numerous angiosperm and gymnosperm species; however, despite several pieces of evidence suggesting SAR may also exist in non-vascular plants6-8, its presence in non-vascular plants has not been conclusively demonstrated, in part due to the lack of an appropriate culture system. Here, we describe and use a novel culture system to demonstrate that the moss species Amblystegium serpens does initiate a SAR-like reaction upon inoculation with Pythium irregulare, a common soil-borne oomycete. Infection of A. serpens gametophores by P. irregulare is characterized by localized cytoplasmic shrinkage within 34 h and chlorosis and necrosis within 7 d of inoculation. Within 24 h of a primary inoculation (induction, moss gametophores grown in culture became highly resistant to infection following subsequent inoculation (challenge by the same pathogen. This increased resistance was a response to the pathogen itself and not to physical wounding. Treatment with β-1,3 glucan, a structural component of oomycete cell walls, was equally effective at triggering SAR. Our results demonstrate, for the first time, that this important defense mechanism exists in a non-vascular plant, and, together with previous studies, suggest that SAR arose prior to the divergence of vascular and non-vascular plants. In addition, this novel moss - pathogen culture system will be valuable for future characterization of the mechanism of SAR in moss, which is necessary for a better understanding of the evolutionary

  11. New And Existing Bridge Constructions - Increase of Fatigue Strength of Welded Joints by High Frequency Mechanical Impact Treatment

    Directory of Open Access Journals (Sweden)

    Ummenhofer Thomas

    2013-07-01

    Full Text Available Numerous studies at KIT prove that high frequency mechanical impact (HFMI treatment is an efficient method for increasing the fatigue strength of welded steel structures. Within different research projects it was found that HFMI-methods can be used successfully for new and existing structures in order to extend the fatigue life. This paper gives an overview of the current status of existing steel bridges in Germany regarding aspects like bridge age distributions and traffic loads. Based on that overview welded joints susceptible to fatigue failure are identified. Using component-like small scale specimens, HFMI-methods were investigated within the objective of implementing an effective application for new and existing structures. Applying the fatigue test data observed, existing design proposals are evaluated and design recommendations for HFMI-treated joints are given. As a result of the research work, a transfer into practice has been realized and different applications are illustrated using the example of bridge constructions made of steel.

  12. Mechanisms of virus resistance and antiviral activity of snake venoms

    Directory of Open Access Journals (Sweden)

    JVR Rivero

    2011-01-01

    Full Text Available Viruses depend on cell metabolism for their own propagation. The need to foster an intimate relationship with the host has resulted in the development of various strategies designed to help virus escape from the defense mechanisms present in the host. Over millions of years, the unremitting battle between pathogens and their hosts has led to changes in evolution of the immune system. Snake venoms are biological resources that have antiviral activity, hence substances of significant pharmacological value. The biodiversity in Brazil with respect to snakes is one of the richest on the planet; nevertheless, studies on the antiviral activity of venom from Brazilian snakes are scarce. The antiviral properties of snake venom appear as new promising therapeutic alternative against the defense mechanisms developed by viruses. In the current study, scientific papers published in recent years on the antiviral activity of venom from various species of snakes were reviewed. The objective of this review is to discuss the mechanisms of resistance developed by viruses and the components of snake venoms that present antiviral activity, particularly, enzymes, amino acids, peptides and proteins.

  13. Mechanisms of Metal Resistance and Homeostasis in Haloarchaea

    Science.gov (United States)

    Srivastava, Pallavee; Kowshik, Meenal

    2013-01-01

    Haloarchaea are the predominant microflora of hypersaline econiches such as solar salterns, soda lakes, and estuaries where the salinity ranges from 35 to 400 ppt. Econiches like estuaries and solar crystallizer ponds may contain high concentrations of metals since they serve as ecological sinks for metal pollution and also as effective traps for river borne metals. The availability of metals in these econiches is determined by the type of metal complexes formed and the solubility of the metal species at such high salinity. Haloarchaea have developed specialized mechanisms for the uptake of metals required for various key physiological processes and are not readily available at high salinity, beside evolving resistance mechanisms for metals with high solubility. The present paper seeks to give an overview of the main molecular mechanisms involved in metal tolerance in haloarchaea and focuses on factors such as salinity and metal speciation that affect the bioavailability of metals to haloarchaea. Global transcriptomic analysis during metal stress in these organisms will help in determining the various factors differentially regulated and essential for metal physiology. PMID:23533331

  14. Mechanisms of metal resistance and homeostasis in haloarchaea.

    Science.gov (United States)

    Srivastava, Pallavee; Kowshik, Meenal

    2013-01-01

    Haloarchaea are the predominant microflora of hypersaline econiches such as solar salterns, soda lakes, and estuaries where the salinity ranges from 35 to 400 ppt. Econiches like estuaries and solar crystallizer ponds may contain high concentrations of metals since they serve as ecological sinks for metal pollution and also as effective traps for river borne metals. The availability of metals in these econiches is determined by the type of metal complexes formed and the solubility of the metal species at such high salinity. Haloarchaea have developed specialized mechanisms for the uptake of metals required for various key physiological processes and are not readily available at high salinity, beside evolving resistance mechanisms for metals with high solubility. The present paper seeks to give an overview of the main molecular mechanisms involved in metal tolerance in haloarchaea and focuses on factors such as salinity and metal speciation that affect the bioavailability of metals to haloarchaea. Global transcriptomic analysis during metal stress in these organisms will help in determining the various factors differentially regulated and essential for metal physiology.

  15. Mechanisms of Metal Resistance and Homeostasis in Haloarchaea

    Directory of Open Access Journals (Sweden)

    Pallavee Srivastava

    2013-01-01

    Full Text Available Haloarchaea are the predominant microflora of hypersaline econiches such as solar salterns, soda lakes, and estuaries where the salinity ranges from 35 to 400 ppt. Econiches like estuaries and solar crystallizer ponds may contain high concentrations of metals since they serve as ecological sinks for metal pollution and also as effective traps for river borne metals. The availability of metals in these econiches is determined by the type of metal complexes formed and the solubility of the metal species at such high salinity. Haloarchaea have developed specialized mechanisms for the uptake of metals required for various key physiological processes and are not readily available at high salinity, beside evolving resistance mechanisms for metals with high solubility. The present paper seeks to give an overview of the main molecular mechanisms involved in metal tolerance in haloarchaea and focuses on factors such as salinity and metal speciation that affect the bioavailability of metals to haloarchaea. Global transcriptomic analysis during metal stress in these organisms will help in determining the various factors differentially regulated and essential for metal physiology.

  16. Activity of ceftazidime-avibactam against multidrug-resistance Enterobacteriaceae expressing combined mechanisms of resistance.

    Science.gov (United States)

    López-Hernández, Inmaculada; Alonso, Noemí; Fernández-Martínez, Marta; Zamorano, Laura; Rivera, Alba; Oliver, Antonio; Conejo, M Carmen; Martínez-Martínez, Luis; Navarro, Ferrán; Pascual, Alvaro

    2017-10-01

    Antimicrobial resistance in Enterobacteriaceae is increasing worldwide and is making treating infections caused by multidrug-resistant Enterobacteriaceae a challenge. The use of β-lactam agents is compromised by microorganisms harboring extended-spectrum β-lactamases (ESBLs) and other mechanisms of resistance. Avibactam is a non β-lactam agent that inhibits clinically relevant β-lactamases, such as ESBL and AmpC. The ceftazidime-avibactam combination (CAZ-AVI) was recently approved for use in certain complicated infections, and may provide a therapeutic alternative for infections caused by these microorganisms. The in vitro activity of CAZ and CAZ-AVI (AVI at a fixed concentration of 4mg/L) was tested against 250 clinical isolates of Enterobacteriaceae using broth microdilution. EUCAST breakpoint criteria were used for CAZ, and FDA criteria for CAZ-AVI. Clinical isolates included bacteria producing extended-spectrum β-lactamases (ESBLs) and acquired AmpC β-lactamases (AACBLs). Porin loss in Klebsiella pneumoniae was also evaluated. The combination of AVI with CAZ displayed excellent activity against clinical isolates of ESBL-producing Escherichia coli and Klebsiella pneumoniae, rendering all the ceftazidime-resistant isolates susceptible to ceftazidime. CAZ-AVI retained activity against porin-deficient isolates of K. pneumoniae producing ESBLs, AACBLs, or both, although MIC values were higher compared to porin-expressing isolates. CAZ-AVI rendered all the ceftazidime-resistant AACBL-producing Enterobacteriaceae tested susceptible to ceftazidime. CAZ-AVI showed potent in vitro activity against clinical isolates of Enterobacteriaceae producing ESBLs and/or AACBLs, including K. pneumoniae with loss of porins. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  17. Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms.

    Science.gov (United States)

    Tacão, Marta; Correia, António; Henriques, Isabel S

    2015-10-01

    Carbapenems are last-resort antibiotics to handle serious infections caused by multiresistant bacteria. The incidence of resistance to these antibiotics has been increasing and new resistance mechanisms have emerged. The dissemination of carbapenem resistance in the environment has been overlooked. The main goal of this research was to assess the prevalence and diversity of carbapenem-resistant bacteria in riverine ecosystems. The presence of frequently reported carbapenemase-encoding genes was inspected. The proportion of imipenem-resistant bacteria was on average 2.24 CFU/ml. Imipenem-resistant strains (n=110) were identified as Pseudomonas spp., Stenotrophomonas maltophilia, Aeromonas spp., Chromobacterium haemolyticum, Shewanella xiamenensis, and members of Enterobacteriaceae. Carbapenem-resistant bacteria were highly resistant to other beta-lactams such as quinolones, aminoglycosides, chloramphenicol, tetracyclines, and sulfamethoxazole/trimethoprim. Carbapenem resistance was mostly associated with intrinsically resistant bacteria. As intrinsic resistance mechanisms, we have identified the blaCphA gene in 77.3% of Aeromonas spp., blaL1 in all S. maltophilia, and blaOXA-48-like in all S. xiamenensis. As acquired resistance mechanisms, we have detected the blaVIM-2 gene in six Pseudomonas spp. (5.45%). Integrons with gene cassettes encoding resistance to aminoglycosides (aacA and aacC genes), trimethoprim (dfrB1b), and carbapenems (blaVIM-2) were found in Pseudomonas spp. Results suggest that carbapenem resistance dissemination in riverine ecosystems is still at an early stage. Nevertheless, monitoring these aquatic compartments for the presence of resistance genes and its host organisms is essential to outline strategies to minimize resistance dissemination.

  18. Life cycle synchronization is a viral drug resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Iulia A Neagu

    2018-02-01

    Full Text Available Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for

  19. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies.

    Science.gov (United States)

    Murray, S; Briasoulis, E; Linardou, H; Bafaloukos, D; Papadimitriou, C

    2012-11-01

    Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most

  20. Wear resistance and fracture mechanics of WC-Co composites

    Energy Technology Data Exchange (ETDEWEB)

    Kaytbay, Saleh [Benha Univ. (Egypt). Dept. of Mechanical Engineering; El-Hadek, Medhat [Port-Said Univ. (Egypt). Dept. of Production and Mechanical Design

    2014-06-15

    Manufacturing of WC-Co composites using the electroless precipitation method at different sintering temperatures of 1 100, 1 250, 1 350 and 1 500 C was successfully achieved. The chemical composition of the investigated materials was 90 wt.% WC with 10 wt.% Co, and 80 wt.% WC with 20 wt.% Co. The specific density, densification, and Vickers microhardness measurements were found to increase with increased sintering temperature for both the WC-Co compositions. The composites of tungsten carbide with 10 wt.% Co had a higher specific density and Vickers microhardness measurements than those for the composites of tungsten carbide with 20 wt.% Co. Composites with WC-10 wt.% Co had better wear resistance. The stress-strain and transverse rupture strength increased monotonically with the increase in sintering temperatures, agreeing with the material hardness and wear resistance behavior. Fractographical scanning electron microscopy analysis of the fracture surface demonstrated a rough characteristic conical shape failure in the direction of the maximum shear stress. A proposed mechanism for the formation of the conical fracture surface under compression testing is presented. (orig.)

  1. Fas ligand exists on intervertebral disc cells: a potential molecular mechanism for immune privilege of the disc.

    Science.gov (United States)

    Takada, Toru; Nishida, Kotaro; Doita, Minoru; Kurosaka, Masahiro

    2002-07-15

    Rat and human intervertebral disc specimens were examined immunohistochemically. Reverse transcription polymerase chain reaction (RT-PCR) analysis was also performed on rat disc tissue to demonstrate the existence of Fas ligand. To clarify the existence of Fas ligand on intact intervertebral disc cells. The nucleus pulposus has been reported to be an immune-privileged site. The immune-privileged characteristic in other tissues such as the retina and testis has been attributed to the local expression of Fas ligand, which acts by inducing apoptosis of invading Fas-positive T-cells. The existence of Fas ligand in normal disc cells has not yet been addressed. Skeletally mature SD male rats were killed, and the coccygeal discs were harvested. Human disc specimens were obtained from idiopathic scoliosis patients during surgical procedures. Immunohistochemical staining for Fas ligand was performed for cross-sections of the discs by standard procedures. Reverse transcription polymerase chain reaction analysis was also carried out to demonstrate Fas ligand mRNA expression on rat intervertebral discs. Testes of the rats were used for positive controls, and muscles were used for negative controls. The sections were observed by light microscopy. The nucleus pulposus cells exhibited intense positive immune staining for Fas ligand. The outer anulus fibrosus cells and notochordal cells exhibited little immunopositivity. The positive controls exhibited positive immune staining, and the negative control showed no immunopositivity. The result of RT-PCR confirmed the existence of Fas ligand in disc cells. The human nucleus pulposus cells showed a similar predilection to rat disc cells. We demonstrated the existence of Fas ligand on disc cells, which should play a key role in the potential molecular mechanism to maintain immune privilege of the disc. Immune privilege and Fas ligand expression of the intervertebral disc may provide a new insight for basic science research as well as

  2. Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors.

    Science.gov (United States)

    Willers, Clarissa; Wentzel, Johannes Frederik; du Plessis, Lissinda Hester; Gouws, Chrisna; Hamman, Josias Hendrik

    2017-01-01

    Microbial resistance against antibiotics is a serious threat to the effective treatment of infectious diseases. Several mechanisms exist through which microorganisms can develop resistance against antimicrobial drugs, of which the overexpression of genes to produce efflux pumps is a major concern. Several efflux transporters have been identified in microorganisms, which infer resistance against specific antibiotics and even multidrug resistance. Areas covered: This paper focuses on microbial resistance against antibiotics by means of the mechanism of efflux and gives a critical overview of studies conducted to overcome this problem by combining efflux pump inhibitors with antibiotics. Information was obtained from a literature search done with MEDLINE, Pubmed, Scopus, ScienceDirect, OneSearch and EBSCO host. Expert opinion: Efflux as a mechanism of multidrug resistance has presented a platform for improved efficacy against resistant microorganisms by co-administration of efflux pump inhibitors with antimicrobial agents. Although proof of concept has been shown for this approach with in vitro experiments, further research is needed to develop more potent inhibitors with low toxicity which is clinically effective.

  3. Resistance to Bacillus thuringiensis Toxin Cry2Ab in Trichoplusia ni Is Conferred by a Novel Genetic Mechanism

    Science.gov (United States)

    Song, Xiaozhao; Kain, Wendy; Cassidy, Douglas

    2015-01-01

    The resistance to the Bacillus thuringiensis (Bt) toxin Cry2Ab in a greenhouse-originated Trichoplusia ni strain resistant to both Bt toxins Cry1Ac and Cry2Ab was characterized. Biological assays determined that the Cry2Ab resistance in the T. ni strain was a monogenic recessive trait independent of Cry1Ac resistance, and there existed no significant cross-resistance between Cry1Ac and Cry2Ab in T. ni. From the dual-toxin-resistant T. ni strain, a strain resistant to Cry2Ab only was isolated, and the Cry2Ab resistance trait was introgressed into a susceptible laboratory strain to facilitate comparative analysis of the Cry2Ab resistance with the susceptible T. ni strain. Results from biochemical analysis showed no significant difference between the Cry2Ab-resistant and -susceptible T. ni larvae in midgut proteases, including caseinolytic proteolytic activity and zymogram profile and serine protease activities, in midgut aminopeptidase and alkaline phosphatase activity, and in midgut esterases and hemolymph plasma melanization activity. For analysis of genetic linkage of Cry2Ab resistance with potential Cry toxin receptor genes, molecular markers for the midgut cadherin, alkaline phosphatase (ALP), and aminopeptidase N (APN) genes were identified between the original greenhouse-derived dual-toxin-resistant and the susceptible laboratory T. ni strains. Genetic linkage analysis showed that the Cry2Ab resistance in T. ni was not genetically associated with the midgut genes coding for the cadherin, ALP, and 6 APNs (APN1 to APN6) nor associated with the ABC transporter gene ABCC2. Therefore, the Cry2Ab resistance in T. ni is conferred by a novel but unknown genetic mechanism. PMID:26025894

  4. Mutational and acquired carbapenem resistance mechanisms in multidrug resistant Pseudomonas aeruginosa clinical isolates from Recife, Brazil.

    Science.gov (United States)

    Cavalcanti, Felipe Lira de Sá; Mirones, Cristina Rodríguez; Paucar, Elena Román; Montes, Laura Álvarez; Leal-Balbino, Tereza Cristina; Morais, Marcia Maria Camargo de; Martínez-Martínez, Luis; Ocampo-Sosa, Alain Antonio

    2015-12-01

    An investigation was carried out into the genetic mechanisms responsible for multidrug resistance in nine carbapenem-resistant Pseudomonas aeruginosa isolates from different hospitals in Recife, Brazil. Susceptibility to antimicrobial agents was determined by broth microdilution. Polymerase chain reaction (PCR) was employed to detect the presence of genes encoding β-lactamases, aminoglycoside-modifying enzymes (AMEs), 16S rRNA methylases, integron-related genes and OprD. Expression of genes coding for efflux pumps and AmpC cephalosporinase were assessed by quantitative PCR. The outer membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The blaSPM-1, blaKPC-2 and blaGES-1 genes were detected in P. aeruginosa isolates in addition to different AME genes. The loss of OprD in nine isolates was mainly due to frameshift mutations, premature stop codons and point mutations. An association of loss of OprD with the overexpression of MexAB-OprM and MexXY-OprM was observed in most isolates. Hyper-production of AmpC was also observed in three isolates. Clonal relationship of the isolates was determined by repetitive element palindromic-PCR and multilocus sequence typing. Our results show that the loss of OprD along with overexpression of efflux pumps and β-lactamase production were responsible for the multidrug resistance in the isolates analysed.

  5. Mechanisms of resistance and cross-resistance to agrochemicals in the fairy shrimp Thamnocephalus platyurus (Crustacea: Anostraca).

    Science.gov (United States)

    Brausch, John M; Smith, Philip N

    2009-05-05

    Extensive pesticide usage in the Southern High Plains has led to the development of resistance in many pest species, as well as some non-target organisms. Thamnocephalus platyurus derived from agriculturally impacted watersheds are between two and three times less sensitive to commonly applied agrochemicals than T. platyurus from native grassland watersheds. Biological mechanisms that convey such resistance are currently unknown. This study identified the contribution of metabolic enzymes to T. platyurus pesticide resistance using the synergists piperonyl butoxide (PBO) and S,S,S-tributyl phosphorotrithioate (DEF) to inhibit cytochrome P450s or hydrolases, respectively. Inhibition of cytochrome P450s and hydrolases partially restored cyfluthrin and DDT sensitivity in T. platyurus, suggesting other resistance inferring mechanism(s) were also involved. However, inhibition of hydrolases with DEF completely restored methyl parathion sensitivity in pesticide resistant T. platyurus. DDT resistance paralleled cyfluthrin resistance, but did not for methyl parathion resistance. These data suggest that the primary mechanism for the development of resistance to agrochemicals in T. platyurus is due to increased metabolic detoxification.

  6. Biochemical Mechanism of HIV-1 Resistance to Rilpivirine*

    Science.gov (United States)

    Singh, Kamalendra; Marchand, Bruno; Rai, Devendra K.; Sharma, Bechan; Michailidis, Eleftherios; Ryan, Emily M.; Matzek, Kayla B.; Leslie, Maxwell D.; Hagedorn, Ariel N.; Li, Zhe; Norden, Pieter R.; Hachiya, Atsuko; Parniak, Michael A.; Xu, Hong-Tao; Wainberg, Mark A.; Sarafianos, Stefan G.

    2012-01-01

    Rilpivirine (RPV) is a second generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) that efficiently inhibits HIV-1 resistant to first generation NNRTIs. Virological failure during therapy with RPV and emtricitabine is associated with the appearance of E138K and M184I mutations in RT. Here we investigate the biochemical mechanism of RT inhibition and resistance to RPV. We used two transient kinetics approaches (quench-flow and stopped-flow) to determine how subunit-specific mutations in RT p66 or p51 affect association and dissociation of RPV to RT as well as their impact on binding of dNTP and DNA and the catalytic incorporation of nucleotide. We compared WT with four subunit-specific RT mutants, p66M184I/p51WT, p66E138K/p51E138K, p66E138K/M184I/p51E138K, and p66M184I/p51E138K. Ile-184 in p66 (p66184I) decreased the catalytic efficiency of RT (kpol/Kd.dNTP), primarily through a decrease in dNTP binding (Kd.dNTP). Lys-138 either in both subunits or in p51 alone abrogated the negative effect of p66184I by restoring dNTP binding. Furthermore, p51138K reduced RPV susceptibility by altering the ratio of RPV dissociation to RPV association, resulting in a net reduction in RPV equilibrium binding affinity (Kd.RPV = koff.RPV/kon.RPV). Quantum mechanics/molecular mechanics hybrid molecular modeling revealed that p51E138K affects access to the RPV binding site by disrupting the salt bridge between p51E138 and p66K101. p66184I caused repositioning of the Tyr-183 active site residue and decreased the efficiency of RT, whereas the addition of p51138K restored Tyr-183 to a WT-like conformation, thus abrogating the Ile-184-induced functional defects. PMID:22955279

  7. Biochemical mechanism of HIV-1 resistance to rilpivirine.

    Science.gov (United States)

    Singh, Kamalendra; Marchand, Bruno; Rai, Devendra K; Sharma, Bechan; Michailidis, Eleftherios; Ryan, Emily M; Matzek, Kayla B; Leslie, Maxwell D; Hagedorn, Ariel N; Li, Zhe; Norden, Pieter R; Hachiya, Atsuko; Parniak, Michael A; Xu, Hong-Tao; Wainberg, Mark A; Sarafianos, Stefan G

    2012-11-02

    Rilpivirine (RPV) is a second generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) that efficiently inhibits HIV-1 resistant to first generation NNRTIs. Virological failure during therapy with RPV and emtricitabine is associated with the appearance of E138K and M184I mutations in RT. Here we investigate the biochemical mechanism of RT inhibition and resistance to RPV. We used two transient kinetics approaches (quench-flow and stopped-flow) to determine how subunit-specific mutations in RT p66 or p51 affect association and dissociation of RPV to RT as well as their impact on binding of dNTP and DNA and the catalytic incorporation of nucleotide. We compared WT with four subunit-specific RT mutants, p66(M184I)/p51(WT), p66(E138K)/p51(E138K), p66(E138K/M184I)/p51(E138K), and p66(M184I)/p51(E138K). Ile-184 in p66 (p66(184I)) decreased the catalytic efficiency of RT (k(pol)/K(d)(.dNTP)), primarily through a decrease in dNTP binding (K(d)(.dNTP)). Lys-138 either in both subunits or in p51 alone abrogated the negative effect of p66(184I) by restoring dNTP binding. Furthermore, p51(138K) reduced RPV susceptibility by altering the ratio of RPV dissociation to RPV association, resulting in a net reduction in RPV equilibrium binding affinity (K(d)(.RPV) = k(off.RPV)/k(on.RPV)). Quantum mechanics/molecular mechanics hybrid molecular modeling revealed that p51(E138K) affects access to the RPV binding site by disrupting the salt bridge between p51(E138) and p66(K101). p66(184I) caused repositioning of the Tyr-183 active site residue and decreased the efficiency of RT, whereas the addition of p51(138K) restored Tyr-183 to a WT-like conformation, thus abrogating the Ile-184-induced functional defects.

  8. Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data.

    Science.gov (United States)

    Oikonomou, O; Sarrou, S; Papagiannitsis, C C; Georgiadou, S; Mantzarlis, K; Zakynthinos, E; Dalekos, G N; Petinaki, E

    2015-12-09

    Colistin-resistant/carbapenem-resistant Acinetobacter baumannii is a significant challenge for antibiotic treatment and infection control policies. Since 2012, in Central Greece an increase of colistin/pan- resistant A. baumannii has occurred, indicating the need for further analysis. A total of 86 colistin-resistant/carbapenem-resistant out of 1228 A. baumannii clinical isolates, consecutively collected between 2012 and 2014 in a tertiary Greek hospital of Central Greece, as well as one environmental isolate from surveillance cultures were studied. Molecular typing and mechanisms of resistance to colistin and to carbapenems were assessed, whereas, epidemiological and clinical data of the patients were reviewed. During the study period, the rate of colistin resistance gradually increased and reached 21.1 % in 2014. All colistin-resistant/carbapenem-resistant A. baumannii belonged to 3LST ST101 clone that corresponds to the international clonal lineage II. Carbapenem resistance was associated with the presence of bla oxa-23-like, while resistance to colistin probably correlated with G54E and R109H amino acid substitutions in PmrA and PmrC, respectively. Epidemiological data of the patients indicated that the first detection of colistin-resistant/carbapenem-resistant ST101 clone in the University Hospital of Larissa (UHL) was associated with a patient who previously had received colistin, while, the movement of the infected patients into the hospital probably resulted to its spread.

  9. Investigation of the Effects of rs137852599 Single-nucleotide Polymorphism Existence in Drug Resistance against Treatment with Enzalutamide in Individuals Diagnosed with Prostate Cancer in Isfahan Province

    Directory of Open Access Journals (Sweden)

    Bita Kaviani

    2018-02-01

    Full Text Available Abstract Background: The aim of this study is to investigate the role of rs137852599 single-nucleotide polymorphism in the androgen receptor coding gene on drug resistance against treatment with Enzalutamide in individuals diagnosed with prostate cancer. Materials and Methods: In this case-control study, the ARMS-PCR analysis was conducted on androgen receptor coding gene in 50 patients diagnosed with prostate cancer with drug resistance and on 50 patients diagnosed with prostate cancer without drug resistance. The statistical analyses were performed using the GeNePop server and then the results were investigated by the SISA server. Results: The allele frequencies of A and C alleles in rs137852599 were 0.78 and 0.22 for drug resistant and 0.94 and 0.06 for non-drug resistance groups. The results indicated that there is a meaningful relationship between drug resistance and rs137852599 single-nucleotide polymorphism (p = 0.020. Conclusion: The existence of single-nucleotide polymorphisms may result in drug resistance in individuals diagnosed with prostate cancer. Therefore, investigation of the existence of such polymorphisms can be effective in prescription of suitable drugs for these patients.

  10. Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants.

    Science.gov (United States)

    Okubo, Tomomi; Atsukawa, Masanori; Tsubota, Akihito; Shimada, Noritomo; Abe, Hiroshi; Yoshizawa, Kai; Arai, Taeang; Nakagawa, Ai; Itokawa, Norio; Kondo, Chisa; Aizawa, Yoshio; Iwakiri, Katsuhiko

    2017-06-01

    Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance-associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 ≤ 20 ng/mL) (P = 5.91 × 10⁻ 5 , odds ratio = 5.015) and elderly age (>70 years) (P = 1.85 × 10 -3 , odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL (P = 4.90 × 10 -3 ). We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection. © 2016 The Japan Society of Hepatology.

  11. Research on Service Life of Flame Resistant Materials in the Exhibition Hall by the Use of Mechanical Method of the Meso Damage Mechanics

    Directory of Open Access Journals (Sweden)

    Zhang Junzhu

    2015-01-01

    Full Text Available The population in the exhibition hall is relatively dense, and fire incidents often occur, so the existence of flame resistant materials is very important. The flame resistant materials are used to analyze the museums, art galleries, science and technology museums and other exhibition halls. Taking two kinds of flame resistant materials, namely, Mg(OH2 and Al(OH3 as an example, this paper establishes a model of meso damage mechanics by the use of mechanical method of the meso damage mechanics, and researches the macro mechanical properties of the thermal insulation materials and decorative materials so as to predict its service life. This research finds that the use of two kinds of flame resistant materials, namely, Mg(OH2 and Al(OH3 can improve the elasticity modulus of the thermal insulation materials and decorative materials used in the construction, so that its macro mechanical properties can have a significant improvement, and its service life can also have a significant improvement after adding flame retardant materials.

  12. Characterization of resistance mechanisms to powdery mildew (Erysiphe betae) in beet (Beta vulgaris).

    Science.gov (United States)

    Fernández-Aparicio, Mónica; Prats, Elena; Emeran, Amero A; Rubiales, Diego

    2009-04-01

    Beet powdery mildew incited by Erysiphe betae is a serious foliar fungal disease of worldwide distribution causing losses of up to 30%. In the present work, we searched for resistance in a germplasm collection of 184 genotypes of Beta vulgaris including fodder (51 genotypes), garden (60 genotypes), leaf (51 genotypes), and sugar (22 genotypes) beet types. Resistant genotypes were identified in the four beet types under study. In addition, mechanisms underlying resistance were dissected through histological studies. These revealed different resistance mechanisms acting at different fungal developmental stages, i.e., penetration resistance, early and late cell death, or posthaustorial resistance. Most genotypes were able to hamper fungal development at several stages. The later are interesting for breeding aiming to resistance durability. Furthermore, characterization of defense mechanisms will be useful for further cellular and molecular studies to unravel the bases of resistance in this species.

  13. Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms.

    Science.gov (United States)

    Hong, Jun; Hu, Jianye; Ke, Fei

    2016-10-01

    Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  14. Origin and evolution of antibiotic resistance: the common mechanisms of emergence and spread in water bodies

    Directory of Open Access Journals (Sweden)

    Agnese eLupo

    2012-01-01

    Full Text Available The environment, and especially fresh water, constitutes a reactor where the evolution and the rise of new resistances occur. In rivers or streams, bacteria from different sources such as urban, industrial and agricultural waste, probably selected by intensive antibiotic usage, are collected and mixed with environmental species. This may cause two effects on the development of antibiotic resistances: First, the contamination of water by antibiotics or other pollutants lead to the rise of resistance due to selection processes. For instance, of strains over-expressing broad range defensive mechanisms, such as efflux pumps. Second, since environmental species are provided with intrinsic antibiotic resistance mechanisms, the mixture with allochthonous species is likely to cause genetic exchange. In this context, the role of phages and integrons for the spread of resistance mechanisms appears significant. Allochthonous species could acquire new resistances from environmental donors and introduce the newly acquired resistance mechanisms into the clinics. This is illustrated by clinically relevant resistance mechanisms, such as the fluoroquinolones resistance genes qnr. Freshwater appears to play an important role in the emergence and in the spread of antibiotic resistances, highlighting the necessity for strategies of water quality improvement. Moreover, further knowledge is needed to better understand the role of the environment as reservoir of antibiotic resistances and to assess the risk of spread of antibiotic resistances via water bodies.

  15. Understanding cellular responses to toxic agents: a model for mechanism-choice in bacterial metal resistance.

    Science.gov (United States)

    Rouch, D A; Lee, B T; Morby, A P

    1995-02-01

    Bacterial resistances to metals are heterogeneous in both their genetic and biochemical bases. Metal resistance may be chromosomally-, plasmid- or transposon-encoded, and one or more genes may be involved: at the biochemical level at least six different mechanisms are responsible for resistance. Various types of resistance mechanisms can occur singly or in combination and for a particular metal different mechanisms of resistance can occur in the same species. To understand better the diverse responses of bacteria to metal ion challenge we have constructed a qualitative model for the selection of metal resistance in bacteria. How a bacterium becomes resistant to a particular metal depends on the number and location of cellular components sensitive to the specific metal ion. Other important selective factors include the nature of the uptake systems for the metal, the role and interactions of the metal in the normal metabolism of the cell and the availability of plasmid (or transposon) encoded resistance mechanisms. The selection model presented is based on the interaction of these factors and allows predictions to be made about the evolution of metal resistance in bacterial populations. It also allows prediction of the genetic basis and of mechanisms of resistance which are in substantial agreement with those in well-documented populations. The interaction of, and selection for resistance to, toxic substances in addition to metals, such as antibiotics and toxic analogues, involve similar principles to those concerning metals. Potentially, models for selection of resistance to any substance can be derived using this approach.

  16. Clinical epidemiology and resistance mechanisms of carbapenem-resistant Acinetobacter baumannii, French Guiana, 2008-2014.

    Science.gov (United States)

    Mahamat, Aba; Bertrand, Xavier; Moreau, Brigitte; Hommel, Didier; Couppie, Pierre; Simonnet, Christine; Kallel, Hatem; Demar, Magalie; Djossou, Felix; Nacher, Mathieu

    2016-07-01

    This study investigated the clinical epidemiology and resistance mechanisms of Acinetobacter baumannii and characterised the clonal diversity of carbapenem-resistant A. baumannii (CRAB) during an ICU-associated outbreak at Cayenne Hospital, French Guiana. All non-duplicate A. baumannii isolates from 2008 to 2014 were tested for antibiotic susceptibility by disk diffusion. Multilocus sequence typing, pulsed-field gel electrophoresis (PFGE) and characterisation of carbapenemase-encoding genes were performed on CRAB. Of the 441 A. baumannii isolates, most were from males (54.0%) and were detected mainly from the ICU (30.8%) and medicine wards (21.8%). In the ICU, strains were mainly isolated from the respiratory tract (44.1%) and bloodstream (14.0%), whereas in medicine wards they mainly were from wound/drainage (36.5%) and bloodstream (25.0%). A. baumannii showed the greatest susceptibility to piperacillin/tazobactam (92.7%), imipenem (92.5%), colistin (95.6%) and amikacin (97.2%), being lower in the ICU and medicine wards compared with other wards. An outbreak of OXA-23-producing CRAB occurred in the 13-bed ICU in 2010. CRAB strains were more co-resistant to other antimicrobials compared with non-CRAB. Molecular genetics analysis revealed five sequence types [ST78, ST107 and ST642 and two new STs (ST830 and ST831)]. Analysis of PFGE profiles indicated cross-transmissions of CRAB within the ICU, between the ICU and one medicine ward during transfer of patients, and within that medicine ward. This study provides the first clinical and molecular data of A. baumannii from French Guiana and the Amazon basin. The ICU was the highest risk unit of this nosocomial outbreak of OXA-23-producing CRAB, which could subsequently disseminate within the hospital. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  17. Insecticide resistance in the dengue vector Aedes aegypti from Martinique: distribution, mechanisms and relations with environmental factors.

    Directory of Open Access Journals (Sweden)

    Sébastien Marcombe

    Full Text Available Dengue is an important mosquito borne viral disease in Martinique Island (French West Indies. The viruses responsible for dengue are transmitted by Aedes aegypti, an indoor day-biting mosquito. The most effective proven method for disease prevention has been by vector control by various chemical or biological means. Unfortunately insecticide resistance has already been observed on the Island and recently showed to significantly reduce the efficacy of vector control interventions. In this study, we investigated the distribution of resistance and the underlying mechanisms in nine Ae. aegypti populations. Statistical multifactorial approach was used to investigate the correlations between insecticide resistance levels, associated mechanisms and environmental factors characterizing the mosquito populations. Bioassays revealed high levels of resistance to temephos and deltamethrin and susceptibility to Bti in the 9 populations tested. Biochemical assays showed elevated detoxification enzyme activities of monooxygenases, carboxylesterases and glutathione S-tranferases in most of the populations. Molecular screening for common insecticide target-site mutations, revealed the presence of the "knock-down resistance" V1016I Kdr mutation at high frequency (>87%. Real time quantitative RT-PCR showed the potential involvement of several candidate detoxification genes in insecticide resistance. Principal Component Analysis (PCA performed with variables characterizing Ae. aegypti from Martinique permitted to underline potential links existing between resistance distribution and other variables such as agriculture practices, vector control interventions and urbanization. Insecticide resistance is widespread but not homogeneously distributed across Martinique. The influence of environmental and operational factors on the evolution of the resistance and mechanisms are discussed.

  18. Resistance to antivirals in human cytomegalovirus: mechanisms and clinical significance.

    Science.gov (United States)

    Pérez, J L

    1997-09-01

    Long term therapies needed for managing human cytomegalovirus (HCMV) infections in immunosupressed patients provided the background for the emergence of the resistance to antivirals active against HCMV. In addition, laboratory selected mutants have also been readily achieved. Both clinical and laboratory resistant strains share the same determinants of resistance. Ganciclovir resistance may be due to a few mutations in the HCMV UL97 gene and/or viral DNA pol gene, the former being responsible for about 70% of clinical resistant isolates. Among them, V464, V594, S595 and F595 are the most frequent mutations. Because of their less extensive clinical use, much less is known about resistance to foscarnet and cidofovir (formerly, HPMPC) but in both cases, it has been associated to mutations in the DNA pol. Ganciclovir resistant strains showing DNA pol mutations are cross-resistant to cidofovir and their corresponding IC50 are normally higher than those from strains harboring only mutations at the UL97 gene. To date, foscarnet resistance seems to be independent of both ganciclovir and cidofovir resistance.

  19. Investigating of four main carbapenem-resistance mechanisms in high-level carbapenem resistant Pseudomonas aeruginosa isolated from burn patients

    Directory of Open Access Journals (Sweden)

    Soodabeh Rostami

    2018-02-01

    Conclusion: Emerging antimicrobial resistance in burn wound bacterial pathogens is a serious therapeutic challenge for clinicians. In the present study, most of the isolates were MDR. This finding indicated an alarming spread of resistant isolates and suggested that infection control strategies should be considered. Resistance to carbapenems is influenced by several factors, not all of which were evaluated in our study; however, the results showed that production of MBLs and overexpression of the mexB gene were the most frequent mechanisms in carbapenem-resistant isolates.

  20. Genetic resistance in experimental autoimmune encephalomyelitis. I. Analysis of the mechanism of LeR resistance using radiation chimeras

    International Nuclear Information System (INIS)

    Pelfrey, C.M.; Waxman, F.J.; Whitacre, C.C.

    1989-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease of the central nervous system that has been extensively studied in the rat. The Lewis rat is highly susceptible to the induction of EAE, while the Lewis resistant (LeR) rat is known to be resistant. In this paper, we demonstrate that the LeR rat, which was derived from the Lewis strain by inbreeding of fully resistant animals, is histocompatible with the Lewis strain. Radiation chimeras, a tool for distinguishing between immunologic and nonimmunologic resistance mechanisms, were utilized to analyze the cellular mechanisms involved in genetic resistance to EAE. By transplanting bone marrow cells from LeR rats into irradiated Lewis recipients, Lewis rats were rendered resistant to EAE induction. Likewise, transplanting Lewis bone marrow cells into irradiated LeR recipients rendered LeR rats susceptible. Mixed lymphoid cell chimeras using bone marrow, spleen, and thymus cells in Lewis recipient rats revealed individual lymphoid cell types and cell interactions that significantly affected the incidence and severity of EAE. Our results suggest that LeR resistance is mediated by hematopoietic/immune cells, and that cells located in the spleen appear to play a critical role in the resistance/susceptibility to EAE induction. Depletion of splenic adherent cells did not change the patterns of EAE resistance. In vivo cell mixing studies suggested the presence of a suppressor cell population in the LeR spleen preparations which exerted an inhibitory effect on Lewis autoimmune responses. Thus, the mechanism of LeR resistance appears to be different from that in other EAE-resistant animals

  1. Characterization of Pseudomonas aeruginosa isolates from dogs and cats in Japan: current status of antimicrobial resistance and prevailing resistance mechanisms.

    Science.gov (United States)

    Harada, Kazuki; Arima, Sayuri; Niina, Ayaka; Kataoka, Yasushi; Takahashi, Toshio

    2012-02-01

    Seventy-three Pseudomonas aeruginosa isolates were collected from dogs and cats in Japan to investigate antimicrobial susceptibility and resistance mechanisms to anti-pseudomonal agents. Resistance rates against orbifloxacin, enrofloxacin, ciprofloxacin, cefotaxime, aztreonam and gentamicin were 34.2, 31.5, 20.5, 17.8, 12.3 and 4.1%, respectively. The degree of resistance to cefotaxime, orbifloxacin, and enrofloxacin was greatly affected by efflux pump inhibitors, indicating overexpression of efflux pump contributes to these resistances. Notably, orbifloxacin and enrofloxacin resistance was observed even in isolates without mutations in the target sites. This is the first report on cephalosporin- and fluoroquinolone-resistant isolates of P. aeruginosa from Japanese companion animals. © 2012 The Societies and Blackwell Publishing Asia Pty Ltd.

  2. Genetic resistance to marrow transplantation as a leukemia defense mechanism

    International Nuclear Information System (INIS)

    Gallagher, M.T.; Lotzova, E.; Trentin, J.J.

    1976-01-01

    The normal role of genetic resistance to bone marrow transplantation was investigated. It is demonstrated, using three different systems e.g. colony studies in the spleen, spleen weight studies and mortality studies, that irradiated or unirradiated mice which show genetic resistance are able to recognize and reject intravenously transplanted parental lymphoma cells, while they accept normal parental bone marrow cells. Either the lymphoma cells have a new antigen which is recognized and reacted to by the cells responsible for genetic resistance and, or, bone marrow cells have a low level of Hh antigen which is increased greatly by the lymphoma transformation process, thereby resulting in the rejection of the lymphoma cells by the cells responsible for genetic resistance. Lymphoma resistance as well as genetic resistance can be overridden by increasing the number of cells injected. Genetic resistance seems to be restricted to the spleen and bone marrow. There is evidence that the normal biological role for genetic resistance may be lymphoma-leukemia surveillance

  3. Defense mechanisms involved in disease resistance of grafted vegetables

    Science.gov (United States)

    Vegetable grafting with resistant rootstocks is an effective strategy to control a variety of soil-borne diseases and root-knot nematodes in the Cucurbitaceae and Solanaceae. In addition, improved resistance to some foliar diseases and viruses has also been reported in grafted plants. Hence, graft...

  4. Mechanisms of PGPR-induced resistance against pathogens

    NARCIS (Netherlands)

    Loon, L.C. van; Bakker, P.A.H.M.; Pieterse, C.M.J.

    1997-01-01

    Plant growth-promoting rhizobacteria can suppress diseases through antagonism between the bacteria and soilborne pathogens, as well as by inducing a systemic resistance in the plant against both root and foliar pathogens. Specific Pseudomonas strains induce systemic resistance in carnation,

  5. Heat-resistant mechanism of transgenic rape by 45Ca isotope tracer

    International Nuclear Information System (INIS)

    Xu Falun; Yang Yuanyou; Liu Ning; Liao Jiali; Yang Jijun; Tang Jun; Liu Zhibin; Yang Yi

    2012-01-01

    The Ca 2+ uptake differences of the rape with heat-resistant gene and the general rape were investigated by 45 Ca isotope tracer. The results showed that the rape with heat-resistant gene can strengthen the regulation of calcium absorption. The calcium regulation ability of the heat-resistant genes may be able to play in the rape aspect of the mechanism of resistance. (authors)

  6. Elucidating the mechanisms of resistance to tyrosine kinase inhibitors in lung cancer patients

    Directory of Open Access Journals (Sweden)

    Asim Joshi

    2017-10-01

    Results: The whole exome data was analyzed using an in-house developed pipeline. Of all the known resistance mutations, we identified EGFR T790M mutation in five out of fifteen patients. Other than T790M we expect to identify novel resistance causing mutations from the analysis of ten patients with unknown resistance mechanisms. Functional validation of these resistance specific alterations would be performed in vitro using drug sensitive lung cancer cell lines.

  7. Telavancin: mechanisms of action, in vitro activity, and mechanisms of resistance.

    Science.gov (United States)

    Karlowsky, James A; Nichol, Kim; Zhanel, George G

    2015-09-15

    Telavancin is a semisynthetic lipoglycopeptide derivative of vancomycin. Telavancin has a dual mechanism of antibacterial action, disrupting peptidoglycan synthesis and cell membrane function. In 2014, the Clinical and Laboratory Standards Institute (CLSI) revised the antimicrobial susceptibility testing method for telavancin, resulting in minimum inhibitory concentration (MIC) determinations that are more accurate and reproducible and demonstrate greater in vitro potency than shown with the previous testing method. The CLSI testing method changes coincided with revised telavancin MIC interpretive break point criteria for susceptibility approved by the US Food and Drug Administration for Staphylococcus aureus (≤0.12 µg/mL), Streptococcus pyogenes (≤0.12 µg/mL), Streptococcus agalactiae (≤0.12 µg/mL), Streptococcus anginosus group (≤0.06 µg/mL), and Enterococcus faecalis (vancomycin susceptible, ≤0.25 µg/mL). Telavancin is equally potent against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It demonstrates activity against isolates of heterogeneous vancomycin-intermediate S. aureus and vancomycin-intermediate S. aureus but is poorly active against vancomycin-resistant S. aureus. It also demonstrates potent activity against Staphylococcus epidermidis and Streptococcus spp. (MIC90 ≤0.03 µg/mL). Thus far, it has not been possible to select for high-level telavancin resistance in the laboratory using serially passaged clinical isolates of MRSA and MSSA. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Insecticide resistance status of Myzus persicae in Greece: long-term surveys and new diagnostics for resistance mechanisms.

    Science.gov (United States)

    Voudouris, Costas Ch; Kati, Amalia N; Sadikoglou, Eldem; Williamson, Martin; Skouras, Panagiotis J; Dimotsiou, Ourania; Georgiou, Stella; Fenton, Brian; Skavdis, George; Margaritopoulos, John T

    2016-04-01

    Myzus persicae nicotianae is an important pest in Greece, controlled mainly by neonicotinoids. Monitoring of the aphid populations for resistance mechanisms is essential for effective control. Two new RFLP-based diagnostics for the detection of the M918T (super-kdr pyrethroid resistance) and nAChR R81T (neonicotinoid resistance) mutations were applied, along with other established assays, on 131 nicotianae multilocus genotypes (MLGs) collected from tobacco and peach in Greece in 2012-2013. Furthermore, we present resistance data from aphid clones (>500, mainly nicotianae) collected in 2006-2007. About half of the clones tested with a diagnostic dose of imidacloprid were tolerant. The R81T mutation was not found in the 131 MLGs and 152 clones examined. Over half (58.6%) of a subset of 29 clones showed a 9-36-fold overexpression of CYP6CY3. M918T was found at low to moderate frequencies. The kdr and MACE mechanisms and carboxylesterase-based resistance were found at high frequency in all years. The aphid retains costly resistance mechanisms even in the absence of pressure from certain insecticides, which could be attributed to factors related to climate and genetic properties of the populations. The indication of build-up of resistance/tolerance to neonicotinoids, related to CYP6CY3 overexpression, is a matter of concern. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  9. Existing drug resistance among Staphylococcus spp. from raw milk samples in Khon Kaen province, Northeastern Thailand by direct quadriplex PCR

    Directory of Open Access Journals (Sweden)

    Buppachat Trakarnchan

    2017-10-01

    Full Text Available To describe the proportion of methicillin resistant Staphylococcus aureus, and mupirocin resistant among the isolates from milk, three hundred and eighty-one samples were collected in Khon Kaen province, Thailand, during January to March, 2014. Quadriplex PCR was a method of choice. The occurrence of S. aureus and other Staphylococcus spp. were 21.26 and 34.12%, respectively. Among the 81 S. aureus isolates, 82.72 (67/81, 11.11 (9/81, and 6.17% (5/81 were S. aureus, S. aureus carrying mecA, and S. aureus harboring mupA genes, respectively. These two mutant genes may possibly be transferred to other bacteria in milk. Therefore, good hygienic practices and strict control may limit the spread.

  10. Resistance of green lacewing, Chrysoperla carnea Stephens to nitenpyram: Cross-resistance patterns, mechanism, stability, and realized heritability.

    Science.gov (United States)

    Mansoor, Muhammad Mudassir; Raza, Abu Bakar Muhammad; Abbas, Naeem; Aqueel, Muhammad Anjum; Afzal, Muhammad

    2017-01-01

    The green lacewing, Chrysoperla carnea Stephens (Neuroptera: Chrysopidae) is a major generalist predator employed in integrated pest management (IPM) plans for pest control on many crops. Nitenpyram, a neonicotinoid insecticide has widely been used against the sucking pests of cotton in Pakistan. Therefore, a field green lacewing strain was exposed to nitenpyram for five generations to investigate resistance evolution, cross-resistance pattern, stability, realized heritability, and mechanisms of resistance. Before starting the selection with nitenpyram, a field collected strain showed 22.08-, 23.09-, 484.69- and 602.90-fold resistance to nitenpyram, buprofezin, spinosad and acetamiprid, respectively compared with the Susceptible strain. After continuous selection for five generations (G1-G5) with nitenpyram in the laboratory, the Field strain (Niten-SEL) developed a resistance ratio of 423.95 at G6. The Niten-SEL strain at G6 showed no cross-resistance to buprofezin and acetamiprid and negative cross-resistance to spinosad compared with the Field strain (G1). For resistance stability, the Niten-SEL strain was left unexposed to any insecticide for four generations (G6-G9) and bioassay results at G10 showed that resistance to nitenpyram, buprofezin and spinosad was stable, while resistance to acetamiprid was unstable. The realized heritability values were 0.97, 0.16, 0.03, and -0.16 to nitenpyram, buprofezin, acetamiprid and spinosad, respectively, after five generations of selection. Moreover, the enzyme inhibitors (PBO or DEF) significantly decreased the nitenpyram resistance in the resistant strain, suggesting that resistance was due to microsomal oxidases and esterases. These results are very helpful for integration of green lacewings in IPM programs. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Evidence against the existence of specific Schistosoma mansoni subpopulations which are resistant to irradiated vaccine-induced immunity

    International Nuclear Information System (INIS)

    Lewis, F.A.; Hieny, S.; Sher, A.

    1985-01-01

    When mice are immunized with irradiated Schistosoma mansoni cercariae a proportion of the subsequent cercarial challenge always escapes killing and matures to egg-laying adults. This report investigates the possibility that incomplete immunity in this system is governed by a genetically-determined insusceptibility of a particular schistosome subpopulation. To do this the authors tested whether more immunoresistant schistosomes would develop following successive passages of progeny of the resistant worms through immunized mice. Mice were immunized with 500 50 Krad-irradiated cercariae, and challenged with normal cercariae when immunity was at its peak. After five successive passages through snails and immune mice, progeny of those parasites which escaped immune killing were no more refractory to vaccine-induced resistance than the original stock maintained in nonimmune mice. Additionally, the passaged isolates did not differ from the original stock in their ability to induce protection following irradiation. The results indicate that with this model of acquired resistance incomplete immunity is unlikely to be due to a subpopulation of the parasites possessing a genetically-determined insusceptibility to killing

  12. Sprint performance and mechanical outputs computed with an iPhone app: Comparison with existing reference methods.

    Science.gov (United States)

    Romero-Franco, Natalia; Jiménez-Reyes, Pedro; Castaño-Zambudio, Adrián; Capelo-Ramírez, Fernando; Rodríguez-Juan, Juan José; González-Hernández, Jorge; Toscano-Bendala, Francisco Javier; Cuadrado-Peñafiel, Víctor; Balsalobre-Fernández, Carlos

    2017-05-01

    The purpose of this study was to assess validity and reliability of sprint performance outcomes measured with an iPhone application (named: MySprint) and existing field methods (i.e. timing photocells and radar gun). To do this, 12 highly trained male sprinters performed 6 maximal 40-m sprints during a single session which were simultaneously timed using 7 pairs of timing photocells, a radar gun and a newly developed iPhone app based on high-speed video recording. Several split times as well as mechanical outputs computed from the model proposed by Samozino et al. [(2015). A simple method for measuring power, force, velocity properties, and mechanical effectiveness in sprint running. Scandinavian Journal of Medicine & Science in Sports. https://doi.org/10.1111/sms.12490] were then measured by each system, and values were compared for validity and reliability purposes. First, there was an almost perfect correlation between the values of time for each split of the 40-m sprint measured with MySprint and the timing photocells (r = 0.989-0.999, standard error of estimate = 0.007-0.015 s, intraclass correlation coefficient (ICC) = 1.0). Second, almost perfect associations were observed for the maximal theoretical horizontal force (F 0 ), the maximal theoretical velocity (V 0 ), the maximal power (P max ) and the mechanical effectiveness (DRF - decrease in the ratio of force over acceleration) measured with the app and the radar gun (r = 0.974-0.999, ICC = 0.987-1.00). Finally, when analysing the performance outputs of the six different sprints of each athlete, almost identical levels of reliability were observed as revealed by the coefficient of variation (MySprint: CV = 0.027-0.14%; reference systems: CV = 0.028-0.11%). Results on the present study showed that sprint performance can be evaluated in a valid and reliable way using a novel iPhone app.

  13. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    Science.gov (United States)

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  14. Alternate efflux pump mechanism may contribute to drug resistance in extensively drug-resistant isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Akbar Kanji

    2016-01-01

    Conclusion: Our data show an nsSNP in the drrA efflux pump gene that may result in upregulation of drug efflux mechanisms in MTB strains. It is therefore imperative to understand the mechanism of efflux and its role in drug resistance, which will enable the identification of new drug targets and development of new drug regimens to counteract the drug efflux mechanism of MTB.

  15. Emergence of macrolide-resistant Campylobacter strains in chicken meat in Poland and the resistance mechanisms involved.

    Science.gov (United States)

    Rożynek, Elżbieta; Maćkiw, Elżbieta; Kamińska, Wanda; Tomczuk, Katarzyna; Antos-Bielska, Małgorzata; Dzierżanowska-Fangrat, Katarzyna; Korsak, Dorota

    2013-07-01

    In this study, we investigated the molecular mechanisms involved in erythromycin resistance in the first resistant Campylobacter strains isolated from chicken meat in Poland, and analyzed their genetic relatedness. A total of 297 samples of raw chicken meat and giblets from retail trade in the Warsaw area collected between 2006 and 2009 were examined. Among 211 Campylobacter strains (52 C. jejuni and 159 C. coli), 10 C. coli isolates (4.7%) were resistant to erythromycin. All the C. jejuni strains were susceptible. Among the high-level macrolide-resistant isolates, two different point mutations within the domain V of the 23S rRNA gene were observed. Eight of the strains had adenine→guanine transitions at position 2075, two other isolates at position 2074. Sequence analysis of ribosomal proteins L4 (rplD) and L22 (rplV) indicated that ribosomal protein modifications did not contribute to macrolide resistance. A mutation in the inverted repeat in the cmeR and cmeABC intergenic region was found in a single resistant strain. The genetic relatedness of Campylobacter isolates showed that two resistant strains obtained from the same production plant in a 2-month interval were genetically identical. The risk of transmission of resistant strains via the food chain highlights the need for constant monitoring of resistance in Campylobacter isolates of human and animal hosts.

  16. Ultrasound-induced new cellular mechanism involved in drug resistance.

    Directory of Open Access Journals (Sweden)

    Mariame A Hassan

    Full Text Available The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance. In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant. The neotic progeny, imaged microscopically 24 hr post sonication, could contribute in modulating the final cell survival when an apoptotic dose of doxorubicin was combined with ultrasound applied either simultaneously or sequentially in dual-treatment protocols. Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

  17. Unravelling the resistance mechanism of lettuce against Nasonovia ribisnigri

    OpenAIRE

    Broeke, ten, C.J.M.

    2013-01-01

    Aphids are serious pests of crop plant species, and host plant resistance is often the most effective and environmentally friendly control strategy to control these pests. One of these aphid pests is the black currant - lettuce aphid, Nasonovia ribisnigri (Mosely), an economically important pest of cultivated lettuce, Lactuca sativa L. Host plant resistance has been used since 1982 to control this aphid species and is mediated by the Nr-gene, originating from wild lettuce Lactuca virosa L. H...

  18. Mechanisms of powdery mildew resistance in the Vitaceae family.

    Science.gov (United States)

    Feechan, Angela; Kabbara, Samuela; Dry, Ian B

    2011-04-01

    The cultivated grapevine, Vitis vinifera, is a member of the Vitaceae family, which comprises over 700 species in 14 genera. Vitis vinifera is highly susceptible to the powdery mildew pathogen Erysiphe necator. However, other species within the Vitaceae family have been reported to show resistance to this fungal pathogen, but little is known about the mechanistic basis of this resistance. Therefore, the frequency of successful E. necator penetration events, in addition to programmed cell death (PCD) responses, were investigated in a representative genotype from a range of different species within the Vitaceae family. The results revealed that penetration resistance and PCD-associated responses, or combinations of both, are employed by the different Vitaceae genera to limit E. necator infection. In order to further characterize the cellular processes involved in the observed penetration resistance, specific inhibitors of the actin cytoskeleton and secretory/endocytic vesicle trafficking function were employed. These inhibitors were demonstrated to successfully break the penetration resistance in V. vinifera against the nonadapted powdery mildew E. cichoracearum. However, the use of these inhibitors with the adapted powdery mildew E. necator unexpectedly revealed that, although secretory and endocytic vesicle trafficking pathways play a crucial role in nonhost penetration resistance, the adapted powdery mildew species may actually require these pathways to successfully penetrate the plant host. © 2010 CSIRO. MOLECULAR PLANT PATHOLOGY © 2010 BSPP AND BLACKWELL PUBLISHING LTD.

  19. Genetic Mechanisms of Antibiotic Resistance and the Role of Antibiotic Adjuvants.

    Science.gov (United States)

    Pontes, Daniela Santos; de Araujo, Rodrigo Santos Aquino; Dantas, Natalina; Scotti, Luciana; Scotti, Marcus Tullius; de Moura, Ricardo Olimpio; Mendonca-Junior, Francisco Jaime Bezerra

    2018-01-01

    The ever increasing number of multidrug-resistant microorganism pathogens has become a great and global public health threat. Antibiotic mechanisms of action and the opposing mechanisms of resistance are intimately associated, but comprehension of the biochemical and molecular functions of such drugs is not a simple exercise. Both the environment, and genetic settings contribute to alterations in phenotypic resistance (natural bacterial evolution), and make it difficult to control the emergence and impacts of antibiotic resistance. Under such circumstances, comprehension of how bacteria develop and/or acquire antibiotic resistance genes (ARG) has a critical role in developing propositions to fight against these superbugs, and to search for new drugs. In this review, we present and discuss both general information and examples of common genetic and molecular mechanisms related to antibiotic resistance, as well as how the expression and interactions of ARGs are important to drug resistance. At the same time, we focus on the recent achievements in the search for antibiotic adjuvants, which help combat antibiotic resistance through deactivation of bacterial mechanisms of action such as β-lactamases. Recent advances involving the use of anti-resistance drugs such as: efflux pump inhibitors; anti-virulence drugs; drugs against quorum sensing; and against type II/III secretion systems are revealed. Such antibiotic adjuvants (as explored herein) collaborate against the problems of antibiotic resistance, and may restore or prolong the therapeutic activity of known antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Whole-Genome Sequencing of Methicillin-Resistant Staphylococcus aureus Resistant to Fifth-Generation Cephalosporins Reveals Potential Non-mecA Mechanisms of Resistance.

    Science.gov (United States)

    Greninger, Alexander L; Chatterjee, Som S; Chan, Liana C; Hamilton, Stephanie M; Chambers, Henry F; Chiu, Charles Y

    2016-01-01

    Fifth-generation cephalosporins, ceftobiprole and ceftaroline, are promising drugs for treatment of bacterial infections from methicillin-resistant Staphylococcus aureus (MRSA). These antibiotics are able to bind native PBP2a, the penicillin-binding protein encoded by the mecA resistance determinant that mediates broad class resistance to nearly all other beta-lactam antibiotics, at clinically achievable concentrations. Mechanisms of resistance to ceftaroline based on mecA mutations have been previously described. Here we compare the genomes of 11 total parent-daughter strains of Staphylococcus aureus for which specific selection by serial passaging with ceftaroline or ceftobiprole was used to identify novel non-mecA mechanisms of resistance. All 5 ceftaroline-resistant strains, derived from 5 different parental strains, contained mutations directly upstream of the pbp4 gene (coding for the PBP4 protein), including four with the same thymidine insertion located 377 nucleotides upstream of the promoter site. In 4 of 5 independent ceftaroline-driven selections, we also isolated mutations to the same residue (Asn138) in PBP4. In addition, mutations in additional candidate genes such as ClpX endopeptidase, PP2C protein phosphatase and transcription terminator Rho, previously undescribed in the context of resistance to ceftaroline or ceftobiprole, were detected in multiple selections. These genomic findings suggest that non-mecA mechanisms, while yet to be encountered in the clinical setting, may also be important in mediating resistance to 5th-generation cephalosporins.

  1. Whole-Genome Sequencing of Methicillin-Resistant Staphylococcus aureus Resistant to Fifth-Generation Cephalosporins Reveals Potential Non-mecA Mechanisms of Resistance.

    Directory of Open Access Journals (Sweden)

    Alexander L Greninger

    Full Text Available Fifth-generation cephalosporins, ceftobiprole and ceftaroline, are promising drugs for treatment of bacterial infections from methicillin-resistant Staphylococcus aureus (MRSA. These antibiotics are able to bind native PBP2a, the penicillin-binding protein encoded by the mecA resistance determinant that mediates broad class resistance to nearly all other beta-lactam antibiotics, at clinically achievable concentrations. Mechanisms of resistance to ceftaroline based on mecA mutations have been previously described. Here we compare the genomes of 11 total parent-daughter strains of Staphylococcus aureus for which specific selection by serial passaging with ceftaroline or ceftobiprole was used to identify novel non-mecA mechanisms of resistance. All 5 ceftaroline-resistant strains, derived from 5 different parental strains, contained mutations directly upstream of the pbp4 gene (coding for the PBP4 protein, including four with the same thymidine insertion located 377 nucleotides upstream of the promoter site. In 4 of 5 independent ceftaroline-driven selections, we also isolated mutations to the same residue (Asn138 in PBP4. In addition, mutations in additional candidate genes such as ClpX endopeptidase, PP2C protein phosphatase and transcription terminator Rho, previously undescribed in the context of resistance to ceftaroline or ceftobiprole, were detected in multiple selections. These genomic findings suggest that non-mecA mechanisms, while yet to be encountered in the clinical setting, may also be important in mediating resistance to 5th-generation cephalosporins.

  2. HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy

    Directory of Open Access Journals (Sweden)

    Kazuaki Chayama

    2015-10-01

    Full Text Available Sustained virological response (SVR rates have increased dramatically following the approval of direct acting antiviral (DAA therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.

  3. Investigating knockdown resistance (kdr) mechanism against pyrethroids/DDT in the malaria vector Anopheles funestus across Africa.

    Science.gov (United States)

    Irving, Helen; Wondji, Charles S

    2017-08-09

    Understanding the molecular basis of insecticide resistance is key to improve the surveillance and monitoring of malaria vector populations under control. In the major malaria vector Anopheles funestus, little is currently known about the role of the knockdown resistance (kdr) mechanism. Here, we investigated the presence and contribution of knockdown resistance (kdr) to pyrethroids/DDT resistance observed in Anopheles funestus across Africa. Pyrosequencing genotyping and sequencing of the voltage gated sodium channel (VGSC) gene did not detect the common L1014F mutation in field collected An. funestus across Africa. Amplification and cloning of the full-length of the sodium channel gene in pyrethroid resistant mosquitoes revealed evidences of alternative splicing events with three transcripts of 2092, 2061 and 2117 amino acids (93% average similarity to An. gambiae). Several amino acid changes were detected close to the domain II of the protein such as L928R, F938 W, I939S, L802S and T1008 M. However, all these mutations are found at low frequency and their role in pyrethroid resistance could not be established. The presence of the exclusive alternative splicing at exon 19 was not associated with resistance phenotype. Analysis of patterns of genetic diversity of the VGSC gene revealed a high polymorphism level of this gene across Africa with no evidence of directional selection suggesting a limited role for knockdown resistance in pyrethroid resistance in An. funestus. Patterns of genetic differentiation correlate with previous observations of the existence of barriers to gene flow Africa-wide with southern population significantly differentiated from other regions. Despite an apparent limited role of knockdown resistance in An. funestus, it is necessary to continue to monitor the contribution of the mutations detected here as increasing selection from insecticide-based interventions may change the dynamic in field populations as previously observed in other

  4. Origin and evolution of antibiotic resistance: the common mechanisms of emergence and spread in water bodies.

    Science.gov (United States)

    Lupo, Agnese; Coyne, Sébastien; Berendonk, Thomas Ulrich

    2012-01-01

    The environment, and especially freshwater, constitutes a reactor where the evolution and the rise of new resistances occur. In water bodies such as waste water effluents, lakes, and rivers or streams, bacteria from different sources, e.g., urban, industrial, and agricultural waste, probably selected by intensive antibiotic usage, are collected and mixed with environmental species. This may cause two effects on the development of antibiotic resistances: first, the contamination of water by antibiotics or other pollutants lead to the rise of resistances due to selection processes, for instance, of strains over-expressing broad range defensive mechanisms, such as efflux pumps. Second, since environmental species are provided with intrinsic antibiotic resistance mechanisms, the mixture with allochthonous species is likely to cause genetic exchange. In this context, the role of phages and integrons for the spread of resistance mechanisms appears significant. Allochthonous species could acquire new resistances from environmental donors and introduce the newly acquired resistance mechanisms into the clinics. This is illustrated by clinically relevant resistance mechanisms, such as the fluoroquinolones resistance genes qnr. Freshwater appears to play an important role in the emergence and in the spread of antibiotic resistances, highlighting the necessity for strategies of water quality improvement. We assume that further knowledge is needed to better understand the role of the environment as reservoir of antibiotic resistances and to elucidate the link between environmental pollution by anthropogenic pressures and emergence of antibiotic resistances. Only an integrated vision of these two aspects can provide elements to assess the risk of spread of antibiotic resistances via water bodies and suggest, in this context, solutions for this urgent health issue.

  5. Multiple mechanisms increase levels of resistance in Rapistrum rugosum to ALS herbicides

    Directory of Open Access Journals (Sweden)

    Zhara M Hatami

    2016-02-01

    Full Text Available Rapistrum rugosum (turnip weed is a common weed of wheat fields in Iran, which is most often controlled by tribenuron-methyl (TM, a sulfonylurea (SU belonging to the acetolactate synthase (ALS inhibiting herbicides group. Several cases of unexplained control failure of R. rugosum by TM have been seen, especially in Golestan province-Iran. Hence, there is lack of research in evaluation of the level of resistance of the R. rugosum populations to TM, using whole plant dose–response and enzyme assays, then investigating some potential resistance mechanisms Results revealed that the resistance factor (RF for resistant (R populations was 2.5 to 6.6 fold higher than susceptible (S plant. Neither foliar retention, nor 14C-TM absorption and translocation were the mechanisms responsible for resistance in turnip weed. Metabolism of TM was the second resistant mechanism in two populations (Ag-R5 and G-1, in which three metabolites were found. The concentration of TM for 50% inhibition of ALS enzyme activity in vitro showed a high level of resistance to the herbicide (resistance factors were from 28 to 38 and cross-resistance to sulfonyl-aminocarbonyl-triazolinone (SCT, pyrimidinyl-thiobenzoate (PTB and triazolopyrimidine (TP, with no cross-resistance to imidazolinone (IMI. Substitution Pro 197 to Ser 197 provided resistance to four of five ALS-inhibiting herbicides including SU, TP, PTB and SCT with no resistance to IMI. These results documented the first case of R. rugosum resistant population worldwide and demonstrated that both RST and NRST mechanisms are involved to the resistance level to TM.

  6. Insecticide Resistance Mechanisms in the Green Peach Aphid Myzus persicae (Hemiptera: Aphididae) I: A Transcriptomic Survey

    Science.gov (United States)

    Silva, Andrea X.; Jander, Georg; Samaniego, Horacio; Ramsey, John S; Figueroa, Christian C.

    2012-01-01

    Background Insecticide resistance is one of the best examples of rapid micro-evolution found in nature. Since the development of the first synthetic insecticide in 1939, humans have invested considerable effort to stay ahead of resistance phenotypes that repeatedly develop in insects. Aphids are a group of insects that have become global pests in agriculture and frequently exhibit insecticide resistance. The green peach aphid, Myzus persicae, has developed resistance to at least seventy different synthetic compounds, and different insecticide resistance mechanisms have been reported worldwide. Methodology/Principal Findings To further characterize this resistance, we analyzed genome-wide transcriptional responses in three genotypes of M. persicae, each exhibiting different resistance mechanisms, in response to an anti-cholinesterase insecticide. The sensitive genotype (exhibiting no resistance mechanism) responded to the insecticide by up-regulating 183 genes primarily ones related to energy metabolism, detoxifying enzymes, proteins of extracellular transport, peptidases and cuticular proteins. The second genotype (resistant through a kdr sodium channel mutation), up-regulated 17 genes coding for detoxifying enzymes, peptidase and cuticular proteins. Finally, a multiply resistant genotype (carrying kdr and a modified acetylcholinesterase), up-regulated only 7 genes, appears not to require induced insecticide detoxification, and instead down-regulated many genes. Conclusions/Significance This study suggests strongly that insecticide resistance in M. persicae is more complex that has been described, with the participation of a broad array of resistance mechanisms. The sensitive genotype exhibited the highest transcriptional plasticity, accounting for the wide range of potential adaptations to insecticides that this species can evolve. In contrast, the multiply resistant genotype exhibited a low transcriptional plasticity, even for the expression of genes encoding

  7. Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage.

    Science.gov (United States)

    Lehtinen, Sonja; Blanquart, François; Croucher, Nicholas J; Turner, Paul; Lipsitch, Marc; Fraser, Christophe

    2017-01-31

    Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

  8. Charge dividing mechanism on resistive electrode in position-sensitive detectors

    International Nuclear Information System (INIS)

    Radeka, V.; Rehak, P.

    1978-10-01

    A complete charge-division mechanism, including both the diffusion and the electromagnetic wave propagation on resistive electrodes, is presented. The charge injected into such a transmission line divides between the two ends according to the ratio of resistancies and independently of the value of the line resistance, of the propagation mechanism and of the distribution of inductance and capacitance along the line. The shortest charge division time is achieved for Rl = 2π (L/C) 1 / 2 , where R, L, C are resistance, inductance and capacitance per unit length and l is the length of the line

  9. Macrolide resistance mechanisms and virulence factors in erythromycin-resistant Campylobacter species isolated from chicken and swine feces and carcasses.

    Science.gov (United States)

    Lim, Suk-Kyung; Moon, Dong-Chan; Chae, Myung Hwa; Kim, Hae Ji; Nam, Hyang-Mi; Kim, Su-Ran; Jang, Gum-Chan; Lee, Kichan; Jung, Suk-Chan; Lee, Hee-Soo

    2017-01-10

    Resistance to antimicrobials was measured in 73 isolates of Campylobacter jejuni (C. jejuni) and 121 isolates of Campylobacter coli (C. coli) from chicken and swine feces and carcasses in Korea. Both bacterial species showed the highest resistance to (fluoro) quinolones (ciprofloxacin and nalidixic acid) out of the nine antimicrobials tested. Erythromycin resistance was much higher in C. coli (19.0%, 23/121) than in C. jejuni (6.8%, 5/73). The mutation in the 23S rRNA gene was primarily responsible for macrolide resistance in Campylobacter isolates. Several amino acid substitutions in the L4 and L22 ribosomal proteins may play a role in the mechanism of resistance, but the role requires further evaluation. A total of eight virulence genes were detected in 28 erythromycin-resistant Campylobacter isolates. All C. jejuni isolates carried more than four such genes, while C. coli isolates carried fewer than three such genes. The high rate of resistance highlights the need to employ more prudent use of critically important antimicrobials, such as fluoroquinolones and macrolides, in swine and poultry production, and to more carefully monitor antimicrobial resistance in Campylobacter isolates in food animals.

  10. Creatine loading, resistance exercise performance, and muscle mechanics.

    Science.gov (United States)

    Stevenson, S W; Dudley, G A

    2001-11-01

    We tested the null hypothesis that creatine monohydrate loading (20 g per day for 7 days, n = 18) would not alter resistance exercise performance, isometric strength, or in vivo contractile properties of the quadriceps femoris muscle compared with loading with placebo (n = 13) in resistance-trained subjects. For the entire study group, the 1 repetition maximum (1RM) and 5-set performance (the number of repetitions) for unilateral, dynamic knee extension increased slightly (2% and 5%, respectively) after dietary supplementation, and these responses did not differ by condition. Maximal voluntary isometric torque and the rate of torque development did not change. During electromyostimulation, torque development and relaxation time were also unaffected. Our data suggest that creatine loading does not augment unilateral strength or multiset resistance exercise performance for knee extensions compared with placebo loading.

  11. The study of resistant mechanisms and reversal in an imatinib resistant Ph+ acute lymphoblastic leukemia cell line.

    Science.gov (United States)

    Xing, Hongyun; Yang, Xi; Liu, Ting; Lin, Juan; Chen, Xiaoyi; Gong, Yuping

    2012-04-01

    In this study, we established an imatinib resistant Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15/RI in vitro and studied the mechanism of imatinib resistance. Our results showed that the BCR-ABL1 fusion gene and the mdr1 gene were 6.1 times and 1.7 times, respectively, as high as that of parental SUP-B15 cell line. We found no mutation in the Abl kinase domain of SUP-B15/RI. Furthermore, the detection of cell signaling pathway of PI3K/AKT/mTOR, RAS/RAF, NF-κB, JNK and STAT showed the up-regulation of phosphorylation of AKT, mTOR, P70S6K, and RAF, ERK, and MEK, down-regulation of PTEN and 4EBP-1, and no change in other cell signaling pathways in SUP-B15/RI. However, dasatinib and nilotinib showed partial resistance. Interestingly, bortezomib had no resistance. Imatinib combination with rapamycin had synergistic effect on overcoming the resistance. Altogether, over-expression of BCR-ABL1 and mdr1 gene were involved in the resistance mechanisms, and up-regulation of the cell signaling pathways of PI3K/AKT/mTOR, RAS/RAF in SUP-B15/RI cell line may be correlated with them. The SUP-B15/RI cell line was also resistant to the second generation tyrosine kinase, dasatinib, and nilotinib, not bortezomib. The combination of imatinib with rapamycin can partially overcome the resistance and blockade of the ubiquitin-proteasome can be also a promising pathway to overcome imatinib resistance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer.

    Science.gov (United States)

    Ter Brugge, Petra; Kristel, Petra; van der Burg, Eline; Boon, Ute; de Maaker, Michiel; Lips, Esther; Mulder, Lennart; de Ruiter, Julian; Moutinho, Catia; Gevensleben, Heidrun; Marangoni, Elisabetta; Majewski, Ian; Józwiak, Katarzyna; Kloosterman, Wigard; van Roosmalen, Markus; Duran, Karen; Hogervorst, Frans; Turner, Nick; Esteller, Manel; Cuppen, Edwin; Wesseling, Jelle; Jonkers, Jos

    2016-11-01

    Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms. © The Author 2016. Published by Oxford University Press. All rights reserved

  13. Mechanisms of quinolone resistance in Salmonella spp. / Mecanismos de resistência às quinolonas em Salmonella spp.

    Directory of Open Access Journals (Sweden)

    Tereza Cristina Rocha Moreira de Oliveira

    2010-07-01

    Full Text Available Salmonellosis is a common and widespread zoonotic disease of humans and a frequent cause of foodborne disease. Treatment of severe and systemic salmonellosis is usually done with fluoroquinolones. In this review resistance mechanisms of Salmonella to quinolones are discussed. Single point mutations in the quinolone resistant determining region (QRDR of the gyrA gene may be sufficient to generate high levels of resistance to non-fluorated quinolones and also may decrease the fluoroquinolones susceptibility. Other resistance mechanisms that should be considered are mutations in parC gene, the possibility of acquiring resistance through plasmidial transference and hyper-expression of efflux pumps. Fluoroquinolones resistance is still relatively uncommon in Salmonella compared to other species belonging to the Enterobacteriaceae family. However, the more careful use of fluoroquinolones in veterinary and human medicine is essential to decrease the selective pressure which can avoid the emergence and spread of resistant clones and consequently maintain the clinical efficacy of this group of antibiotics.A salmonelose é uma zoonose de importância mundial e uma das mais freqüentes doenças de origem alimentar. As fluoroquinolonas são a principal opção para o tratamento de salmoneloses graves ou sistêmicas. Esta revisão de literatura teve como objetivo apresentar os principais mecanismos envolvidos na resistência de Salmonella spp a estes antimicrobianos. Mutações de ponto na Região Determinante de Resistência à Quinolona (QRDR do gene gyrA podem gerar altos níveis de resistência a quinolonas não-fluoradas, além de reduzir a suscetibilidade as fluoroquinolonas. Outros mecanismos de resistência que também precisam ser considerados são as mutações no gene parC, a possibilidade do envolvimento de plasmídios de resistência e o sistema de efluxo ativo. A resistência às fluoroquinolonas ainda é incomum em Salmonella spp., quando

  14. A study on the mechanism of resistance to streptomycin in ...

    African Journals Online (AJOL)

    use

    2011-12-12

    1973), and the length of lesions on the inoculated leaf was measured after 15 days. DNA isolation. DNA was isolated from the wild-type isolate and resistant strains as described by Ausubel et al. (1987). After the bacteria were ...

  15. Evaluation the mechanisms of erythromycin and penicillin resistance ...

    African Journals Online (AJOL)

    user

    2012-01-12

    Jan 12, 2012 ... primer (Table 1) and 10 µl of DNA templates (Fukushima et al.,. 2008). PCR amplification was carried with the cycling parameters as follows: after an initial denaturation .... isolated from children in Japan. Mutations in pbp2x were observed in several strains presenting intermediate resistance to penicillin.

  16. Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori

    NARCIS (Netherlands)

    M.M. Gerrits (Monique)

    2004-01-01

    textabstractAn estimated 4 to 5 million individuals in the Netherlands are actively infected with Helicobacter pylori. Eradication of this bacterium becomes more difficult as the prevalence of antibiotic resistance is increasing worldwide. Most H. pylori infections are now diagnosed by

  17. Molecular mechanisms of insulin resistance | Pillay | South African ...

    African Journals Online (AJOL)

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

  18. Unravelling the resistance mechanism of lettuce against Nasonovia ribisnigri

    NARCIS (Netherlands)

    Broeke, ten C.J.M.

    2013-01-01

    Aphids are serious pests of crop plant species, and host plant resistance is often the most effective and environmentally friendly control strategy to control these pests. One of these aphid pests is the black currant - lettuce aphid, Nasonovia ribisnigri (Mosely), an economically

  19. A study on the mechanism of resistance to streptomycin in ...

    African Journals Online (AJOL)

    11 streptomycin-resistant mutants of Xanthomonas oryzae pv. oryzae were obtained by streptomycin selection. These mutants could grow at 100 μg ml-1 of streptomycin while the wild-type strain (PXO99) could not grow at 2 μg ml-1. Specific primers based on the conserved region of X. oryzae pv. oryzae were designed and ...

  20. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

    Directory of Open Access Journals (Sweden)

    Winyoo Chowanadisai

    Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

  1. Acaricide resistance and resistance mechanisms in Tetranychus urticae populations from rose greenhouses in the Netherlands

    NARCIS (Netherlands)

    Khajehali, J.; Van Nieuwenhuyse, P.; Demaeght, P.; Tirry, L.; Van Leeuwen, T.

    2011-01-01

    BACKGROUND: Spider mites are important crop pests that rapidly develop resistance to acaricides. To investigate whether acaricide resistance is a threat to greenhouse rose culture in the Netherlands, the susceptibility of 15 strains of Tetranychus urticae was tested to several currently used

  2. The prevalence of the pre-existing hepatitis C viral variants and the evolution of drug resistance in patients treated with the NS3-4a serine protease inhibitor telaprevir

    Energy Technology Data Exchange (ETDEWEB)

    Rong, Libin [Los Alamos National Laboratory; Ribeiro, Ruy M [Los Alamos National Laboratory; Perelson, Alan S [Los Alamos National Laboratory

    2008-01-01

    Telaprevir (VX-950), a novel hepatitis C virus (HCV) NS3-4A serine protease inhibitor, has demonstrated substantial antiviral activity in patients infected with HCV genotype 1. Some patients experience viral breakthrough, which has been shown to be associated with emergence of telaprevir-resistant HCV variants during treatment. The exact mechanisms underlying the rapid selection of drug resistant viral variants during dosing are not fully understood. In this paper, we develop a two-strain model to study the pre-treatment prevalence of the mutant virus and derive an analytical solution of the mutant frequency after administration of the protease inhibitor. Our analysis suggests that the rapid increase of the mutant frequency during therapy is not due to mutant growth but rather due to the rapid and profound loss of wild-type virus, which uncovers the pre-existing mutant variants. We examine the effects of backward mutation and hepatocyte proliferation on the pre-existence of the mutant virus and the competition between wild-type and drug resistant virus during therapy. We then extend the simple model to a general model with multiple viral strains. Mutations during therapy do not play a significant role in the dynamics of various viral strains, although they are capable of generating low levels of HCV variants that would otherwise be completely suppressed because of fitness disadvantages. Hepatocyte proliferation may not affect the pretreatment frequency of mutant variants, but is able to influence the quasispecies dynamics during therapy. It is the relative fitness of each mutant strain compared with wild-type that determines which strain(s) will dominate the virus population. The study provides a theoretical framework for exploring the prevalence of pre-existing mutant variants and the evolution of drug resistance during treatment with other protease inhibitors or HCV polymerase inhibitors.

  3. Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs.

    Science.gov (United States)

    Soares, Geisla Mary Silva; Figueiredo, Luciene Cristina; Faveri, Marcelo; Cortelli, Sheila Cavalca; Duarte, Poliana Mendes; Feres, Magda

    2012-01-01

    Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole) and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of β-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections.

  4. Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs

    Directory of Open Access Journals (Sweden)

    Geisla Mary Silva Soares

    2012-06-01

    Full Text Available Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of β-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections.

  5. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function

    Directory of Open Access Journals (Sweden)

    Martins Amanda R

    2012-02-01

    Full Text Available Abstract Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.

  6. Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

    Science.gov (United States)

    Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

    2018-03-30

    Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

  7. Multiple mechanisms underlying acquired resistance to taxanes in selected docetaxel-resistant MCF-7 breast cancer cells

    OpenAIRE

    Wang, Harris; Vo, The; Hajar, Ali; Li, Sarah; Chen, Xinmei; Parissenti, Amadeo M; Brindley, David N; Wang, Zhixiang

    2014-01-01

    Background Chemoresistance is a major factor involved in a poor response and reduced overall survival in patients with advanced breast cancer. Although extensive studies have been carried out to understand the mechanisms of chemoresistance, many questions remain unanswered. Methods In this research, we used two isogenic MCF-7 breast cancer cell lines selected for resistance to doxorubicin (MCF-7DOX) or docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to study mechanisms und...

  8. Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase.

    OpenAIRE

    Piton , Jérémie; Petrella , Stéphanie; Delarue , Marc; André-Leroux , Gwénaëlle; Jarlier , Vincent; Aubry , Alexandra; Mayer , Claudine

    2010-01-01

    International audience; Mycobacterium tuberculosis DNA gyrase, an indispensable nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and is hence the sole target for quinolone action, a crucial drug active against multidrug-resistant tuberculosis. To understand at an atomic level the quinolone resistance mechanism, which emerges in extensively drug resistant tuberculosis, we performed combined functional, biophysical and structural...

  9. Acaricide resistance mechanisms in Rhipicephalus (Boophilus microplus Mecanismos de resistência aos acaricidas em Rhipicephalus (Boophilus microplus

    Directory of Open Access Journals (Sweden)

    Felix David Guerrero

    2012-03-01

    Full Text Available Acaricide resistance has become widespread in countries where cattle ticks, Rhipicephalus (Boophilus microplus, are a problem. Resistance arises through genetic changes in a cattle tick population that causes modifications to the target site, increased metabolism or sequestration of the acaricide, or reduced ability of the acaricide to penetrate through the outer protective layers of the tick’s body. We review the molecular and biochemical mechanisms of acaricide resistance that have been shown to be functional in R. (B. microplus. From a mechanistic point of view, resistance to pyrethroids has been characterized to a greater degree than any other acaricide class. Although a great deal of research has gone into discovery of the mechanisms that cause organophosphate resistance, very little is defined at the molecular level and organophosphate resistance seems to be maintained through a complex and multifactorial process. The resistance mechanisms for other acaricides are less well understood. The target sites of fipronil and the macrocyclic lactones are known and resistance mechanism studies are in the early stages. The target site of amitraz has not been definitively identified and this is hampering mechanistic studies on this acaricide.A resistência aos acaricidas tornou-se amplamente difundida nos países onde os carrapatos bovinos, Rhipicephalus .Boophilus. microplus, são um problema. A resistência surge por meio de alterações genéticas em umapopulação de carrapatos que causam modificações no local de ação, aumento do metabolismo ou sequestro do acaricida, ou ainda redução na capacidade do acaricida em penetrar através das camadas protetoras do corpo do carrapato. Neste artigo, foram revisados os mecanismos moleculares e bioquímicos da resistência aos acaricidas que ocorrem em R. (B. microplus. A partir de um ponto de vista dos mecanismos envolvidos, a resistência aos piretróides tem sido caracterizada em maior grau do

  10. Evolution of amoxicillin resistance of Helicobacter pylori in vitro: characterization of resistance mechanisms.

    Science.gov (United States)

    Qureshi, Nadia N; Gallaher, Brandon; Schiller, Neal L

    2014-12-01

    Helicobacter pylori is the major cause of peptic ulcers and gastric cancer in humans. Treatment involves a two or three drug cocktail, typically including amoxicillin. Increasing levels of resistance to amoxicillin contribute to treatment failures, and higher levels of resistance are believed to be due to multiple genetic mutations. In this study, we examined the progression of spontaneous genetic mutations that contribute to amoxicillin resistance in H. pylori when exposed to increasing concentrations of amoxicillin in vitro. During the selection process, we isolated five strains each of which had progressively higher levels of resistance. Using a whole genome sequencing approach, we identified mutations in a number of genes, notably pbp1, pbp2, hefC, hopC, and hofH, and by sequencing these genes in each isolate we were able to map the order and gradual accumulation of mutations in these isolates. These five isolates, each expressing multiple mutated genes and four transformed strains expressing individually mutated pbp1, hefC, or hofH, were characterized using minimum inhibitory concentrations, amoxicillin uptake, and efflux studies. Our results indicate that mutations in pbp1, hefC, hopC, hofH, and possibly pbp2 contribute to H. pylori high-level amoxicillin resistance. The data also provide evidence for the complexity of the evolution of amoxicillin resistance in H. pylori and indicate that certain families of genes might be more susceptible to amoxicillin resistance mutations than others.

  11. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance

    Directory of Open Access Journals (Sweden)

    Tameka A Bailey

    2011-01-01

    Full Text Available The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu is overexpressed in about 20 - 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin™, Genentech Inc, San Francisco, CA, a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology that are being explored to overcome resistance to Trastuzumab therapy.

  12. Analysis of antimicrobial resistance mechanisms in multi-drug resistant (MDR) Salmonella enterica by high-throughput DNA sequencing

    Science.gov (United States)

    Background: Multi drug resistant (MDR) Salmonella enterica is found in food animals and may consequently pose a risk to humans through food borne transmission. To understand the mechanisms that drive this problem, the genetic elements associated with MDR need to be determined. These MDR elements in ...

  13. Repeatable change in electrical resistance of Si surface by mechanical and electrical nanoprocessing.

    Science.gov (United States)

    Miyake, Shojiro; Suzuki, Shota

    2014-01-01

    The properties of mechanically and electrically processed silicon surfaces were evaluated by atomic force microscopy (AFM). Silicon specimens were processed using an electrically conductive diamond tip with and without vibration. After the electrical processing, protuberances were generated and the electric current through the silicon surface decreased because of local anodic oxidation. Grooves were formed by mechanical processing without vibration, and the electric current increased. In contrast, mechanical processing with vibration caused the surface to protuberate and the electrical resistance increased similar to that observed for electrical processing. With sequential processing, the local oxide layer formed by electrical processing can be removed by mechanical processing using the same tip without vibration. Although the electrical resistance is decreased by the mechanical processing without vibration, additional electrical processing on the mechanically processed area further increases the electrical resistance of the surface.

  14. Mechanism of Trypanosoma brucei gambiense resistance to human serum

    DEFF Research Database (Denmark)

    Uzureau, Pierrick; Uzureau, Sophie; Lecordier, Laurence

    2013-01-01

    The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease...... in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via......GP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According...

  15. Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

    Directory of Open Access Journals (Sweden)

    H. M. Adnan Hameed

    2018-04-01

    Full Text Available Tuberculosis (TB is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and total drug-resistant tuberculosis (TDR-TB, due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

  16. Development of LRFD resistance factors for mechanically stabilized earth (MSE) walls : [technical summary].

    Science.gov (United States)

    2013-12-01

    Bridge approach embankments and many other : transportation-related applications make use of : reinforced earth retaining structures. Mechanically : Stabilized Earth (MSE) walls are designed under : the Load and Resistance Factor Design (LRFD) : meth...

  17. Mechanism of Action of Substituted Indanones in Multidrug Resistant Breast Cancer

    National Research Council Canada - National Science Library

    Leoni, Lorenzo

    2001-01-01

    ... (Cancer Res 2001 Oct 1;61(19):7248.54) - analyzed the indanocine-resistant stable cell line - identified the potential indanocine-binding site on tubulin - continued the animal testing of indanocine - studies the pro-apoptotic mechanism...

  18. Mechanisms of resistance to chloramphenicol in Pseudomonas putida KT2440.

    Science.gov (United States)

    Fernández, Matilde; Conde, Susana; de la Torre, Jesús; Molina-Santiago, Carlos; Ramos, Juan-Luis; Duque, Estrella

    2012-02-01

    Pseudomonas putida KT2440 is a chloramphenicol-resistant bacterium that is able to grow in the presence of this antibiotic at a concentration of up to 25 μg/ml. Transcriptomic analyses revealed that the expression profile of 102 genes changed in response to this concentration of chloramphenicol in the culture medium. The genes that showed altered expression include those involved in general metabolism, cellular stress response, gene regulation, efflux pump transporters, and protein biosynthesis. Analysis of a genome-wide collection of mutants showed that survival of a knockout mutant in the TtgABC resistance-nodulation-division (RND) efflux pump and mutants in the biosynthesis of pyrroloquinoline (PQQ) were compromised in the presence of chloramphenicol. The analysis also revealed that an ABC extrusion system (PP2669/PP2668/PP2667) and the AgmR regulator (PP2665) were needed for full resistance toward chloramphenicol. Transcriptional arrays revealed that AgmR controls the expression of the pqq genes and the operon encoding the ABC extrusion pump from the promoter upstream of open reading frame (ORF) PP2669.

  19. Differential Resistance Mechanisms to Glyphosate Result in Fitness Cost for Lolium perenne and L. multiflorum

    Directory of Open Access Journals (Sweden)

    Pablo T. Fernández-Moreno

    2017-10-01

    Full Text Available Multiple mechanisms of resistance to glyphosate are exhibited by populations of Lolium spp. worldwide. Association of resistance with growth and reproductive fitness is an important predictor for long-term success of glyphosate-resistant (R versus glyphosate-susceptible (S biotypes. Numerous studies were conducted on R- and S-biotypes of Italian ryegrass (Lolium multiflorum and perennial ryegrass (L. perenne to characterize the underlying mechanism(s of glyphosate resistance and associate this with growth and reproductive fitness. L. perenne expressed both altered uptake and translocation as well as a genetic change at 106-Pro to –Ser, This pattern for two resistance mechanisms is unique. L. multiflorum also exhibited altered uptake and translocation as well as duplication of EPSPS gene copies. Reduced plant biomass and height for R-versus S-biotypes of both species was evident over two growing seasons. This resulted in S- versus R- L. multiflorum producing up to 47 and 38% more seeds in 2014 and 2015, respectively. S- L. perenne produced up to 20 and 30% more seeds in 2014 and 2015, respectively. Both non-target site and target-site mechanisms of glyphosate resistance can render Lolium spp. at a competitive disadvantage. This has long-term implications for the success of glyphosate-resistant plants in the absence of selection pressure.

  20. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance.

    Science.gov (United States)

    O'Connor, R

    2009-05-01

    Drug resistance is a serious limitation to the effective treatment of a number of common malignancies. Thirty years of laboratory and clinical research have greatly defined the molecular alterations underlying many drug resistance processes in cancer. Based on this knowledge, strategies to overcome the impact of resistance and increase the efficacy of cancer treatment have been translated from laboratory models to clinical trials. This article reviews laboratory and, in particular, clinical attempts at drug resistance circumvention from early forays in the inhibition of cellular efflux pump-mediated drug resistance through to more selective circumvention agent strategies and into inhibition of the other important mechanisms which can allow cancer cells to survive therapy, such as apoptosis resistance. Despite some promising results to date, resistance inhibition strategies have largely failed due to poor understanding of the pharmacology, dynamics and complexity of the resistance phenotype. With the realisation that new molecularly-targeted agents can also be rendered ineffectual by the actions of resistance mechanisms, a major focus is once again emerging on identifying new strategies/pharmaceuticals which can augment the activity of the arsenal of more conventional cytotoxics and newer targeted anti-cancer drugs. Future tactical directions where old and new resistance strategies may merge to overcome this challenge are discussed.

  1. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa isolates from Chinese hospitals.

    Science.gov (United States)

    Wang, Jie; Zhou, Jian-ying; Qu, Ting-ting; Shen, Ping; Wei, Ze-qing; Yu, Yun-song; Li, Lan-juan

    2010-05-01

    We investigated the molecular epidemiology and carbapenem resistance mechanisms of 258 non-duplicate carbapenem-resistant clinical isolates of Pseudomonas aeruginosa collected from 2006 to 2007 at 28 hospitals in China. Up to 88% of the carbapenem-resistant isolates were multidrug-resistant. Pulsed-field gel electrophoresis (PFGE) revealed that levels of intrahospital and interhospital dissemination of clones were low. To assess the mechanisms leading to resistance, all 258 carbapenem-resistant isolates were analysed for expression of the chromosomal beta-lactamase (AmpC), the porin important for entry of carbapenems (OprD) and an efflux system (MexAB-OprM) known to extrude some beta-lactams. Carbapenem resistance was driven mainly by mutational inactivation of OprD, accompanied or not by hyperexpression of AmpC or MexAB-OprM. Metallo-beta-lactamase genes were detected in 22 carbapenem-resistant isolates in China, belonging to eight pulsotypes. The bla(OXA-50) gene was detected among all of the carbapenem-resistant isolates, whereas the bla(GES-5) gene was detected in only one carbapenem-resistant isolate. Copyright 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  2. Mechanisms of Invasion Resistance of Aquatic Plant Communities

    Science.gov (United States)

    Petruzzella, Antonella; Manschot, Johan; van Leeuwen, Casper H. A.; Grutters, Bart M. C.; Bakker, Elisabeth S.

    2018-01-01

    Invasive plant species are among the major threats to freshwater biodiversity. Few experimental studies have investigated whether native plant diversity can provide biotic resistance to invaders in freshwater ecosystems. At small spatial scales, invasion resistance may increase with plant species richness due to a better use of available resources, leaving less available for a potential invader (Complementarity effect) and/or the greater probability to have a highly competitive (or productive) native species in the community (Selection effect). In submerged aquatic plant communities, we tested the following hypotheses: (1) invader establishment success is greatest in the absence of a native plant community; (2) lower in plant communities with greater native species richness, due to complementary and/or selection effects; and (3) invader establishment success would be lowest in rooted plant communities, based on the limiting similarity theory as the invader is a rooted submerged species. In a greenhouse experiment, we established mesocosms planted with 0 (bare sediment), 1, 2, and 4 submerged plant species native to NW Europe and subjected these to the South African invader Lagarosiphon major (Ridl.) Moss. We used two rooted (Myriophyllum spicatum L., Potamogeton perfoliatus L.) and two non-rooted native species (Ceratophyllum demersum L., Utricularia vulgaris L.) representing two distinct functional groups considering their nutrient acquisition strategy which follows from their growth form, with, respectively, the sediment and water column as their main nutrient source. We found that the presence of native vegetation overall decreased the establishment success of an alien aquatic plant species. The strength of this observed biotic resistance increased with increasing species richness of the native community. Mainly due to a selection effect, the native biomass of mixed communities overyielded, and this further lowered the establishment success of the invader in our

  3. The molecular changing mechanism of Ampicillin-Sulbactam resistant Staphylococcus aureus towards Methicillin resistant Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Mieke Hemiawati Satari

    2005-12-01

    Full Text Available The aim of this study was to determine the molecular changing of S.aureus, which is resistant to Ampicillin-Sulbactam and then become resistant to Methicillin as a result of improper dosage. The study was conducted by isolating Ampicillin-Sulbactam resistant and Methicillin Resistant S.aureus (MRSA, afterwards an amplification process was performed by PCR (Polymerase Chain Reaction. to isolate the betalactamase enzyme regulator and PBP 2a genes. The result of this research showed that there were a deletion of few amino acids from the regulator gene, and a suspicion that the DNA sequence had been substituted from PBP 2 gene into PBP 2a (gen mec. This process had formed MRSA.

  4. Fibril morphology and tendon mechanical properties in patellar tendinopathy: effects of heavy slow resistance training

    DEFF Research Database (Denmark)

    Kongsgaard, Mads; Qvortrup, Klaus; Larsen, Jytte Overgaard

    2010-01-01

    BACKGROUND: Patellar tendinopathy is characterized by pathologic abnormalities. Heavy slow resistance training (HSR) is effective in the management of patellar tendinopathy, but the underlying functional mechanisms remain elusive. PURPOSE: To investigate fibril morphology and mechanical properties...... area. Heavy slow resistance training improved the clinical outcome of patellar tendinopathy, and these improvements were associated with normalization of fibril morphology, most likely due to a production of new fibrils....

  5. Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

  6. Production of sintered alumina from powder; optimization of the sinterized parameters for the maximum mechanical resistence

    International Nuclear Information System (INIS)

    Rocha, J.C. da.

    1981-02-01

    Pure, sinterized alumina and the optimization of the parameters of sinterization in order to obtain the highest mechanical resistence are discussed. Test materials are sinterized from a fine powder of pure alumina (Al 2 O 3 ), α phase, at different temperatures and times, in air. The microstructures are analysed concerning porosity and grain size. Depending on the temperature or the time of sinterization, there is a maximum for the mechanical resistence. (A.R.H.) [pt

  7. Thiamethoxam Resistance in the House Fly, Musca domestica L.: Current Status, Resistance Selection, Cross-Resistance Potential and Possible Biochemical Mechanisms.

    Directory of Open Access Journals (Sweden)

    Hafiz Azhar Ali Khan

    Full Text Available The house fly, Musca domestica L., is an important ectoparasite with the ability to develop resistance to insecticides used for their control. Thiamethoxam, a neonicotinoid, is a relatively new insecticide and effectively used against house flies with a few reports of resistance around the globe. To understand the status of resistance to thiamethoxam, eight adult house fly strains were evaluated under laboratory conditions. In addition, to assess the risks of resistance development, cross-resistance potential and possible biochemical mechanisms, a field strain of house flies was selected with thiamethoxam in the laboratory. The results revealed that the field strains showed varying level of resistance to thiamethoxam with resistance ratios (RR at LC50 ranged from 7.66-20.13 folds. Continuous selection of the field strain (Thia-SEL for five generations increased the RR from initial 7.66 fold to 33.59 fold. However, resistance declined significantly when the Thia-SEL strain reared for the next five generations without exposure to thiamethoxam. Compared to the laboratory susceptible reference strain (Lab-susceptible, the Thia-SEL strain showed cross-resistance to imidacloprid. Synergism tests revealed that S,S,S-tributylphosphorotrithioate (DEF and piperonyl butoxide (PBO produced synergism of thiamethoxam effects in the Thia-SEL strain (2.94 and 5.00 fold, respectively. In addition, biochemical analyses revealed that the activities of carboxylesterase (CarE and mixed function oxidase (MFO in the Thia-SEL strain were significantly higher than the Lab-susceptible strain. It seems that metabolic detoxification by CarE and MFO was a major mechanism for thiamethoxam resistance in the Thia-SEL strain of house flies. The results could be helpful in the future to develop an improved control strategy against house flies.

  8. A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutations.

    Science.gov (United States)

    Roche, Michael; Salimi, Hamid; Duncan, Renee; Wilkinson, Brendan L; Chikere, Kelechi; Moore, Miranda S; Webb, Nicholas E; Zappi, Helena; Sterjovski, Jasminka; Flynn, Jacqueline K; Ellett, Anne; Gray, Lachlan R; Lee, Benhur; Jubb, Becky; Westby, Mike; Ramsland, Paul A; Lewin, Sharon R; Payne, Richard J; Churchill, Melissa J; Gorry, Paul R

    2013-04-20

    The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo, we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad divergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively "weak" and "strong" resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly divergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Clinical resistance to MVC may involve divergent Env

  9. Nucleus geometry and mechanical properties of resistance spot ...

    Indian Academy of Sciences (India)

    Department of Mechanical Engineering, Engineering Faculty, Mersin University, 33343 Ciftlikkoy, Mersin, Turkey; Metallurgy Materials Engineering Department, Engineering Faculty, Karabuk University Baliklarkayasi, Karabuk, Turkey; Faculty of Tarsus Technical Education, Mersin University, 33480 Tarsus, Turkey ...

  10. Global policy and programme guidance on maternal nutrition: what exists, the mechanisms for providing it, and how to improve them?

    Science.gov (United States)

    Shrimpton, Roger

    2012-07-01

    Undernutrition in one form or another affects the majority of women of reproductive age in most developing countries. However, there are few or no effective programmes trying to solve maternal undernutrition problems. The purpose of the paper is to examine global policy and programme guidance mechanisms for nutrition, what their content is with regard to maternal nutrition in particular, as well as how these might be improved. Almost all countries have committed themselves politically to ensuring the right of pregnant and lactating women to good nutrition through the Convention on the Elimination of all Forms of Discrimination Against Women. Despite this, the World Health Organization (WHO) has not endorsed any policy commitments with regard to maternal nutrition. The only policy guidance coming from the various technical departments of WHO relates to the control of maternal anaemia. There is no policy or programme guidance concerning issues of maternal thinness, weight gain during pregnancy and/or low birthweight prevention. Few if any countries have maternal nutrition programmes beyond those for maternal anaemia, and most of those are not effective. The lack of importance given to maternal nutrition is related in part to a weakness of evidence, related to the difficulty of getting ethical clearance, as well as a generalised tendency to downplay the importance of those interventions found to be efficacious. No priority has been given to implementing existing policy and programme guidance for the control of maternal anaemia largely because of a lack of any dedicated funding, linked to a lack of Millennium Development Goals indicator status. This is partly due to the poor evidence base, as well as to the common belief that maternal anaemia programmes were not effective, even if efficacious. The process of providing evidence-based policy and programme guidance to member states is currently being revamped and strengthened by the Department of Nutrition for Health and

  11. [Fluoroquinolones in ophthalmology: mechanisms of action and resistance].

    Science.gov (United States)

    Labetoulle, M; Chiquet, C

    2008-10-01

    The arrival of fluoroquinolones in the 1980s aroused enormous enthusiasm in the medical community, justified by the spectrum of antibacterial activity, good tolerance, and wide distribution in tissues, even after oral administration. However, the extensive use of these new antibiotiques finally ended in emerging resistance, which limits the efficiency of all the molecules in the class, including those that have appeared in the last few years. Ocular diseases also benefited from the emergence of fluoroquinolones, notably for topical treatments. It is now mandatory to adapt the prescriptions to the best indications, in order to protect the vast therapeutic potential of these molecules.

  12. Activation and Transfer of the Chromosomal Phage Resistance Mechanism AbiV in Lactococcus lactis

    DEFF Research Database (Denmark)

    Haaber, J.; Moineau, S.; Hammer, Karin

    2009-01-01

    AbiV is a chromosomally encoded phage resistance mechanism that is silent in the wild-type phage-sensitive strain Lactococcus lactis subsp. cremoris MG1363. Spontaneous phage-resistant mutants of L. lactis MG1363 were analyzed by reverse transcriptase PCR and shown to express AbiV. This expression...... was related to a reorganization in the upstream region of abiV. Transfer of abiV between two lactococcal strains, most likely by conjugation, was also demonstrated. To our knowledge, this is the first report of natural transfer of a chromosomally encoded phage resistance mechanism....

  13. Genomic sequencing of a strain of Acinetobacter baumannii and potential mechanisms to antibiotics resistance.

    Science.gov (United States)

    Zhao, Lei; Li, Hongru; Zhu, Ziwen; Wakefield, Mark R; Fang, Yujiang; Ye, Ying

    2017-06-01

    Acinetobacter baumannii has been becoming a great challenge to clinicians due to their resistance to almost all available antibiotics. In this study, we sequenced the genome from a multiple antibiotics resistant Acinetobacter baumannii stain which was named A. baumannii-1isolated from China by SMRT sequencing technology to explore its potential mechanisms to antibiotic resistance. We found that several mechanisms might contribute to the antibiotic resistance of Acinetobacter baumannii. Specifically, we found that SNP in genes associated with nucleotide excision repair and ABC transporter might contribute to its resistance to multiple antibiotics; we also found that specific genes associated with bacterial DNA integration and recombination, DNA-mediated transposition and response to antibiotics might contribute to its resistance to multiple antibiotics; Furthermore, specific genes associated with penicillin and cephalosporin biosynthetic pathway and specific genes associated with CHDL and MBL β-lactamase genes might contribute to its resistance to multiple antibiotics. Thus, the detailed mechanisms by which Acinetobacter baumannii show extensive resistance to multiple antibiotics are very complicated. Such a study might be helpful to develop new strategies to control Acinetobacter baumannii infection. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. [Advances in molecular mechanisms of bacterial resistance caused by stress-induced transfer of resistance genes--a review].

    Science.gov (United States)

    Sun, Dongchang; Wang, Bing; Zhu, Lihong

    2013-07-04

    The transfer of resistance gene is one of the most important causes of bacterial resistance. Recent studies reveal that stresses induce the transfer of antibiotic resistance gene through multiple mechanisms. DNA damage stresses trigger bacterial SOS response and induce the transfer of resistance gene mediated by conjugative DNA. Antibiotic stresses induce natural bacterial competence for transformation in some bacteria which lack the SOS system. In addition, our latest studies show that the general stress response regulator RpoS regulates a novel type of resistance gene transfer which is mediated by double-stranded plasmid DNA and occurs exclusively on the solid surface. In this review, we summarized recent advances in SOS dependent and independent stress-induced DNA transfer which is mediated by conjugation and transformation respectively, and the transfer of double-stranded plasmid DNA on the solid surface which is regulated by RpoS. We propose that future work should address how stresses activate the key regulators and how these regulators control the expression of gene transfer related genes. Answers to the above questions would pave the way for searching for candidate targets for controlling bacterial resistance resulted from the transfer of antibiotic genes.

  15. Mechanisms and management of diuretic resistance in congestive heart failure.

    Science.gov (United States)

    De Bruyne, L K M

    2003-05-01

    Diuretic drugs are used almost universally in patients with congestive heart failure, most frequently the potent loop diuretics. Despite their unproven effect on survival, their indisputable efficacy in relieving congestive symptoms makes them first line therapy for most patients. In the treatment of more advanced stages of heart failure diuretics may fail to control salt and water retention despite the use of appropriate doses. Diuretic resistance may be caused by decreased renal function and reduced and delayed peak concentrations of loop diuretics in the tubular fluid, but it can also be observed in the absence of these pharmacokinetic abnormalities. When the effect of a short acting diuretic has worn off, postdiuretic salt retention will occur during the rest of the day. Chronic treatment with a loop diuretic results in compensatory hypertrophy of epithelial cells downstream from the thick ascending limb and consequently its diuretic effect will be blunted. Strategies to overcome diuretic resistance include restriction of sodium intake, changes in dose, changes in timing, and combination diuretic therapy.

  16. Interplay between mutational and horizontally acquired resistance mechanisms and its association with carbapenem resistance amongst extensively drug-resistant Pseudomonas aeruginosa (XDR-PA).

    Science.gov (United States)

    Shu, Jwu-Ching; Chia, Ju-Hsin; Siu, Leung-Kei; Kuo, An-Jing; Huang, Shu-Huan; Su, Lin-Hui; Wu, Tsu-Lan

    2012-03-01

    Between 2003 and 2009, the prevalence of extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) increased significantly in northern Taiwan from 1.0% to 2.1%. Molecular methods were used to investigate the genetic relatedness and carbapenem resistance mechanisms of a collection of 203 non-repetitive XDR-PA isolates available for study. Using pulsed-field gel electrophoresis (PFGE), 52 genotypes were observed; one predominant genotype (pulsotype 1) was found in 57.6% of the isolates. Polymerase chain reaction (PCR), sequencing and quantitative reverse-transcriptase PCR analyses demonstrated that one horizontally acquired mechanism [metallo-β-lactamase (MBL) genes] and two mutational mechanisms (efflux and porins) accounted for the carbapenem resistance. The most predominant horizontally acquired mechanism was carriage of bla(VIM-3), which was found in 61.1% of isolates. Decreased expression of oprD was the most prevalent mutational mechanism and was found in 70.0% of the XDR-PA isolates, whereas overexpression of mexA was found in 27.6% of the isolates. The highlight of this study was the discovery of statistically significant relationships between certain horizontally acquired and mutational resistance mechanisms and their contribution to carbapenem susceptibility. MBL-producers expressed significantly lower MexAB and higher OprD than non-MBL-producers. Amongst isolates without an acquired β-lactamase gene, oprD expression was significantly reduced, whilst expression of efflux pumps was increased. Reduced OprD expression alone or the production of VIM-type MBLs showed similar contributions to a low to intermediate MIC(50) (minimum inhibitory concentration for 50% of the organisms) for carbapenems. Isolates with reduced OprD expression that simultaneously harboured bla(VIM) exhibited high levels of resistance to carbapenems, which implied that these two mechanisms had a synergistic effect on the MICs. Copyright © 2011 Elsevier B.V. and the International

  17. Mechanism of Action and Resistance to Daptomycin in Staphylococcus aureus and Enterococci.

    Science.gov (United States)

    Miller, William R; Bayer, Arnold S; Arias, Cesar A

    2016-11-01

    Lipopeptides are natural product antibiotics that consist of a peptide core with a lipid tail with a diverse array of target organisms and mechanisms of action. Daptomycin (DAP) is an example of these compounds with specific activity against Gram-positive organisms. DAP has become increasingly important to combat infections caused by Gram-positive bacteria because of the presence of multidrug resistance in these organisms, particularly in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). However, emergence of resistance to DAP during therapy is a well-described phenomenon that threatens the clinical use of this antibiotic, limiting further the therapeutic options against both MRSA and VRE. This work will review the historical aspects of the development of DAP, as well as the current knowledge on its mechanism of action and pathways to resistance in a clinically relevant context. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  18. Co-existence of bla OXA-23 and bla NDM-1 genes of Acinetobacter baumannii isolated from Nepal: antimicrobial resistance and clinical significance

    Directory of Open Access Journals (Sweden)

    Prabhu Raj Joshi

    2017-02-01

    Full Text Available Abstract Background Molecular analysis of carbapenem-resistant genes in Acinetobacter baumannii, an emerging pathogen, is less commonly reported from Nepal. In this study we determined the antibiotic susceptibility profile and genetic mechanism of carbapenem resistance in clinical isolates of A. baumannii. Methods A. baumannii were isolated from various clinical specimens and identified based on Gram staining, biochemical tests, and PCR amplification of organism specific 16S rRNA and bla OXA-51 genes. The antibiotic susceptibility testing was performed using disc diffusion and E-test method. Multiplex PCR assays were used to detect the following β-lactamase genes: four class D carbapenem hydrolyzing oxacillinases (bla OXA-51, bla OXA-23, bla OXA-24 and bla OXA-58. Uniplex PCRs were used to detect three class B metallo-β-lactamases genes (bla IMP, bla VIM and bla NDM-1, class C cephalosporin resistance genes (bla ADC, aminoglycoside resistance gene (aphA6, and ISAba1 of all isolates. Insertion sequence ISAba125 among NDM-1 positive strains was detected. Clonal relatedness of all isolates were analyzed using repetitive sequence-based PCR (rep-PCR. Results Of total 44 analyzed isolates, 97.7% (n = 43 were carbapenem-resistant A. baumannii (CR-AB and 97.7% (n = 43 were multidrug resistant A. baumannii (MDR-AB. One isolate was detected to be extremely drug resistant A. baumannii (XDR-AB. All the isolates were fully susceptible to colistin (MICs < 2 μg/ml. The bla OXA-23 gene was detected in all isolates, while bla NDM-1 was detected in 6 isolates (13.6%. Insertion sequence, ISAba1 was detected in all of bla OXA-23 positive isolates. ISAba125 was detected in all bla NDM-1 positive strains. The bla ADC and aphA6 genes were detected in 90.1 and 40.1%, respectively. The rep-PCR of all isolates represented 7 different genotypes. Conclusion We found high prevalence of CR-AB and MDR-AB with bla OXA-23 gene in a tertiary care hospital in

  19. A fracture mechanics assessment of surface cracks existing in protective layers of multi-layer composite pipes

    Czech Academy of Sciences Publication Activity Database

    Hutař, Pavel; Náhlík, Luboš; Šestáková, Lucie; Ševčík, Martin; Knésl, Zdeněk; Nezbedová, E.

    2010-01-01

    Roč. 92, č. 5 (2010), s. 1120-1125 ISSN 0263-8223 R&D Projects: GA ČR GA106/09/0279 Institutional research plan: CEZ:AV0Z20410507 Keywords : Protective layers * Multi-layer pipes damage * Fracture mechanics * Bi-material interface * Generalized stress intensity factor Subject RIV: JL - Materials Fatigue, Friction Mechanics Impact factor: 2.028, year: 2010

  20. Insecticide resistance is mediated by multiple mechanisms in recently introduced Aedes aegypti from Madeira Island (Portugal).

    Science.gov (United States)

    Seixas, Gonçalo; Grigoraki, Linda; Weetman, David; Vicente, José Luís; Silva, Ana Clara; Pinto, João; Vontas, John; Sousa, Carla Alexandra

    2017-07-01

    Aedes aegypti is a major mosquito vector of arboviruses, including dengue, chikungunya and Zika. In 2005, Ae. aegypti was identified for the first time in Madeira Island. Despite an initial insecticide-based vector control program, the species expanded throughout the Southern coast of the island, suggesting the presence of insecticide resistance. Here, we characterized the insecticide resistance status and the underlying mechanisms of two populations of Ae. aegypti from Madeira Island, Funchal and Paúl do Mar. WHO susceptibility bioassays indicated resistance to cyfluthrin, permethrin, fenitrothion and bendiocarb. Use of synergists significantly increased mortality rates, and biochemical assays indicated elevated activities of detoxification enzymes, suggesting the importance of metabolic resistance. Microarray-based transcriptome analysis detected significant upregulation in both populations of nine cytochrome P450 oxidase genes (including four known pyrethroid metabolizing enzymes), the organophosphate metabolizer CCEae3a, Glutathione-S-transferases, and multiple putative cuticle proteins. Genotyping of knockdown resistance loci linked to pyrethroid resistance revealed fixation of the 1534C mutation, and presence with moderate frequencies of the V1016I mutation in each population. Significant resistance to three major insecticide classes (pyrethroid, carbamate and organophosphate) is present in Ae. aegypti from Madeira Island, and appears to be mediated by multiple mechanisms. Implementation of appropriate resistance management strategies including rotation of insecticides with alternative modes of action, and methods other than chemical-based vector control are strongly advised to delay or reverse the spread of resistance and achieve efficient control.

  1. New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.

    Science.gov (United States)

    Zhang, Ying; Yang, Shao-Hui; Guo, Xiu-Li

    2017-12-01

    Nowadays, lung cancer, as a health problem in worldwide, has high mortality both in men and women. Despite advances in diagnosis and surgical techniques of lung cancer in recent decades, chemotherapy is still a fundamentally and extensively useful strategy. Vinca alkaloids are a class of important and widely used drugs in the treatment of lung cancer, targeting on the Vinca binding site at the exterior of microtubule plus ends. Either intrinsic or acquired resistance to chemotherapy of Vinca alkaloids has been a major obstacle to the treatment of lung cancer, which arose great interests in studies of understanding and overcoming resistance. In this review, we focused on the application and resistance mechanisms of the Vinca alkaloids such as vinblastine, vincristine, vinorelbine and vinflunine in lung cancer. We reviewed characteristic resistance mechanisms in lung cancer including over-expression of ATP-binding cassette (ABC) transporters P-glycoprotein and structural, functional or expression alterations of β-tubulin (βII, βIII, βIV) which may devote to the development of acquired resistance to the Vinca alkaloids; multidrug-resistance proteins (MRP1, MRP2, MRP3) and RLIP76 protein have also been identified that probably play a significant role in intrinsic resistance. Lung resistance-related protein (LRP) is contributed to lung cancer therapy resistance, but is not deal with the Vinca alkaloids resistance in lung cancer. Understanding the principle of the Vinca alkaloids in clinical application and mechanisms of drug resistance will support individualized lung cancer therapy and improve future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. [Carbapenem resistance in Pseudomonas aeruginosa isolates: an example of interaction between different mechanisms].

    Science.gov (United States)

    Santella, Gisela; Pollini, Simona; Docquier, Jean-Denis; Almuzara, Marisa; Gutkind, Gabriel; Rossolini, Gian Maria; Radice, Marcela

    2011-12-01

    To identify the outer membrane protein absent in the resistant isolates and to determine both the causes of its absence in the membrane and the presence of other mechanisms of carbapenem resistance in clinical isolates of Pseudomonas aeruginosa. Twenty isolates from an outbreak of P. aeruginosa previously characterized as metallo-beta-lactamase IMP-13 producers were studied. All the isolates exhibited equal expression of the IMP-13 enzyme, but only five of them were carbapenem-resistant. It was found that the five resistant isolates lacked a outer membrane protein. The oprD and ampC genes were sequenced; the outer membrane proteins were identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry; the OprD and AmpC expressions, as well as the Mex efflux system, were assessed by real-time polymerase chain reaction; and finally, the contribution of reduced OprD to carbapenem resistance was determined. The absent outer membrane protein in group R was identified as OprD-TS; however, no variations in its expression were observed. The oprD gene presented mutations in the five resistant isolates. The production of AmpC PDC-5-type enzyme and the MexAB-OprM efflux system was the same in both carbapenem-sensitive and -resistant isolates. The contribution of the combined presence of IMP-13 and reduced OprD to increased resistance was examined. Different mechanisms contribute to carbapenem resistance in IMP-13-producing isolates. The possibility that these IMP-13-producing isolates could go undetected poses a latent risk when selecting mutants with added resistance mechanisms in order to enhance carbapenem resistance.

  3. Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes.

    Science.gov (United States)

    Poirel, Laurent; Jayol, Aurélie; Nordmann, Patrice

    2017-04-01

    SUMMARYPolymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented. Copyright © 2017 American Society for Microbiology.

  4. The model of mechanisms of materials resistance to fracture

    International Nuclear Information System (INIS)

    Tyugashov, P.F.

    1994-01-01

    A description is made for shear, break-up and combined fracture mechanisms. The potentiality of the model proposed is demonstrated on study of load-elongation diagram for titanium alloy type VT3-1. Comparison of calculation result to with available experimental data confirms the validity of assumptions about materials behaviour under creep conditions. 3 refs., 3 tabs

  5. Nucleus geometry and mechanical properties of resistance spot ...

    Indian Academy of Sciences (India)

    ‡Faculty of Tarsus Technical Education, Mersin University, 33480 Tarsus, Turkey. MS received 10 April 2012; revised 5 July 2012. Abstract. In this study, mechanical ... Depending on the weld current and time, effects of zinc coating on tensile properties, microhardness values as well as microstructure nugget geometry and ...

  6. Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications

    Czech Academy of Sciences Publication Activity Database

    Spížek, Jaroslav; Řezanka, Tomáš

    2017-01-01

    Roč. 133, June 1 SI (2017), s. 20-28 ISSN 0006-2952 Institutional support: RVO:61388971 Keywords : Lincosamides * Chemical structure * Biosynthesis and mechanism of action Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 4.581, year: 2016

  7. A mechanism of acquired resistance to complement-mediated lysis by Entamoeba histolytica.

    Science.gov (United States)

    Gutiérrez-Kobeh, L; Cabrera, N; Pérez-Montfort, R

    1997-04-01

    Some Entamoeba histolytica strains resist complement-mediated lysis by serum. Susceptible and resistant strains activate the complement system equivalently, but resistant amebas evade killing by membrane attack complexes. Our objective was to determine the mechanism by which trophozoites of E. histolytica resist lysis by human serum. Amebas were made resistant to lysis by incubation with increasing concentrations of normal human serum. The possibility that resistant cells ingest membrane attack complexes was explored by subcellular fractionation of susceptible and resistant trophozoites treated with sublytic concentrations of human serum containing radiolabeled C9. In both cases, most of the label was in the fractions containing plasma membrane. The susceptible strain consistently showed more label associated with these fractions than the resistant strain. Thus, the possibility that the membrane attack complexes were released to the medium was explored. Both resistant and susceptible trophozoites release to the medium similar amounts of material excluded by Sepharose CL-2B in the presence or absence of normal human serum. Labeled C9 elutes together with the main bulk of proteins from the medium: this indicates that it is not in vesicles or high molecular weight aggregates. Coincubation of susceptible amebas with lysates of resistant trophozoites confers resistance to susceptible cells within 30 min. Resistance to lysis by serum can also be acquired by susceptible amebas after coincubation with lysates from human erythrocytes or after feeding them with whole human red blood cells. Resistant but not susceptible trophozoites show intense immunofluorescent staining on their surface with anti-human erythrocytic membrane antibody. These results suggest that amebas acquire resistance to lysis by serum by incorporating into their membranes complement regulatory proteins.

  8. Molecular mechanisms associated with Fluconazole resistance in clinical Candida albicans isolates from India.

    Science.gov (United States)

    Mane, Arati; Vidhate, Pallavi; Kusro, Chanchal; Waman, Vaishali; Saxena, Vandana; Kulkarni-Kale, Urmila; Risbud, Arun

    2016-02-01

    Resistance to azole antifungals is a significant problem in Candida albicans. An understanding of resistance at molecular level is essential for the development of strategies to tackle resistance and rationale design of newer antifungals and target-based molecular approaches. This study presents the first evaluation of molecular mechanisms associated with fluconazole resistance in clinical C.albicans isolates from India. Target site (ERG11) alterations were determined by DNA sequencing, whereas real-time PCRs were performed to quantify target and efflux pump genes (CDR1, CDR2, MDR1) in 87 [Fluconazole susceptible (n = 30), susceptible-dose dependent (n = 30) and resistant (n = 27)] C.albicans isolates. Cross-resistance to fluconazole, ketoconazole and itraconazole was observed in 74.1% isolates. Six amino acid substitutions were identified, including 4 (E116D, F145L, E226D, I437V) previously reported ones and 2 (P406L, Q474H) new ones. CDR1 over-expression was seen in 77.7% resistant isolates. CDR2 was exclusively expressed with CDR1 and their concomitant over-expression was associated with azole cross-resistance. MDR1 and ERG11 over-expression did not seem to be associated with resistance. Our results show that drug efflux mediated by Adenosine-5'-triphosphate (ATP)-binding cassette transporters, especially CDR1 is the predominant mechanism of fluconazole resistance and azole cross-resistance in C. albicans and indicate the need for research directed towards developing strategies to tackle efflux mediated resistance to salvage azoles. © 2015 Blackwell Verlag GmbH.

  9. Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

    International Nuclear Information System (INIS)

    Brown, Iain; Shalli, Kawan; McDonald, Sarah L; Moir, Susan E; Hutcheon, Andrew W; Heys, Steven D; Schofield, Andrew C

    2004-01-01

    Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

  10. Functional characterization of bacteria isolated from ancient arctic soil exposes diverse resistance mechanisms to modern antibiotics.

    Directory of Open Access Journals (Sweden)

    Gabriel G Perron

    Full Text Available Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, β-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, β-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes.

  11. Functional characterization of bacteria isolated from ancient arctic soil exposes diverse resistance mechanisms to modern antibiotics.

    Science.gov (United States)

    Perron, Gabriel G; Whyte, Lyle; Turnbaugh, Peter J; Goordial, Jacqueline; Hanage, William P; Dantas, Gautam; Desai, Michael M

    2015-01-01

    Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, β-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, β-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes.

  12. Functional Characterization of Bacteria Isolated from Ancient Arctic Soil Exposes Diverse Resistance Mechanisms to Modern Antibiotics

    Science.gov (United States)

    Perron, Gabriel G.; Whyte, Lyle; Turnbaugh, Peter J.; Goordial, Jacqueline; Hanage, William P.; Dantas, Gautam; Desai, Michael M.

    2015-01-01

    Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, β-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, β-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes. PMID:25807523

  13. The mechanics of tessellations - bioinspired strategies for fracture resistance.

    Science.gov (United States)

    Fratzl, Peter; Kolednik, Otmar; Fischer, F Dieter; Dean, Mason N

    2016-01-21

    Faced with a comparatively limited palette of minerals and organic polymers as building materials, evolution has arrived repeatedly on structural solutions that rely on clever geometric arrangements to avoid mechanical trade-offs in stiffness, strength and flexibility. In this tutorial review, we highlight the concept of tessellation, a structural motif that involves periodic soft and hard elements arranged in series and that appears in a vast array of invertebrate and vertebrate animal biomaterials. We start from basic mechanics principles on the effects of material heterogeneities in hypothetical structures, to derive common concepts from a diversity of natural examples of one-, two- and three-dimensional tilings/layerings. We show that the tessellation of a hard, continuous surface - its atomization into discrete elements connected by a softer phase - can theoretically result in maximization of material toughness, with little expense to stiffness or strength. Moreover, the arrangement of soft/flexible and hard/stiff elements into particular geometries can permit surprising functions, such as signal filtering or 'stretch and catch' responses, where the constrained flexibility of systems allows a built-in safety mechanism for ensuring that both compressive and tensile loads are managed well. Our analysis unites examples ranging from exoskeletal materials (fish scales, arthropod cuticle, turtle shell) to endoskeletal materials (bone, shark cartilage, sponge spicules) to attachment devices (mussel byssal threads), from both invertebrate and vertebrate animals, while spotlighting success and potential for bio-inspired manmade applications.

  14. Characterization of fecal vancomycin-resistant enterococci with acquired and intrinsic resistance mechanisms in wild animals, Spain.

    Science.gov (United States)

    Lozano, Carmen; Gonzalez-Barrio, David; Camacho, Maria Cruz; Lima-Barbero, Jose Francisco; de la Puente, Javier; Höfle, Ursula; Torres, Carmen

    2016-11-01

    The objectives were to evaluate the presence of vancomycin-resistant enterococci with acquired (VRE-a) and intrinsic (VRE-i) resistance mechanisms in fecal samples from different wild animals, and analyze their phenotypes and genotypes of antimicrobial resistance. A total of 348 cloacal/rectal samples from red-legged partridges (127), white storks (81), red kites (59), and wild boars (81) (June 2014/February 2015) were inoculated in Slanetz-Bartley agar supplemented with vancomycin (4 μg/mL). We investigated the susceptibility to 12 antimicrobials and the presence of 19 antimicrobial resistance and five virulence genes. In addition, we performed multilocus sequence typing, detection of IS16 and studied Tn1546 structure. One VRE-a isolate was identified in one wild boar. This isolate was identified as Enterococcus faecium, harbored vanA gene included into Tn1546 (truncated with IS1542/IS1216), and belonged to the new ST993. This isolate contained the erm(A), erm(B), tet(M), dfrG, and dfrK genes. Neither element IS16 nor the studied virulence genes were detected. Ninety-six VRE-i isolates were identified (89 Enterococcus gallinarum and seven Enterococcus casseliflavus), with the following prevalence: red kites (71.2 %), white storks (46.9 %), red-legged partridges (7.9 %), and wild boars (4.9 %). Most E. gallinarum isolates showed resistance to tetracycline (66.3 %) and/or erythromycin (46.1 %). High-level resistance to aminoglycosides was present among our VRE-i isolates: kanamycin (22.9 %), streptomycin (11.5 %), and gentamicin (9.4 %). In general, VRE-i isolates of red kites showed higher rates of resistance for non-glycopeptide agents than those of other animal species. The dissemination of acquired resistance mechanisms in natural environments could have implications in the global spread of resistance with public health implications.

  15. The Mechanisms of Maize Resistance to Fusarium verticillioides by comprehensive analysis of RNA-seq Data

    Directory of Open Access Journals (Sweden)

    Yanping Wang

    2016-11-01

    Full Text Available Fusarium verticillioides is the most commonly reported fungal species responsible for ear rot of maize which substantially reduces grain yield. It also results in a substantial accumulation of mycotoxins that give rise to toxic response when ingested by animals and humans. For inefficient control by chemical and agronomic measures, it thus becomes more desirable to select more resistant varieties. However, the molecular mechanisms underlying the infection process remain poorly understood, which hampers the application of quantitative resistance in breeding programs. Here, we reveal the disease-resistance mechanism of the maize inbred line of BT-1 which displays high resistance to ear rot using RNA high throughput sequencing. By analyzing RNA-seq data from the BT-1 kernels before and after F. verticillioides inoculation, we found that transcript levels of genes associated with key pathways are dramatically changed compared with the control treatment. Differential gene expression in ear rot resistant and susceptible maize was confirmed by RNA microarray and qRT-PCR analyses. Further investigation suggests that the small heat shock protein family, some secondary metabolites, and the signaling pathways of abscisic acid (ABA, jasmonic acid (JA or salicylic acids (SA may be involved in the pathogen-associated molecular pattern-triggered immunity against F. verticillioides. These data will not only provide new insights into the molecular resistant mechanisms against fungi invading, but may also result in the identification of key molecular factors associated with ear rot resistance in maize.

  16. Characterization of resistance mechanisms and genetic relatedness of carbapenem-resistant Acinetobacter baumannii isolated from blood, Italy.

    Science.gov (United States)

    Migliavacca, Roberta; Espinal, Paula; Principe, Luigi; Drago, Monica; Fugazza, Giulia; Roca, Ignasi; Nucleo, Elisabetta; Bracco, Silvia; Vila, Jordi; Pagani, Laura; Luzzaro, Francesco

    2013-02-01

    The aim of this study was to characterize the resistance mechanisms and genetic relatedness of 21 carbapenem-resistant Acinetobacter baumannii blood isolates collected in Italy during a 1-year multicenter prospective surveillance study. Genes coding for carbapenemase production were identified by polymerase chain reaction (PCR) and sequencing. Pulsed-field gel electrophoresis (PFGE), multiplex PCRs for group identification, and multilocus sequence typing (MLST) were used to determine genetic relationships. Carbapenem resistance was consistently related to the production of oxacillinases, mostly the plasmid-mediated OXA-58 enzyme. Strains producing the OXA-23 enzyme (chromosomally mediated) were also detected. Seven PFGE clones were identified, some of which being related to international (ICL- I and ICL-II) or national clonal lineages. Multiplex PCRs identified 4 different groups (group 2 being dominant), further distinguishable in 6 sequence types by MLST. The heterogeneity of profiles highlights the diffusion of international and national clonal lineages in Italy. Continuous surveillance is needed for monitoring the spread of these worrisome strains equipped with multiple drug resistance mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Non-genetic mechanisms communicating antibiotic resistance: rethinking strategies for antimicrobial drug design.

    Science.gov (United States)

    El-Halfawy, Omar M; Valvano, Miguel A

    2012-10-01

    Infections by multidrug-resistant bacteria are of great concern worldwide. In many cases, resistance is not due to the presence of specific antibiotic-modifying enzymes, but rather associated with a general impermeability of the bacterial cell envelope. The molecular bases of this intrinsic resistance are not completely understood. Moreover, horizontal gene transfers cannot solely explain the spread of intrinsic resistance among bacterial strains. This review focuses on the increased intrinsic antibiotic resistance mediated by small molecules. These small molecules can either be secreted from bacterial cells of the same or different species (e.g., indole, polyamines, ammonia, and the Pseudomonas quinolone signal) or be present in the bacterial cell milieu, whether in the environment, such as indole acetic acid and other plant hormones, or in human tissues and body fluids, such as polyamines. These molecules are metabolic byproducts that act as infochemicals and modulate bacterial responses toward antibiotics leading to increasing or decreasing resistance levels. The non-genetic mechanisms of antibiotic response modulation and communication discussed in this review should reorient our thinking of the mechanisms of intrinsic resistance to antibiotics and its spread across bacterial cell populations. The identification of chemical signals mediating increased intrinsic antibiotic resistance will expose novel critical targets for the development of new antimicrobial strategies.

  18. Drug Resistance in Malaria: Investigation of Mechanisms and Patterns of Drug Resistance and Cross Resistance in Malaria.

    Science.gov (United States)

    1987-10-19

    patients with G6PD deficiency . Furthermore, the increase in fer- riheme may mediate the selective toxicity of menadione for Plasmodium falciparum...may account for the resistance to malaria afforded by G6PD deficiency ." Next, we focused on the process of FP detoxification. Initially, we searched

  19. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK

    International Nuclear Information System (INIS)

    Sun, Hui-Yong; Ji, Feng-Qin

    2012-01-01

    Highlights: ► The study revealed the detailed resistance mechanism of the non-active mutation C1156Y in ALK. ► C1156Y leads to crizotinib displacement and conformational changes in the binding cavity. ► The conformations cause a decline in the vdW and electrostatic energy between crizotinib and ALK. -- Abstract: Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.

  20. Fluoroquinolone Resistance Mechanisms in an Escherichia coli Isolate, HUE1, Without Quinolone Resistance-Determining Region Mutations

    Directory of Open Access Journals (Sweden)

    Toyotaka eSato

    2013-05-01

    Full Text Available Fluoroquinolone resistance can cause major clinical problems. Here, we investigated fluoroquinolone resistance mechanisms in a clinical Escherichia coli isolate, HUE1, which had no mutations quinolone resistance-determining regions (QRDRs of DNA gyrase and topoisomerase IV. HUE1 demonstrated MICs that exceeded the breakpoints for ciprofloxacin, levofloxacin, and norfloxacin. HUE1 harbored oqxAB and qnrS1 on distinct plasmids. In addition, it exhibited lower intracellular ciprofloxacin concentrations and higher mRNA expression levels of efflux pumps and their global activators than did reference strains. The genes encoding AcrR (local AcrAB repressor and MarR (MarA repressor were disrupted by insertion of the transposon IS3-IS629 and a frameshift mutation, respectively. A series of mutants derived from HUE1 were obtained by plasmid curing and gene knockout using homologous recombination. Compared to the MICs of the parent strain HUE1, the fluoroquinolone MICs of these mutants indicated that qnrS1, oqxAB, acrAB, acrF, acrD, mdtK, mdfA, and tolC contributed to the reduced susceptibility to fluoroquinolone in HUE1. Therefore, fluoroquinolone resistance in HUE1 is caused by concomitant acquisition of QnrS1 and OqxAB and overexpression of AcrAB−TolC and other chromosome-encoded efflux pumps. Thus, we have demonstrated that QRDR mutations are not absolutely necessary for acquiring fluoroquinolone resistance in E. coli.

  1. Prevalence and Mechanism of Fluoroquinolone Resistance in Escherichia coli Isolated from Swine Feces in Korea.

    Science.gov (United States)

    Hu, Yoon Sung; Shin, Sook; Park, Yong Ho; Park, Kun Taek

    2017-07-01

    In this study, we investigated the prevalence and fluoroquinolone (FQ) resistance mechanisms in Escherichia coli isolated from swine fecal samples. E. coli isolates were collected from 171 (72.2%) of 237 swine fecal samples. Of these, 59 isolates (34.5%) were confirmed as FQ-resistant E. coli by the disk diffusion method. Of the FQ-resistant isolates, three major FQ resistance mechanisms were investigated. Of the 59 isolates, plasmid-mediated quinolone resistance genes were detected in 9 isolates (15.3%). Efflux pump activity was found in 56 isolates (94.9%); however, this was not correlated with the increased FQ resistance measured by determining the MIC. Point mutations in quinolone resistance-determining regions were the main cause of FQ resistance. All 59 ciprofloxacin-resistant isolates had mutations in quinolone resistance-determining regions; of these 59 isolates, all (100%) had mutations in gyrA, 58 (98.3%) had mutations in parC, 22 (37.3%) had mutations in parE, and none had mutations in gyrB. The predominant mutation type was double mutation in gyrA (Ser83Leu plus mutation in aspartic acid 87), and all FQ-resistant isolates (except one) that had mutations in parC or parE also had double mutations in gyrA. Importantly, the frequencies of multidrug-resistant and extended-spectrum β-lactamase-producing E. coli were significantly higher in the high ciprofloxacin MIC group in this study. Compared with previous studies in Korea, the prevalence of FQ resistance and plasmid-mediated quinolone resistance genes had increased considerably in swine. Although the use of FQ as a feed additive is prohibited in Korea, use for self-treatment and therapeutic purposes has been increasing, which may be responsible for the higher FQ resistance rate observed in this study. Therefore, prudent use of FQ on animal farms is warranted to reduce the evolution of FQ-resistant bacteria in the animal industry.

  2. Corrosion resistant iron aluminides exhibiting improved mechanical properties and corrosion resistance

    Science.gov (United States)

    Liu, Chain T.; McKamey, Claudette G.; Tortorelli, Peter F.; David, Stan A.

    1994-01-01

    The specification discloses a corrosion-resistant intermetallic alloy comprising, in atomic percent, an FeAl iron aluminide containing from about 30 to about 40% aluminum alloyed with from about 0.01 to 0.4% zirconium and from 0.01 to about 0.8% boron. The alloy exhibits considerably improved room temperature ductility for enhanced usefulness in structural applications. The high temperature strength and fabricability is improved by alloying with molybdenum, carbon, chromium and vanadium.

  3. Friction in Sliding Orthodontic Mechanics: Ceramic Brackets, Teflon-Coated Wires and Comparative Resistances

    Science.gov (United States)

    1989-01-01

    N Tn FRICTION IN SLIDING ORTHODONTIC MECHANICS: N CERAMIC BRACKETS, TEFLON-COATED WIRES , AND COMPARATIVE RESISTANCES 0 DTICSFLECTED James R. Gill1...obsolete. SECURITY CLASSIFICATION OF THIS PAGE AFIT/CI "OVERPRINT" I FRICTION IN SLIDING ORTHODONTIC MECHANICS: CERAMIC BRACKETS, TEFLON-COATED WIRES ...brackets, arch- wires , and ligations during simulated orthodontic edgewise sliding mechanics. Independent variables and their values were 1) bracket

  4. Development of a resilient mechanical sealing solution to resist electro corrosion in ultrapure feedwater applications

    Energy Technology Data Exchange (ETDEWEB)

    Loenhout, Gerard van [Flowservice Flow Solutions Division, Etten-Leur (Netherlands); Enders, Klaus; Schmerberg, Rainer [Vattenfall Europe Generation AG, Peitz (Germany)

    2012-11-01

    Ever since the introduction of mechanical seals on high speed boiler feed pumps in the sixties, mechanical seals have proven to be a reliable, cost effective sealing method. However, since the introduction of combined water treatment chemistry used in today's modern fossil-fuelled power stations, keeping mechanical seal reliability high, became a challenge. A pragmatic approach is presented. A resilient sealing solution was developed to resist electro corrosion for such critical feed water pumps. (orig.)

  5. Mechanism of single-layer 193-nm dissolution inhibition resist

    Science.gov (United States)

    Yan, Zhenglin; Houlihan, Francis M.; Reichmanis, Elsa; Nalamasu, Omkaram; Reiser, Arnost; Dabbagh, Gary; Hutton, Richard S.; Osei, Dan; Sousa, Jose; Bolan, Kevin J.

    2000-06-01

    We have found that the progress of developer base into films of terpolymers of norbornene (NB)-maleic anhydride (MA) and acrylic acid (AA) is a percolation process with a critical site concentration of x(c) equals 0.084 which suggests that every acrylic acid site in the terpolymer of norbornene-maleic anhydride-acrylic acid can make 12 monomer units of the polymer water compatible. In practice these systems are being used with various tert-butyl esters of cholic acid as dissolution inhibitors. The cholates differ very much in their dissolution inhibition factors (lowest t-butyl cholate (1.3) to highest t-butyl lithocholate glutarate dimer (7.4). The change in these factors corrected for molarity follow the hydrophobic character of the dissolution as measured by log(p). A quick screening method has also been established to evaluate dissolution inhibitors based on our observation that the cloud point (the volume % acetone in a water/acetone which gives persistent cloudiness) parallels the dissolution inhibiting power as measured by the dissolution inhibition factor. For dissolution promotion, optimal results are obtained with t-butyl 1,3,5-cyclohexanetricarboxylate (f equals -6.3) and poorest results with t-butyl lithocholate (f equals -2.8); this appears to track with the number of carboxyl groups and the hydrophobicity of the carboxylic acids. The Rmax found for resist formulations tracks well with these findings. Another factor in determining the ultimate achievable contrast is the degree of acidolytic deprotection achieved by the material. It appears that acidolyticaly cleaveable carboxylate esters with a higher concentration of electron withdrawing groups such as t-butyl 1,3,5-cyclohexanetricarboxylate are more effective.

  6. Molecular epidemiology and drug resistant mechanism in carbapenem-resistant Klebsiella pneumoniae isolated from pediatric patients in Shanghai, China.

    Science.gov (United States)

    Zhang, Xingyu; Chen, Di; Xu, Guifeng; Huang, Weichun; Wang, Xing

    2018-01-01

    Infection by carbapenem-resistant Klebsiella pneumoniae (CR-KP) is a public health challenge worldwide, in particular among children, which was associated with high morbidity and mortality rates. There was limited data in pediatric populations, thus this study aimed to investigate molecular epidemiology and drug resistant mechanism of CR-KP strains from pediatric patients in Shanghai, China. A total of 41 clinical CR-KP isolates from sputum, urine, blood or drainage fluid were collected between July 2014 and May 2015 in Shanghai Children's Medical Center. Multilocus sequence typing (MLST), antibiotic susceptibility testing, PCR amplification and sequencing of the drug resistance associated genes were applied to all these isolates. MLST analysis revealed 16 distinct STs identified within the 41 isolates, among which the most frequently represented were ST11(19.5%),ST25(14.6%),ST76(14.6%),ST37(9.8%).One new ST was first identified. All CR-KP isolates showed MDR phenotypes and were resistance to ceftazidime, imipenem, piperacillin / tazobactam, ceftriaxone, ampicillin /sulbactam, aztreonam. They were confirmed as carbapenemase producer, NDM-1 (56.1%, 23/41), IMP (26.8%, 11/41), KPC-2 (22.0%, 9/41) were detected. Of note, two isolates carried simultaneously both NDM-1 and IMP-4. All CR-KP strains contained at least one of extended spectrum β-lactamase genes tested(TEM, SHV, OXA-1, CTX-M group) and six isolates carried both ESBL and AmpC genes(DHA-1). Among the penicllinase and β-lactamase genes, the most frequently one is SHV(92.7%,38/41), followed by TEM-1(68.3%,28/41), CTX-M-14(43.9%,18/41), CTX-M-15(43.9%,14/41), OXA-1(14.6%,6/41). In the present study, NDM-1-producing isolates was the predominant CR-KP strains in children, follow by IMP and KPC-producing strains. NDM-1and IMP-4 were more frequent than KPC-2 and showed a multiclonal background. Those suggested carbapenem-resistant in children is diverse, and certain resistance mechanisms differ from prevalent

  7. Resistive switching properties and physical mechanism of europium oxide thin films

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Wei; Zou, Changwei [School of Physical Science and Technology, Lingnan Normal University, Zhanjiang (China); Bao, Dinghua [State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou (China)

    2017-09-15

    A forming-free resistive switching effect was obtained in Pt/Eu{sub 2}O{sub 3}/Pt devices in which the Eu{sub 2}O{sub 3} thin films were fabricated by a chemical solution deposition method. The devices show unipolar resistive switching with excellent switching parameters, such as high resistance ratio (10{sup 7}), stable resistance values (read at 0.2 V), low reset voltage, good endurance, and long retention time (up to 10{sup 4} s). On the basis of the analysis of the current-voltage (I-V) curves and the resistance-temperature dependence, it can be concluded that the dominant conducting mechanisms were ohmic behavior and Schottky emission at low resistance state and high resistance state, respectively. The resistive switching behavior could be explained by the formation and rupture of conductive filament, which is related to the abundant oxygen vacancies generated in the deposition process. This work demonstrates the great potential opportunities of Eu{sub 2}O{sub 3} thin film in resistive switching memory applications, which might possess distinguished properties. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  8. Adenocarcinoma of the lung with EGFR gene mutation and subsequent resistance mechanisms exploration: case report

    Directory of Open Access Journals (Sweden)

    Xu L

    2017-09-01

    Full Text Available Li Xu,1,2 Qian Z Wang,1,2 Lin Wu1,2 1Department of the Second Chest Medicine, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 2Department of the Second Chest Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China Abstract: The treatment of lung cancer has made paradigm-shift advancements in the past decade with the development of therapies directed at specific genetic alterations, such as epidermal growth factor receptor (EGFR. Here, we present a rare case of lung adenocarcinoma harboring EGFR activating mutation and ALK overexpression. During the EGFR-tyrosine kinase inhibitors treatment, next-generation sequencing revealed phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway amplifications in tumor specimen and subsequent T790M mutation via plasma circulating tumor DNA. In conclusion, this case illustrates the existence of concomitant resistance mechanisms and demonstrates that circulating tumor DNA can reflect tumor heterogeneity. Keywords: epidermal growth factor receptor, PI3K/Akt/mTOR pathway, T790M, next-generation sequencing, circulating tumor DNA

  9. Investigation of corrosion resistance of alloys with high mechanical characteristics in some environments of food industry

    International Nuclear Information System (INIS)

    Tremoureux, Yves

    1978-01-01

    This research thesis aimed at improving knowledge in the field of stress-free corrosion of alloys with high mechanical characteristics in aqueous environments, at highlighting some necessary aspects of their behaviour during cleaning or disinfection, and at selecting alloys which possess a good stress-free corrosion resistance in view of a later investigation of their stress corrosion resistance. After a presentation of the metallurgical characteristics of high mechanical strength alloys and the report of a bibliographical study on corrosion resistance of these alloys, the author presents and discusses the results obtained in the study of a possible migration of metallic ions in a milk product which is submitted to a centrifugation, and of the corrosion resistance of selected alloys with respect to the different media they will be in contact with during ultra-centrifugation. The following alloys have been used in this research: Marval 18, Marphynox, Marval X12, 17-4PH steel, Inconel 718 [fr

  10. Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options

    Science.gov (United States)

    Lee, Chang-Ro; Lee, Jung Hun; Park, Moonhee; Park, Kwang Seung; Bae, Il Kwon; Kim, Young Bae; Cha, Chang-Jun; Jeong, Byeong Chul; Lee, Sang Hee

    2017-01-01

    Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized. PMID:28348979

  11. Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice

    DEFF Research Database (Denmark)

    Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper

    2017-01-01

    A single-nucleotide polymorphism in the human arylamine N-acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we...... examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle...... adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid...

  12. Insulin Signaling, Resistance, and the Metabolic Syndrome: Insights from Mouse Models to Disease Mechanisms

    OpenAIRE

    Guo, Shaodong

    2014-01-01

    Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal stud...

  13. Bulgecin A as a β-lactam enhancer for carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii clinical isolates containing various resistance mechanisms

    Directory of Open Access Journals (Sweden)

    Skalweit MJ

    2016-09-01

    Full Text Available Marion J Skalweit,1–5 Mei Li2 1Department of Medicine, 2Research Section, 3Infectious Diseases Section, Louis Stokes Cleveland Department of Veterans, 4Department of Medicine, 5Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA Abstract: Genetic screening of Pseudomonas aeruginosa (PSDA and Acinetobacter ­baumannii (ACB reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn2+ metallo-β-lactamases like L1 of Stenotrophomonas maltophilia. We hypothesized that because of its unique mechanism of action, BlgA could restore susceptibility to carbapenems in carbapenem-resistant PSDA (CR-PSDA and carbapenem-resistant ACB, as well as ACB resistant to sulbactam. A BlgA-containing extract was prepared using a previously published protocol. CR-PSDA clinical isolates demonstrating a variety of carbapenem resistance mechanisms (VIM-2 carbapenemases, efflux mechanisms, and AmpC producer expression were characterized with agar dilution minimum inhibitory concentration (MIC testing and polymerase chain reaction. Growth curves using these strains were prepared using meropenem, BlgA extract, and meropenem plus BlgA extract. A concentrated Blg A extract combined with low concentrations of meropenem, was able to inhibit the growth of clinical strains of CR-PSDA for strains that had meropenem MICs ≥8 mg/L by agar dilution, and a clinical strain of an OXA-24 producing ACB that had a meropenem MIC >32 mg/L and intermediate ampicillin/sulbactam susceptibility. Similar experiments were conducted on a TEM-1 producing ACB strain resistant to sulbactam. BlgA with ampicillin/sulbactam inhibited the growth

  14. Molecular mechanisms associated with nosocomial carbapenem-resistant Acinetobacter baumannii in Mexico.

    Science.gov (United States)

    Alcántar-Curiel, María Dolores; García-Torres, Luis Francisco; González-Chávez, María Inés; Morfín-Otero, Rayo; Gayosso-Vázquez, Catalina; Jarillo-Quijada, Ma Dolores; Fernández-Vázquez, José Luis; Giono-Cerezo, Silvia; Rodríguez-Noriega, Eduardo; Santos-Preciado, José Ignacio

    2014-10-01

    Acinetobacter baumannii is an emerging pathogen worldwide that is most commonly associated with nosocomial infections and multi-drug resistance. In the present study we determined the mechanisms of carbapenem resistance and clonal diversity of A. baumannii nosocomial isolates in Hospital Civil de Guadalajara, Mexico. A total of 303 clinical isolates of A. baumannii identified during a period expanding from 2004-2011 were analyzed for carbapenem resistance using several microbiological and molecular methods. Clonal relatedness of these isolates was determined using pulsed-field gel electrophoresis. Of the 303 isolates, 84% were resistant to meropenem, 71.3% to imipenem and 78.3% the resistant isolates were positive for metallo-β-lactamases as determined by the phenotypic assay. In addition, 49.6% of carbapenem-intermediate or -resistant isolates carried the blaOXA-72 gene and 1.2% carried the blaVIM-1 gene. Efflux pump phenotype was responsible for reduced susceptibility to meropenem in 14.5% and to imipenem in 31.6% of the resistant isolates, respectively in the presence of the efflux pump inhibitor, carbonyl cyanide 3-chlorophenylhydrazone. Strains representing different carbapenem-resistant patterns exhibited reduced expression of 22, 29, 33, and 43 kDa OMPs. Among the bacterial collection studied, 48 different clones were identified, two of which were predominant and persistently transmitted. Carbapenemase production in combination with efflux pump expression, reduction in OMPs expression and the cross-transmission of clones appear to be major contributors to the high frequency of carbapenem-resistance observed in A. baumannii. To our knowledge, this is the first study to define the molecular mechanisms associated with carbapenem-resistance in A. baumannii in Mexico. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

  15. Use of mutagenesis, genetic mapping and next generation transcriptomics to investigate insecticide resistance mechanisms.

    Directory of Open Access Journals (Sweden)

    Predrag Kalajdzic

    Full Text Available Insecticide resistance is a worldwide problem with major impact on agriculture and human health. Understanding the underlying molecular mechanisms is crucial for the management of the phenomenon; however, this information often comes late with respect to the implementation of efficient counter-measures, particularly in the case of metabolism-based resistance mechanisms. We employed a genome-wide insertional mutagenesis screen to Drosophila melanogaster, using a Minos-based construct, and retrieved a line (MiT[w(-]3R2 resistant to the neonicotinoid insecticide Imidacloprid. Biochemical and bioassay data indicated that resistance was due to increased P450 detoxification. Deep sequencing transcriptomic analysis revealed substantial over- and under-representation of 357 transcripts in the resistant line, including statistically significant changes in mixed function oxidases, peptidases and cuticular proteins. Three P450 genes (Cyp4p2, Cyp6a2 and Cyp6g1 located on the 2R chromosome, are highly up-regulated in mutant flies compared to susceptible Drosophila. One of them (Cyp6g1 has been already described as a major factor for Imidacloprid resistance, which validated the approach. Elevated expression of the Cyp4p2 was not previously documented in Drosophila lines resistant to neonicotinoids. In silico analysis using the Drosophila reference genome failed to detect transcription binding factors or microRNAs associated with the over-expressed Cyp genes. The resistant line did not contain a Minos insertion in its chromosomes, suggesting a hit-and-run event, i.e. an insertion of the transposable element, followed by an excision which caused the mutation. Genetic mapping placed the resistance locus to the right arm of the second chromosome, within a ∼1 Mb region, where the highly up-regulated Cyp6g1 gene is located. The nature of the unknown mutation that causes resistance is discussed on the basis of these results.

  16. Antimicrobial resistance (AMR) nanomachines-mechanisms for fluoroquinolone and glycopeptide recognition, efflux and/or deactivation.

    Science.gov (United States)

    Phillips-Jones, Mary K; Harding, Stephen E

    2018-04-01

    In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics-the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins. Expression of efflux systems is regulated by GntR-like (S. aureus NorG), MarR-like (MgrA, MepR) regulators or a two-component signal transduction system (TCS) (S. aureus ArlSR). Resistance to the glycopeptide antibiotic teicoplanin occurs via efflux regulated by the TcaR regulator in S. aureus. Resistance to vancomycin occurs through modification of the D-Ala-D-Ala target in the cell wall peptidoglycan and removal of high affinity precursors, or by target protection via cell wall thickening. Of the six Van resistance types (VanA-E, VanG), the VanA resistance type is considered in this review, including its regulation by the VanSR TCS. We describe the recent application of biophysical approaches such as the hydrodynamic technique of analytical ultracentrifugation and circular dichroism spectroscopy to identify the possible molecular effector of the VanS receptor that activates expression of the Van resistance genes; both approaches demonstrated that vancomycin interacts with VanS, suggesting that vancomycin itself (or vancomycin with an accessory factor) may be an effector of vancomycin resistance. With 16 and 19 proteins or protein complexes involved in fluoroquinolone and glycopeptide resistances, respectively, and the complexities of bacterial sensing mechanisms that

  17. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Pseudomonas aeruginosa May Accumulate Drug Resistance Mechanisms without Losing Its Ability To Cause Bloodstream Infections▿

    Science.gov (United States)

    Hocquet, Didier; Berthelot, Philippe; Roussel-Delvallez, Micheline; Favre, Roger; Jeannot, Katy; Bajolet, Odile; Marty, Nicole; Grattard, Florence; Mariani-Kurkdjian, Patricia; Bingen, Edouard; Husson, Marie-Odile; Couetdic, Gérard; Plésiat, Patrick

    2007-01-01

    In this study, we systematically investigated the resistance mechanisms to β-lactams, aminoglycosides, and fluoroquinolones of 120 bacteremic strains of Pseudomonas aeruginosa. Pulsed-field gel electrophoresis genotyping showed that 97 of these strains were represented by a single isolate, 10 by 2 and 1 by 3 clonally related isolates, respectively. Seventy-five percent (90 out of 120) of the bacteremic P. aeruginosa strains displayed a significant resistance to one or more of the tested antimicrobials (up to 11 for 1 strain). These strains were found to harbor a great diversity of resistance mechanisms (up to 7 in 1 strain), leading to various levels of drug resistance. Interestingly, 11 and 36% of the isolates appeared to overproduce the MexAB-OprM and MexXY-OprM efflux systems, respectively. Altogether, our results show that P. aeruginosa may accumulate intrinsic (overproduction of cephalosporinase AmpC, increased drug efflux, fluoroquinolone target mutations, and deficient production of porin OprD) and exogenous (production of secondary β-lactamases and aminoglycoside-modifying enzymes) resistance mechanisms without losing its ability to generate severe bloodstream infections. Consequently, clinicians should be aware that multidrug-resistant P. aeruginosa may remain fully pathogenic. PMID:17682106

  19. Survey on the phage resistance mechanisms displayed by a dairy Lactobacillus helveticus strain.

    Science.gov (United States)

    Zago, Miriam; Orrù, Luigi; Rossetti, Lia; Lamontanara, Antonella; Fornasari, Maria Emanuela; Bonvini, Barbara; Meucci, Aurora; Carminati, Domenico; Cattivelli, Luigi; Giraffa, Giorgio

    2017-09-01

    In this study the presence and functionality of phage defence mechanisms in Lactobacillus helveticus ATCC 10386, a strain of dairy origin which is sensitive to ΦLh56, were investigated. After exposure of ATCC 10386 to ΦLh56, the whole-genome sequences of ATCC 10386 and of a phage-resistant derivative (LhM3) were compared. LhM3 showed deletions in the S-layer protein and a higher expression of the genes involved in the restriction/modification (R/M) system. Genetic data were substantiated by measurements of bacteriophage adsorption rates, efficiency of plaquing, cell wall protein size and by gene expression analysis. In LhM3 two phage resistance mechanisms, the inhibition of phage adsorption and the upregulation of Type I R/M genes, take place and explain its resistance to ΦLh56. Although present in both ATCC 10386 and LhM3 genomes, the CRISPR machinery did not seem to play a role in the phage resistance of LhM3. Overall, the natural selection of phage resistant strains resulted successful in detecting variants carrying multiple phage defence mechanisms in L. helveticus. The concurrent presence of multiple phage-resistance systems should provide starter strains with increased fitness and robustness in dairy ecosystems. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    Biagio Arcidiacono

    2012-01-01

    Full Text Available Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D, in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance and the increase in bioavailable insulin-like growth factor I (IGF-I appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG, whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

  1. Mechanisms of pyrethroid resistance inHaematobia irritans (Muscidae from Mato Grosso do Sul state, Brazil

    Directory of Open Access Journals (Sweden)

    Antonio Thadeu Medeiros Barros

    Full Text Available Horn fly resistance to pyrethroid insecticides occurs throughout Brazil, but knowledge about the involved mechanisms is still in an incipient stage. This survey was aimed to identify the mechanisms of horn fly resistance to cypermethrin in Mato Grosso do Sul state, Brazil. Impregnated filter paper bioassays using cypermethrin, synergized or not with piperonyl butoxide (PBO and triphenyl phosphate (TPP, were conducted from March 2004 to June 2005 in horn fly populations (n = 33 from all over the state. All populations were highly resistant to cypermethrin, with resistance factors (RF ranging from 89.4 to 1,020.6. Polymerase chain reaction (PCR assays to detect the knockdown resistance (kdr mutation also were performed in 16 samples. The kdr mutation was found in 75% of the tested populations, mostly with relatively low frequencies (<20%, and was absent in some highly resistant populations. Addition of TPP did not significantly reduce the LC50 in any population. However, PBO reduced LC50s above 40-fold in all tested populations, resulting in RFs ≤ 10 in most cases. Horn fly resistance to cypermethrin is widespread in the state, being primarily caused by an enhanced activity of P450 mono-oxygenases and secondarily by reduced target site sensitivity.

  2. Conducting mechanism of Ag-diffused Bi-Te based resistive switching devices

    Science.gov (United States)

    Liu, N.; Yan, P.; Li, Y.; Lu, K.; Sun, H. J.; Ji, H. K.; Xue, K. H.; Miao, X. S.

    2018-02-01

    The forming-free resistive switching (RS) and conducting mechanism of Ag-diffused BiTe chalcogenide thin film has been investigated. The mutual diffusion of Ag, Bi and Te elements at the interface is proved to suppress the crystallization of the as-deposited BiTe film. The amorphization of BiTe and the Schottky barrier between Ag and BiTe contribute to high resistance state (HRS) of the switching devices. When switched to low resistance state (LRS), the coexistence of metallic conduction and variable-range hopping is found to be the dominant conduction mechanism. The temperature dependence of LRS exhibits an interesting transport behavior, so that a positive temperature coefficient becomes a negative one at 24 K. Our results help to further understand the conduction mechanism and promote the design for future nonvolatile memory applications.

  3. [Isolation of a carbapenem-resistant K1 serotype Klebsiella pneumonia strain and the study of resistance mechanism].

    Science.gov (United States)

    Zhang, Rong; Wang, Xuan; Lü, Jianxin

    2014-12-16

    To study the virulence and mechanism of carbapenem resistance of a clinical isolate of carbapenem-resistant K1 serotype Klebsiella pneumonia strain. Identification of isolate was carried out with VITEK-2 compact system. Antimicrobial susceptibility was determined by E-test; Metallo β-lactamases and carbapenemases screening were conducted by imipenem-EDTA double disc synergy test and modified Hodge test, respectively.Specific polymerehse chain reaction (PCR) and DNA sequencing were preformed to detect the virulence genes including K1, K2, K5, K20, K54, K57, magA, rmpA, wcaG and a series of β-lactamase resistence genes. Conjunction experiment was also performed. The plasmids of transconjugants were submitted to PCR-based replicon typing (PBRT) method. Molecular typing was performed by multilocus sequence typing (MLST). Antimicrobial susceptibility testing revealed that the Klebsiella pneumonia strain was resistant to most of the antibiotics used in clinic. Phynotype confirmary rest revealed the production of carbapanemases, while Metallo β-lactamases were negative; PCR and DNA sequencing confirmed the isolate was positive for blaKPC-2, blaCTX-M-15, blaTEM-1, blaSHV-1 and virulence genes K1, magA, rmpA, wcaG simultaneously; blaKPC-2 was transferred from donor to Escherichia EC600 by conjunction experiment, while no virulence genes were found in the transconjugants. PBRT revealed that Frep plasmid was found in transconjugants. MLST analysis revealed that this strain belonged to ST23. K1 serotype Klebsiella pneumonia strain carries virulence genes and carbapenem resistance gene blaKPC-2, noteworthily the carbapenem resistance genes can be transferred through horizontal transmission on plasmids.

  4. Mechanisms of group A Streptococcus resistance to reactive oxygen species

    Science.gov (United States)

    Henningham, Anna; Döhrmann, Simon; Nizet, Victor; Cole, Jason N.

    2015-01-01

    Streptococcus pyogenes, also known as group A Streptococcus (GAS), is an exclusively human Gram-positive bacterial pathogen ranked among the ‘top 10’ causes of infection-related deaths worldwide. GAS commonly causes benign and self-limiting epithelial infections (pharyngitis and impetigo), and less frequent severe invasive diseases (bacteremia, toxic shock syndrome and necrotizing fasciitis). Annually, GAS causes 700 million infections, including 1.8 million invasive infections with a mortality rate of 25%. In order to establish an infection, GAS must counteract the oxidative stress conditions generated by the release of reactive oxygen species (ROS) at the infection site by host immune cells such as neutrophils and monocytes. ROS are the highly reactive and toxic byproducts of oxygen metabolism, including hydrogen peroxide (H2O2), superoxide anion (O2•−), hydroxyl radicals (OH•) and singlet oxygen (O2*), which can damage bacterial nucleic acids, proteins and cell membranes. This review summarizes the enzymatic and regulatory mechanisms utilized by GAS to thwart ROS and survive under conditions of oxidative stress. PMID:25670736

  5. Mechanisms of group A Streptococcus resistance to reactive oxygen species.

    Science.gov (United States)

    Henningham, Anna; Döhrmann, Simon; Nizet, Victor; Cole, Jason N

    2015-07-01

    Streptococcus pyogenes, also known as group A Streptococcus (GAS), is an exclusively human Gram-positive bacterial pathogen ranked among the 'top 10' causes of infection-related deaths worldwide. GAS commonly causes benign and self-limiting epithelial infections (pharyngitis and impetigo), and less frequent severe invasive diseases (bacteremia, toxic shock syndrome and necrotizing fasciitis). Annually, GAS causes 700 million infections, including 1.8 million invasive infections with a mortality rate of 25%. In order to establish an infection, GAS must counteract the oxidative stress conditions generated by the release of reactive oxygen species (ROS) at the infection site by host immune cells such as neutrophils and monocytes. ROS are the highly reactive and toxic byproducts of oxygen metabolism, including hydrogen peroxide (H2O2), superoxide anion (O2•(-)), hydroxyl radicals (OH•) and singlet oxygen (O2*), which can damage bacterial nucleic acids, proteins and cell membranes. This review summarizes the enzymatic and regulatory mechanisms utilized by GAS to thwart ROS and survive under conditions of oxidative stress. © FEMS 2015.

  6. Low strigolactone root exudation: a novel mechanism of broomrape (Orobanche and Phelipanche spp.) resistance available for faba bean breeding.

    Science.gov (United States)

    Fernández-Aparicio, Mónica; Kisugi, Takaya; Xie, Xiaonan; Rubiales, Diego; Yoneyama, Koichi

    2014-07-23

    Faba bean yield is severely constrained in the Mediterranean region and Middle East by the parasitic weeds Orobanche crenata, O. foetida, and Phelipanche aegyptiaca. Seed germination of these weeds is triggered upon recognition of host root exudates. Only recently faba bean accessions have been identified with resistance based in low induction of parasitic seed germination, but the underlying mechanism was not identified. Strigolactones are a group of terpenoid lactones involved in the host recognition by parasitic plants. Our LC-MS/MS analysis of root exudates of the susceptible accession Prothabon detected orobanchol, orobanchyl acetate, and a novel germination stimulant. A time course analysis indicated that their concentration increased with plant age. However, low or undetectable amounts of these germination stimulants were detected in root exudates of the resistant lines Quijote and Navio at all plant ages. A time course analysis of seed germination induced by root exudates of each faba bean accession indicated important differences in the ability to stimulate parasitic germination. Results presented here show that resistance to parasitic weeds based on low strigolactone exudation does exist within faba bean germplasm. Therefore, selection for this trait is feasible in a breeding program. The remarkable fact that low induction of germination is similarly operative against O. crenata, O. foetida, and P. aegyptiaca reinforces the value of this resistance.

  7. New Introductions, Spread of Existing Matrilines, and High Rates of Pyrethroid Resistance Result in Chronic Infestations of Bed Bugs (Cimex lectularius L. in Lower-Income Housing.

    Directory of Open Access Journals (Sweden)

    Ronald W Raab

    Full Text Available Infestations of the common bed bug (Cimex lectularius L. have increased substantially in the United States in the past 10-15 years. The housing authority in Harrisonburg, Virginia, conducts heat-treatments after bed bugs are detected in a lower-income housing complex, by treating each infested unit at 60°C for 4-6 hours. However, a high frequency of recurrent infestations called into question the efficacy of this strategy. Genetic analysis using Bayesian clustering of polymorphic microsatellite loci from 123 bed bugs collected from 23 units from May 2012 to April 2013 in one building indicated that (a 16/21 (73% infestations were genetically similar, suggesting ineffective heat-treatments or reintroductions from within the building or from a common external source, followed by local spread of existing populations; and (b up to 5 of the infestations represented new genotypes, indicating that 5 new populations were introduced into this building in one year, assuming they were not missed in earlier screens. There was little to no gene flow among the 8 genetic clusters identified in the building. Bed bugs in the U.S. often possess one or both point mutations in the voltage-gated sodium channel, termed knockdown resistance (kdr, from valine to leucine (V419L and leucine to isoleucine (L925I that confer target-site resistance against pyrethroid insecticides. We found that 48/121 (40% bed bugs were homozygous for both kdr mutations (L419/I925, and a further 59% possessed at least one of the kdr mutations. We conclude that ineffective heat treatments, new introductions, reintroductions and local spread, and an exceptionally high frequency of pyrethroid resistance are responsible for chronic infestations in lower-income housing. Because heat treatments fail to protect from reintroductions, and pesticide use has not decreased the frequency of infestations, preventing new introductions and early detection are the most effective strategies to avoid bed bug

  8. Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata.

    Directory of Open Access Journals (Sweden)

    Sheena D Singh-Babak

    Full Text Available The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E mutation acquired before FKS2-T1987C(S663P, conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S mutation after FKS2-T1987C(S663P, ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations

  9. Mechanism of sulfonylurea herbicide resistance in the broadleaf weed, Kochia scoparia

    International Nuclear Information System (INIS)

    Saari, L.L.; Cotterman, J.C.; Primiani, M.M.

    1990-01-01

    Selection of kochia (Kochia scoparia) biotypes resistant to the sulfonylurea herbicide chlorsulfuron has occurred through the continued use of this herbicide in monoculture cereal-growing areas in the United States. The apparent sulfonylurea resistance observed in kochia was confirmed in greenhouse tests. Fresh and dry weight accumulation in the resistance kochia was 2- to >350-fold higher in the presence of four sulfonylurea herbicides as compared to the susceptible biotype. Acetolactate synthase (ALS) activity isolated from sulfonylurea-resistant kochia was less sensitive to inhibition by three classes of ALS-inhibiting herbicides, sulfonylureas, imidazolinones, and sulfonanilides. The decrease in ALS sensitivity to inhibition (as measured by the ratio of resistant I 50 to susceptible I 50 ) was 5- to 28-fold, 2- to 6-fold, and 20-fold for sulfonylurea herbicides, imidazolinone herbicides, and a sulfonanilide herbicide, respectively. No differences were observed in the ALS-specific activities or the rates of [ 14 C]chlorsulfuron uptake, translocation, and metabolism between susceptible and resistant kochia biotypes. The K m values for pyruvate using ALS from susceptible and resistant kochia were 2.13 and 1.74 mM, respectively. Based on these results, the mechanism of sulfonylurea resistance in this kochia biotype is due solely to a less sulfonylurea-sensitive ALS enzyme

  10. Scorecard - An innovative simplified tool to supplement the existing monitoring mechanism to assess and improve performance of antiretroviral treatment centers

    Directory of Open Access Journals (Sweden)

    Sudhir Chawla

    2017-01-01

    Full Text Available Introduction: All 26 antiretroviral treatment (ART centers of Gujarat were monitored by Gujarat State AIDS Control Society under the National AIDS Control Program. A comprehensive tool is needed to identify gap in service delivery and to prioritize monitoring visits. Objectives: To supplement the existing monitoring system, identify strengths/weakness of ART centers, and give recommendations. Methodology: Scorecard was developed in spreadsheet format with 17 scoring indicators on monthly base from March 2014 onward. The centers were classified in three color zones: green (score ≥80%, yellow (score <80% and ≥50%, and red (score <50%. Visits were prioritized at centers with more indicators in yellow/red zone. The performance of centers was compared for March 2014 and March 2015. Results: The statistically significant improvement was observed in indicator “ART initiation within 2 months of eligibility,” while after removing red zone from analysis, four more indicators named “eligible patients transferred out before ART initiation, general clients started on ART, antenatal women started on ART, and pre-ART follow-up CD4 done” reflect statistically significant improvement. Quadrant analysis was done for some indicators, which provide insight that less number of eligible patients may be a reason for low initiation of ART at one center, and at four other centers, the possible reasons for low retention are high death rate and high lost to follow-up rate. Based on these findings, the recommendations were made to regular mentoring centers, improve coordination between ART center and care and support centers (CSCs, and conduct verbal autopsy. Conclusion: Scorecard is a simple and cost-effective tool for monitoring, and by highlighting low-performing indicators, it helps in improving quality of services provided at ART centers.

  11. Mechanisms of Bactericide Resistance in Phytopathogenic Bacteria(Abstracts of the Research by the Winners of the Young Scientist Award)

    OpenAIRE

    Masami, NAKAJIMA; School of Agriculture, Ibaraki University

    2002-01-01

    Bactericides containing copper and streptomycin have been widely used to control bacterial plant diseases. However, the efficacy of copper and streptomycin have been reduced by the development of copper- and streptomycin-resistant bacterial strains. Understanding the mechanism of resistance is necessary for the prevention and management of resistance. In this study, the mechanisms of copper and streptomycin resistance in Pseudomonas syringae pv. actinidiae were analyzed.

  12. A cfr-positive clinical staphylococcal isolate from India with multiple mechanisms of linezolid-resistance

    Directory of Open Access Journals (Sweden)

    Vineeth Rajan

    2014-01-01

    Full Text Available Background & objectives: Linezolid, a member of the oxazolidinone class of antibiotics, has been an effective therapeutic option to treat severe infections caused by multidrug resistant Gram positive bacteria. Emergence of linezolid resistant clinical strains is a serious issue in the healthcare settings worldwide. We report here the molecular characterization of a linezolid resistant clinical isolate of Staphylococcus haemolyticus from India. Methods: The species of the clinical isolate was identified by 16S rRNA gene sequencing. The minimum inhibitory concentrations (MICs of linezolid, clindamycin, chloramphenicol and oxacillin were determined by E-test method. To elucidate the mechanism of linezolid-resistance, presence of cfr gene (chloramphenicol florfenicol resistance and mutations in 23S rRNA and ribosomal proteins (L3, L4 and L22 were investigated. Staphylococcal Cassette Chromosome mec (SCCmec typing was performed by multiplex PCR. Results: The study documented a rare clinical S. haemolyticus strain with three independent mechanisms of linezolid-resistance. The strain carried cfr gene, the only known transmissible mechanism of linezolid-resistance. The strain also possessed resistance-conferring mutations such as G 2576 T in domain V of 23S rRNA gene and Met 156 Thr in L3 ribosomal protein. The other ribosomal proteins (L4 and L22 did not exhibit mutations accountable for linezolid-resistance. Restriction digestion by NheI revealed that all the alleles of 23S rRNA gene were mutated. The isolate showed elevated MIC values (>256 ΅g ml -[1] of linezolid, clindamycin, chloramphenicol and oxacillin. Methicillin resistance was conferred by type I SCCmec element. The strain also harboured lsa(B gene which encodes an ABC transporter that can efflux clindamycin. Interpretation & conclusions: The present study reports the first clinical strain from India with transmissible and multiple mechanisms of linezolid-resistance. Judicious use of

  13. Prestressing Shock Resistant Mechanical Components and Mechanisms Made from Hard, Superelastic Materials

    Science.gov (United States)

    DellaCorte, Christopher (Inventor)

    2014-01-01

    A method and an apparatus confer full superelastic properties to the active surface of a mechanical component constructed of a superelastic material prior to service. A compressive load is applied to the active surface of the mechanical component followed by removing the compressive load from the active surface whereby substantially all load strain is recoverable after applying and removing of subsequent compressive loads.

  14. Bulgecin A as a β-lactam enhancer for carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii clinical isolates containing various resistance mechanisms.

    Science.gov (United States)

    Skalweit, Marion J; Li, Mei

    2016-01-01

    Genetic screening of Pseudomonas aeruginosa (PSDA) and Acinetobacter baumannii (ACB) reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA) is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn 2+ metallo-β-lactamases like L1 of Stenotrophomonas maltophilia . We hypothesized that because of its unique mechanism of action, BlgA could restore susceptibility to carbapenems in carbapenem-resistant PSDA (CR-PSDA) and carbapenem-resistant ACB, as well as ACB resistant to sulbactam. A BlgA-containing extract was prepared using a previously published protocol. CR-PSDA clinical isolates demonstrating a variety of carbapenem resistance mechanisms (VIM-2 carbapenemases, efflux mechanisms, and AmpC producer expression) were characterized with agar dilution minimum inhibitory concentration (MIC) testing and polymerase chain reaction. Growth curves using these strains were prepared using meropenem, BlgA extract, and meropenem plus BlgA extract. A concentrated Blg A extract combined with low concentrations of meropenem, was able to inhibit the growth of clinical strains of CR-PSDA for strains that had meropenem MICs ≥8 mg/L by agar dilution, and a clinical strain of an OXA-24 producing ACB that had a meropenem MIC >32 mg/L and intermediate ampicillin/sulbactam susceptibility. Similar experiments were conducted on a TEM-1 producing ACB strain resistant to sulbactam. BlgA with ampicillin/sulbactam inhibited the growth of this organism. As in Enterobacteriaceae, BlgA appears to restore the efficacy of meropenem in suppressing the growth of CR-PSDA and carbapenem-resistant ACB strains with a variety of common carbapenem resistance mechanisms. BlgA extract also inhibits VIM-2 β-lactamase in vitro. BlgA may prove to be

  15. Mechanism of HIV-1 Resistance to an Electronically Constrained α-Helical Peptide Membrane Fusion Inhibitor.

    Science.gov (United States)

    Wu, Xiyuan; Liu, Zixuan; Ding, Xiaohui; Yu, Danwei; Wei, Huamian; Qin, Bo; Zhu, Yuanmei; Chong, Huihui; Cui, Sheng; He, Yuxian

    2018-04-01

    SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor that is highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (N43K/E49A) or three (Q39R/N43K/N126K and N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20 and C34) and newly designed (sifuvirtide, MT-SC29EK, and 2P23) fusion inhibitors. The resistance mutations could reduce the binding stability of SC29EK, impair viral Env-mediated cell fusion and entry, and change the conformation of the gp41 core structure. Further, we determined the crystal structure of SC29EK in complex with a target mimic peptide, which revealed the critical intra- and interhelical interactions underlying the mode of action of SC29EK and the genetic pathway to HIV-1 resistance. Taken together, the present data provide new insights into the structure and function of gp41 and the structure-activity relationship (SAR) of viral fusion inhibitors. IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection, but it has relatively low anti-HIV activity and genetic barriers for resistance, thus calling for new drugs blocking the viral fusion process. As an electronically constrained α-helical peptide, SC29EK is highly potent against both wild-type and T20-resistant HIV-1 strains. Here, we report the characterization of HIV-1 variants resistant to SC29EK and the crystal structure of SC29EK. The key mutations mediating high resistance to SC29EK and cross-resistance to the first and new generations of fusion inhibitors as well as the underlying mechanisms were identified. The crystal structure of SC29EK

  16. Systolic and Diastolic Left Ventricular Mechanics during and after Resistance Exercise.

    Science.gov (United States)

    Stöhr, Eric J; Stembridge, Mike; Shave, Rob; Samuel, T Jake; Stone, Keeron; Esformes, Joseph I

    2017-10-01

    To improve the current understanding of the impact of resistance exercise on the heart, by examining the acute responses of left ventricular (LV) strain, twist, and untwisting rate ("LV mechanics"). LV echocardiographic images were recorded in systole and diastole before, during and immediately after (7-12 s) double-leg press exercise at two intensities (30% and 60% of maximum strength, one-repetition maximum). Speckle tracking analysis generated LV strain, twist, and untwisting rate data. Additionally, beat-by-beat blood pressure was recorded and systemic vascular resistance (SVR) and LV wall stress were calculated. Responses in both exercise trials were statistically similar (P > 0.05). During effort, stroke volume decreased, whereas SVR and LV wall stress increased (P mechanics (P 0.05). Immediately after exercise, systolic LV mechanics returned to baseline levels (P mechanics, but increases diastolic mechanics after exercise, suggesting that resistance exercise has a differential impact on systolic and diastolic heart muscle function. The findings may explain why acute resistance exercise has been associated with reduced stroke volume but chronic exercise training may result in increased LV volumes.

  17. Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.

    Science.gov (United States)

    Stolz, Claudia; Schuler, Martin

    2009-06-01

    The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.

  18. Insertion torque versus mechanical resistance of mini-implants inserted in different cortical thickness.

    Science.gov (United States)

    Santos, Renata Faria; Ruellas, Antonio Carlos de Oliveira; Fernandes, Daniel Jogaib; Elias, Carlos Nelson

    2014-01-01

    This study aimed to measure insertion torque, tip mechanical resistance to fracture and transmucosal neck of mini-implants (MI) (Conexão Sistemas de PróteseT), as well as to analyze surface morphology. Mechanical tests were carried out to measure the insertion torque of MIs in different cortical thicknesses, and tip mechanical resistance to fracture as well as transmucosal neck of MIs. Surface morphology was assessed by scanning electron microscopy (SEM) before and after the mechanical tests. Values of mechanical resistance to fracture (22.14 N.cm and 54.95 N.cm) were higher and statistically different (P 0.05) to torsional fracture in the tip of MI (22.14 N.cm) when 3 mm cortical thickness (16.11 N.cm) and dense bone (23.95 N.cm) were used. Torsional fracture of the transmucosal neck (54.95 N.cm) was higher and statistically different (P mini-implants tested presented adequate surface morphology. The resistance of mini-implants to fracture safely allows placement in 1 and 2-mm cortical thickness. However, in 3-mm cortical thickness and dense bones, pre-drilling with a bur is recommended before insertion.

  19. Insertion torque versus mechanical resistance of mini-implants inserted in different cortical thickness

    Science.gov (United States)

    Santos, Renata de Faria; Ruellas, Antonio Carlos de Oliveira; Fernandes, Daniel Jogaib; Elias, Carlos Nelson

    2014-01-01

    Objective This study aimed to measure insertion torque, tip mechanical resistance to fracture and transmucosal neck of mini-implants (MI) (Conexão Sistemas de PróteseT), as well as to analyze surface morphology. Methods Mechanical tests were carried out to measure the insertion torque of MIs in different cortical thicknesses, and tip mechanical resistance to fracture as well as transmucosal neck of MIs. Surface morphology was assessed by scanning electron microscopy (SEM) before and after the mechanical tests. Results Values of mechanical resistance to fracture (22.14 N.cm and 54.95 N.cm) were higher and statistically different (P 0.05) to torsional fracture in the tip of MI (22.14 N.cm) when 3 mm cortical thickness (16.11 N.cm) and dense bone (23.95 N.cm) were used. Torsional fracture of the transmucosal neck (54.95 N.cm) was higher and statistically different (P mini-implants tested presented adequate surface morphology. The resistance of mini-implants to fracture safely allows placement in 1 and 2-mm cortical thickness. However, in 3-mm cortical thickness and dense bones, pre-drilling with a bur is recommended before insertion. PMID:25162571

  20. Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome

    Directory of Open Access Journals (Sweden)

    Dollfus Catherine

    2009-09-01

    Full Text Available Abstract Background Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. Patients and Methods We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. Results Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%: drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available and in newborn lymphocytes (6/8 suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10 and neonatal lymphocytes (2/8 suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. Conclusion This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%, drug

  1. On the existence of the H3 tautomer of adenine in aqueous solution. Rationalizations based on hybrid quantum mechanics/molecular mechanics predictions

    DEFF Research Database (Denmark)

    Aidas, Kestutis; Mikkelsen, Kurt V; Kongsted, Jacob

    2010-01-01

    The (15)N NMR spectrum of adenine in aqueous solution has been modeled using high-level combined density functional theory/molecular mechanics techniques coupled to a dynamical averaging scheme. The explicit consideration of the three lowest-energy tautomers of adenine-H9, H7 and H3-allows for a ...

  2. Strengthening mechanisms and mechanical properties of high interstitial stainless steel for drill collar and its corrosion resistance

    Science.gov (United States)

    Lee, Eunkyung

    Two types (CN66, CN71) of high interstitial stainless steels (HISSs) were investigated for down-hole application in sour gas well environments. Experiments were designed to identify factors that have a significant effect on mechanical properties. The three factors examined in the study were carbon + nitrogen content (0.66 or 0.71 mass %), cooling rate in quenching (air or water), and heat treatment time (2 or 4 hours). The results showed that the cooling rate, C+N content, and the two-factor interaction of these variables have a significant effect on the mechanical properties of HISSs. Based on the statistical analysis results on mechanical properties, extensive analyses were undertaken to understand the strengthening mechanisms of HISSs. Microstructure analysis revealed that a pearlite phase with a high carbide and/or nitride content is dissolved in the matrix by heat treatment at 1,200 ºC which is considered the dissolution to increase the concentration of interstitial elements in steels. The distribution of elements in HISSs was investigated by quantitative mapping using EPMA, which showed that the high carbon concentration (carbide/cementite) area was decreased by increases in both the cooling rate and C+N content. The ferrite volume fraction of each specimen is increased by an increase in cooling rate, because there is insufficient time to form austenite from retained ferrite. The lattice expansion of HISS was investigated by the calculation of lattice parameters under various conditions, and these investigations confirm the solid solution strengthening effect on HISSs. CN66 with heat treatment at fast cooling has the highest wear resistance; a finding that was consistent with hardening mechanisms that occur due to an increased ferrite volume fraction. In addition, precipitates on the surface and the chemical bonding of chromium were investigated. As the amount of CrN bonding increased, the wear resistance also increased. This study also assessed the

  3. Clostridium difficile Infections: A Global Overview of Drug Sensitivity and Resistance Mechanisms

    Directory of Open Access Journals (Sweden)

    Saeed S. Banawas

    2018-01-01

    Full Text Available Clostridium difficile (C. difficile is the most prevalent causative pathogen of healthcare-associated diarrhea. Notably, over the past 10 years, the number of Clostridium difficile outbreaks has increased with the rate of morbidity and mortality. The occurrence and spread of C. difficile strains that are resistant to multiple antimicrobial drugs complicate prevention as well as potential treatment options. Most C. difficile isolates are still susceptible to metronidazole and vancomycin. Incidences of C. difficile resistance to other antimicrobial drugs have also been reported. Most of the antibiotics correlated with C. difficile infection (CDI, such as ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones, continue to be associated with the highest risk for CDI. Still, the detailed mechanism of resistance to metronidazole or vancomycin is not clear. Alternation in the target sites of the antibiotics is the main mechanism of erythromycin, fluoroquinolone, and rifamycin resistance in C. difficile. In this review, different antimicrobial agents are discussed and C. difficile resistance patterns and their mechanism of survival are summarized.

  4. Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfomycin Resistance

    Directory of Open Access Journals (Sweden)

    Alexandro Rodríguez-Rojas

    2013-04-01

    Full Text Available Bacterial infections caused by antibiotic-resistant isolates have become a major health problem in recent years, since they are very difficult to treat, leading to an increase in morbidity and mortality. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits cell wall biosynthesis in both Gram-negative and Gram-positive bacteria. This antibiotic has a unique mechanism of action and inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA. Fosfomycin has been used successfully for the treatment of urinary tract infections for a long time, but the increased emergence of antibiotic resistance has made fosfomycin a suitable candidate for the treatment of infections caused by multidrug-resistant pathogens, especially in combination with other therapeutic partners. The acquisition of fosfomycin resistance could threaten the reintroduction of this antibiotic for the treatment of bacterial infection. Here, we analyse the mechanism of action and molecular mechanisms for the development of fosfomycin resistance, including the modification of the antibiotic target, reduced antibiotic uptake and antibiotic inactivation. In addition, we describe the role of each pathway in clinical isolates.

  5. Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc.

    Science.gov (United States)

    Lobritz, Michael A; Ratcliff, Annette N; Marozsan, Andre J; Dudley, Dawn M; Tilton, John C; Arts, Eric J

    2013-06-01

    Small-molecule CCR5 antagonists, such as maraviroc (MVC), likely block HIV-1 through an allosteric, noncompetitive inhibition mechanism, whereas inhibition by agonists such as PSC-RANTES is less defined and may involve receptor removal by cell surface downregulation, competitive inhibition by occluding the HIV-1 envelope binding, and/or allosteric effects by altering CCR5 conformation. We explored the inhibitory mechanisms of maraviroc and PSC-RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors. Intrinsic PSC-RANTES-resistant virus (YA versus RT) or those selected in PSC-RANTES treated macaques (M584 versus P3-4) only displayed resistance in multiple-cycle assays or with a CCR5 mutant that cannot be downregulated. In single-cycle assays, these HIV-1 clones displayed equal sensitivity to PSC-RANTES inhibition, suggesting effective receptor downregulation. Prolonged PSC-RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration (substrate) could saturate the receptors and overcome PSC-RANTES inhibition. In contrast, resistance to MVC was observed with the MVC-resistant HIV-1 (R3 versus S2) in both multiple- and single-cycle assays and with altered virus concentrations, which is indicative of allosteric inhibition. MVC could also mediate inhibition and possibly resistance through competitive mechanisms.

  6. Spanish multicenter study of the epidemiology and mechanisms of amoxicillin-clavulanate resistance in Escherichia coli.

    Science.gov (United States)

    Ortega, Adriana; Oteo, Jesús; Aranzamendi-Zaldumbide, Maitane; Bartolomé, Rosa M; Bou, Germán; Cercenado, Emilia; Conejo, M Carmen; González-López, Juan José; Marín, Mercedes; Martínez-Martínez, Luis; Merino, María; Navarro, Ferran; Oliver, Antonio; Pascual, Alvaro; Rivera, Alba; Rodríguez-Baño, Jesús; Weber, Irene; Aracil, Belén; Campos, José

    2012-07-01

    We conducted a prospective multicenter study in Spain to characterize the mechanisms of resistance to amoxicillin-clavulanate (AMC) in Escherichia coli. Up to 44 AMC-resistant E. coli isolates (MIC ≥ 32/16 μg/ml) were collected at each of the seven participant hospitals. Resistance mechanisms were characterized by PCR and sequencing. Molecular epidemiology was studied by pulsed-field gel electrophoresis (PFGE) and by multilocus sequence typing. Overall AMC resistance was 9.3%. The resistance mechanisms detected in the 257 AMC-resistant isolates were OXA-1 production (26.1%), hyperproduction of penicillinase (22.6%), production of plasmidic AmpC (19.5%), hyperproduction of chromosomic AmpC (18.3%), and production of inhibitor-resistant TEM (IRT) (17.5%). The IRTs identified were TEM-40 (33.3%), TEM-30 (28.9%), TEM-33 (11.1%), TEM-32 (4.4%), TEM-34 (4.4%), TEM-35 (2.2%), TEM-54 (2.2%), TEM-76 (2.2%), TEM-79 (2.2%), and the new TEM-185 (8.8%). By PFGE, a high degree of genetic diversity was observed although two well-defined clusters were detected in the OXA-1-producing isolates: the C1 cluster consisting of 19 phylogroup A/sequence type 88 [ST88] isolates and the C2 cluster consisting of 19 phylogroup B2/ST131 isolates (16 of them producing CTX-M-15). Each of the clusters was detected in six different hospitals. In total, 21.8% of the isolates were serotype O25b/phylogroup B2 (O25b/B2). AMC resistance in E. coli is widespread in Spain at the hospital and community levels. A high prevalence of OXA-1 was found. Although resistant isolates were genetically diverse, clonality was linked to OXA-1-producing isolates of the STs 88 and 131. Dissemination of IRTs was frequent, and the epidemic O25b/B2/ST131 clone carried many different mechanisms of AMC resistance.

  7. Ester-free Thiol-X Resins: New Materials with Enhanced Mechanical Behavior and Solvent Resistance

    OpenAIRE

    Podgórski, Maciej; Becka, Eftalda; Chatani, Shunsuke; Claudino, Mauro; Bowman, Christopher N.

    2015-01-01

    A series of thiol-Michael and radical thiol-ene network polymers were successfully prepared from ester-free as well as ester-containing monomer formulations. Polymerization reaction rates, dynamic mechanical analysis, and solvent resistance experiments were performed and compared between compositions with varied ester loading. The incorporation of ester-free alkyl thiol, vinyl sulfone and allylic monomers significantly improved the mechanical properties when compared with commercial, mercapto...

  8. Biochemical mechanisms of insecticide resistance in field population of Dengue vector Aedes aegypti (Diptera: Culicidae.

    Directory of Open Access Journals (Sweden)

    R. Muthusamy

    2014-03-01

    Full Text Available Insecticide resistance has been known to be prevalent in several insect species including mosquito. It has become a major problem in vector control programme due to pesticide resistance through detoxification enzymes. The present study investigated the toxicity of Ae. aegypti to organophosphates and pyrethroid insecticide and biochemical mechanisms involved in insecticide resistance in larval population. Larval bioassay revealed an LC50 value of 0.734 ppm for dichlorvos and 1.140 ppm for λ-cyhalothrin exposure. Biochemical assay revealed increased activity of AChE (0.3 µmole/mg protein and GST in dichlorvos (1-1.5 µmole/mg protein treatment and esterase activity in λ-cyhalothrin treated compared to control activity. These studies suggest that AChE and GST is associated with organophosphate and esterase associated with pyrethroid resistance in Ae. aegypti.

  9. [Effects and mechanisms of plant roots on slope reinforcement and soil erosion resistance: a research review].

    Science.gov (United States)

    Xiong, Yan-Mei; Xia, Han-Ping; Li, Zhi-An; Cai, Xi-An

    2007-04-01

    Plant roots play an important role in resisting the shallow landslip and topsoil erosion of slopes by raising soil shear strength. Among the models in interpreting the mechanisms of slope reinforcement by plant roots, Wu-Waldron model is a widely accepted one. In this model, the reinforced soil strength by plant roots is positively proportional to average root tensile strength and root area ratio, the two most important factors in evaluating slope reinforcement effect of plant roots. It was found that soil erosion resistance increased with the number of plant roots, though no consistent quantitative functional relationship was observed between them. The increase of soil erosion resistance by plant roots was mainly through the actions of fiber roots less than 1 mm in diameter, while fiber roots enhanced the soil stability to resist water dispersion via increasing the number and diameter of soil water-stable aggregates. Fine roots could also improve soil permeability effectively to decrease runoff and weaken soil erosion.

  10. Some resistance mechanisms to ultraviolet radiation; Algunos mecanismos de resistencia a radiacion ultravioleta

    Energy Technology Data Exchange (ETDEWEB)

    Alcantara D, D. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

    2002-12-15

    The cyclical exposure of bacterial cells to the ultraviolet light (UV) it has as consequence an increment in the resistance to the lethal effects of this type of radiation, increment that happens as a result of a selection process of favorable genetic mutations induced by the same UV light. With object to study the reproducibility of the genetic changes and the associate mechanisms to the resistance to UV in the bacteria Escherichia coli, was irradiated cyclically with UV light five different derived cultures of a single clone, being obtained five stumps with different resistance grades. The genetic mapping Hfr revealed that so much the mutation events like of selection that took place during the adaptation to the UV irradiation, happened of random manner, that is to say, each one of the resistant stumps it is the result of the unspecified selection of mutations arisen at random in different genes related with the repair and duplication of the DNA. (Author)

  11. Effect of Al on the mechanical properties and corrosion resistance of Pb-Al alloy

    Science.gov (United States)

    LU, Zhicheng; LIU, Zhenlin; LI, Yongliang; WU, Dan; WANG, Fuming

    2017-05-01

    A set of binary Pb-Al alloys with different Al contents were designed in this work. The mechanical properties and corrosion resistance of Pb-Al alloys were investigated with help of tensile test, Charpy V-notch impact test and salt spray corrosion test (SSCT). And the microstructure was observed by optical microscopy. The results showed that microstructure of all alloys were twin structure, and the twin structure was gradually refined with the increase of Al content. Al dissolved in matrix could significantly improve the tensile strength, impact energy and corrosion resistance. However, a higher content of Al would harm the mechanical properties and corrosion resistance. It may be due to the heterogeneous precipitation of Al rich phase.

  12. Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

    Directory of Open Access Journals (Sweden)

    Ryan Morrison

    2011-01-01

    Full Text Available Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs.

  13. Resistance of transgenic eggplant carrying the oryzacystatin gene to Mechanitis polymnia and Mechanitis lysimnia - DOI: 10.4025/actasciagron.v27i4.1345

    OpenAIRE

    Ribeiro, Ana Paula de Oliveira; UFV; Otoni, Wagner Campos; UFV; Picanço, Marcelo Coutinho; Universidade Federal de Viçosa, Centro de Ciências Biológicas e da Saúde; Galvan, Tederson Luiz; UFV; Pereira, Eliseu José Guedes; UFV; Picoli, Edgard Augusto de Toledo; UFV; Silva, Derly José Henriques da; UFV

    2008-01-01

    This research aimed to evaluate the resistance of transgenic eggplant (Solanum melongena) carrying the oryzacystatin gene to Mechanitis polymnia L. and Mechanitis lysimnia Fabr. (Lepidoptera: Nymphalidae). The leaf area consumed, the mortality and duration of the larval and pupal phases of M. polymnia and M. lysimnia were evaluated. Results showed the transgenic eggplant is not resistant to Lepidoptera M. polymnia and M. lysimnia Esta pesquisa objetivou avaliar a resistência da berinjela (...

  14. Emergence and Spread of A Plasmid-Mediated Polymyxin Resistance Mechanism, MCR-1: Are Bacteria Winning?

    Directory of Open Access Journals (Sweden)

    Chao Yang

    2015-12-01

    Full Text Available The report of the emergence of mcr-1, the first plasmid-mediated polymyxin resistance mechanism, in Enterobacteriaceae in November 2015 challenged our last psychological line of defense. However, we still trusted that this resistance factor had not spread globally. One month later, in December 2015, the detection of mcr-1 in an Escherichia coliisolate from a septicemic patient in Denmark and in five E. coli isolates from imported chicken meat really defeated us. The worst news was that one of the chicken meat isolates belonged to ST131, a spreading epidemic sequence type. In China, 15%-21% of E. coli strains isolated from raw meat and animals carried mcr-1, and about 1% of patient isolates carried this gene, indicating that E. coli carrying this plasmid is not a rare phenomenon. This gene is transferable by conjugation and can be maintained in Klebsiella pneumonia and Pseudomonas aeruginosa, suggesting the risk of transfer between different bacterial genera. The good news is that the strains carrying mcr-1 do not contain genes for pan-resistance profiles, although some Danish strains contain 15 different resistance genes, including genes for extended-spectrum beta-lactam antibiotics, and gene mutations leading to high-level fluoroquinolone resistance. If the mcr-1-bearing strains acquire multidrug resistance, extensive drug resistance, or pandrug resistance, no antibiotic drugs will be available with which clinicians can treat infected patients. Therefore, the use of antibiotics in both hospitals and the animal breeding industry must be strictly regulated. The origin of mcr-1 may be associated with the wide use of colistin in agriculture. There is no evidence that the Danish mcr-1 gene spread from China. Therefore, it is likely that mcr-1 genes originated in multiple sites simultaneously under the pressure of colistin use, because India and Denmark are the world’ s greatest users of this antibiotic. More surveys must be conducted in different

  15. Molecular survey of pyrethroid resistance mechanisms in Mexican field populations of Rhipicephalus (Boophilus) microplus

    Science.gov (United States)

    Susceptibility to synthetic pyrethroids (SP´s) and the role of two major resistance mechanisms were evaluated in Mexican Rhipicephalus microplus tick populations. Larval packet test (LPT), knock-down (kdr) PCR allele-specific assay (PASA) and esterase activity assays were conducted in tick populatio...

  16. Mechanism of Action of Substituted Indanones in Multidrug Resistant Breast Cancer

    National Research Council Canada - National Science Library

    Leoni, Lorenzo

    2002-01-01

    ... (Cancer Res 2001 Oct 1 61(1 9):7248-54) - analyzed the indanocine-resistant stable cell line - identified the potential indanocine-binding site on tubulin - continued the animal testing of indanocine - studies the pro-apoptotic mechanism...

  17. SEVERAL MECHANISMS OF MERCURY RESISTANCE FOUND IN SOIL ISOLATES FROM PAVLODAR, KAZAKHSTAN

    Science.gov (United States)

    Abdrashitova, Svetlava A., M.A. Ilyushchenko, A. Yu Kalmykv, S.A. Aitkeldieva, Wendy J. Davis-Hoover and Richard Devereux. In press. Several Mechanisms of Mercury Resistance Found in Soil Isolates from Pavlodar, Kazakhstan (Abstract). To be presented at the Battelle Conference on...

  18. Mechanisms of methicillin resistance in Staphylococcus aureus and methods for laboratory detection.

    Science.gov (United States)

    Jorgensen, J H

    1991-01-01

    Three distinctly different mechanisms of methicillin resistance have been described in Staphylococcus aureus. The best-documented and probably most important mechanism is production of a unique, low affinity penicillin-binding protein, PBP 2a. Strains possessing PBP 2a are resistant to methicillin, oxacillin, and probably all other currently available beta-lactam antibiotics. Two additional mechanisms of reduced susceptibility to methicillin have been described. Borderline resistance (BORSA) to the semi-synthetic penicillins has been attributed to the hyperproduction of normal staphylococcal beta-lactamase. A third mechanism has recently been advanced that describes an intermediate level of resistance to methicillin due to production of modified, normal PBPs with reduced affinity for beta-lactams (MODSA). Little is known regarding the prevalence or clinical significance of the BORSA and MODSA strains. The most reliable in vitro susceptibility test methods for detecting MRSA (strains possessing PBP 2a) include the microdilution minimum inhibitory concentration (MIC) test (with 2% NaCl supplemented broth), the oxacillin agar screen plate test (incorporating 6 micrograms/ml oxacillin in 4% NaCl supplemented agar), and the National Committee for Clinical Laboratory Standards (NCCLS) disk diffusion test with oxacillin. All three methods use direct inoculum preparation and incubation of tests at 35 degrees C for a full 24 hours.

  19. Evaluating the role of root citrate exudation as a mechanism of aluminium resistance in maize genotypes

    NARCIS (Netherlands)

    Mariano, E.D.; Keltjens, W.G.

    2003-01-01

    Organic anion exudation by roots as a mechanism of aluminium (Al) resistance has been intensively studied lately. In the present study, we evaluated qualitative and quantitative aspects of root exudation of organic anions in maize genotypes of distinct sensitivity to Al in response to Al exposure.

  20. Mechanism of Enhanced Activity of Liposome-Entrapped Aminoglycosides against Resistant Strains of Pseudomonas aeruginosa

    Science.gov (United States)

    Mugabe, Clement; Halwani, Majed; Azghani, Ali O.; Lafrenie, Robert M.; Omri, Abdelwahab

    2006-01-01

    Pseudomonas aeruginosa is inherently resistant to most conventional antibiotics. The mechanism of resistance of this bacterium is mainly associated with the low permeability of its outer membrane to these agents. We sought to assess the bactericidal efficacy of liposome-entrapped aminoglycosides against resistant clinical strains of P. aeruginosa and to define the mechanism of liposome-bacterium interactions. Aminoglycosides were incorporated into liposomes, and the bactericidal efficacies of both free and liposomal drugs were evaluated. To define the mechanism of liposome-bacterium interactions, transmission electron microscopy (TEM), flow cytometry, lipid mixing assay, and immunocytochemistry were employed. Encapsulation of aminoglycosides into liposomes significantly increased their antibacterial activity against the resistant strains used in this study (MICs of ≥32 versus ≤8 μg/ml). TEM observations showed that liposomes interact intimately with the outer membrane of P. aeruginosa, leading to the membrane deformation. The flow cytometry and lipid mixing assays confirmed liposome-bacterial membrane fusion, which increased as a function of incubation time. The maximum fusion rate was 54.3% ± 1.5% for an antibiotic-sensitive strain of P. aeruginosa and 57.8% ± 1.9% for a drug-resistant strain. The fusion between liposomes and P. aeruginosa significantly enhanced the antibiotics' penetration into the bacterial cells (3.2 ± 2.3 versus 24.2 ± 6.2 gold particles/bacterium, P ≤ 0.001). Our data suggest that liposome-entrapped antibiotics could successfully resolve infections caused by antibiotic-resistant P. aeruginosa through an enhanced mechanism of drug entry into the bacterial cells. PMID:16723560

  1. Investigating the molecular mechanisms of organophosphate and pyrethroid resistance in the fall armyworm Spodoptera frugiperda.

    Directory of Open Access Journals (Sweden)

    Renato A Carvalho

    Full Text Available The fall armyworm Spodoptera frugiperda is an economically important pest of small grain crops that occurs in all maize growing regions of the Americas. The intensive use of chemical pesticides for its control has led to the selection of resistant populations, however, to date, the molecular mechanisms underlying resistance have not been characterised. In this study the mechanisms involved in the resistance of two S. frugiperda strains collected in Brazil to chlorpyrifos (OP strain or lambda-cyhalothrin (PYR strain were investigated using molecular and genomic approaches. To examine the possible role of target-site insensitivity the genes encoding the organophosphate (acetylcholinesterase, AChE and pyrethroid (voltage-gated sodium channel, VGSC target-site proteins were PCR amplified. Sequencing of the S. frugiperda ace-1 gene identified several nucleotide changes in the OP strain when compared to a susceptible reference strain (SUS. These result in three amino acid substitutions, A201S, G227A and F290V, that have all been shown previously to confer organophosphate resistance in several other insect species. Sequencing of the gene encoding the VGSC in the PYR strain, identified mutations that result in three amino acid substitutions, T929I, L932F and L1014F, all of which have been shown previously to confer knockdown/super knockdown-type resistance in several arthropod species. To investigate the possible role of metabolic detoxification in the resistant phenotype of the OP and PYR stains all EST sequences available for S. frugiperda were used to design a gene-expression microarray. This was then used to compare gene expression in the resistant strains with the susceptible reference strain. Members of several gene families, previously implicated in metabolic resistance in other insects were found to be overexpressed in the resistant strains including glutathione S-transferases, cytochrome P450s and carboxylesterases. Taken together these results

  2. Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide.

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    Isabelle Dusfour

    2015-11-01

    Full Text Available Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America, Guadeloupe islands (Lesser Antilles as well as New Caledonia (Pacific Ocean, have encountered such resistance.We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534.This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence.

  3. Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide.

    Science.gov (United States)

    Dusfour, Isabelle; Zorrilla, Pilar; Guidez, Amandine; Issaly, Jean; Girod, Romain; Guillaumot, Laurent; Robello, Carlos; Strode, Clare

    2015-11-01

    Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America), Guadeloupe islands (Lesser Antilles) as well as New Caledonia (Pacific Ocean), have encountered such resistance. We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534. This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence.

  4. Acinetobacter spp. Infections in Malaysia: A Review of Antimicrobial Resistance Trends, Mechanisms and Epidemiology

    Directory of Open Access Journals (Sweden)

    Farahiyah Mohd. Rani

    2017-12-01

    Full Text Available Acinetobacter spp. are important nosocomial pathogens, in particular the Acinetobacter baumannii-calcoaceticus complex, which have become a global public health threat due to increasing resistance to carbapenems and almost all other antimicrobial compounds. High rates of resistance have been reported among countries in Southeast Asia, including Malaysia. In this review, we examine the antimicrobial resistance profiles of Acinetobacter spp. hospital isolates from Malaysia over a period of nearly three decades (1987–2016 with data obtained from various peer-reviewed publications as well as the Malaysian National Surveillance on Antibiotic Resistance (NSAR. NSAR data indicated that for most antimicrobial compounds, including carbapenems, the peak resistance rates were reached around 2008–2009 and thereafter, rates have remained fairly constant (e.g., 50–60% for carbapenems. Individual reports from various hospitals in Peninsular Malaysia do not always reflect the nationwide resistance rates and often showed higher rates of resistance. We also reviewed the epidemiology and mechanisms of resistance that have been investigated in Malaysian Acinetobacter spp. isolates, particularly carbapenem resistance and found that blaOXA-23 is the most prevalent acquired carbapenemase-encoding gene. From the very few published reports and whole genome sequences that are available, most of the Acinetobacter spp. isolates from Malaysia belonged to the Global Clone 2 (GC2 CC92 group with ST195 being the predominant sequence type. The quality of data and analysis in the national surveillance reports could be improved and more molecular epidemiology and genomics studies need to be carried out for further in-depth understanding of Malaysian Acinetobacter spp. isolates.

  5. A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Monique Nijhuis

    2007-01-01

    Full Text Available BACKGROUND: HIV protease inhibitor (PI therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors. METHODS AND FINDINGS: We have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649 and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%. Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088 to demonstrate that these NC/p1 cleavage site changes are

  6. Insecticide Resistance and Metabolic Mechanisms Involved in Larval and Adult Stages of Aedes aegypti Insecticide-Resistant Reference Strains from Cuba.

    Science.gov (United States)

    Bisset, Juan Andrés; Rodríguez, María Magdalena; French, Leydis; Severson, David W; Gutiérrez, Gladys; Hurtado, Daymi; Fuentes, Ilario

    2014-12-01

    Studies were conducted to compare levels of insecticide resistance and to determine the metabolic resistance mechanisms in larval and adult stages of Aedes aegypti from Cuba. Three insecticide-resistant reference strains of Ae. aegypti from Cuba were examined. These strains were derived from a Santiago de Cuba strain isolated in 1997; it was previously subjected to a strong selection for resistance to temephos (SAN-F6), deltamethrin (SAN-F12), and propoxur (SAN-F13) and routinely maintained in the laboratory under selection pressure up to the present time, when the study was carried out. In addition, an insecticide-susceptible strain was used for comparison. The insecticide resistance in larvae and adults was determined using standard World Health Organization methodologies. Insecticide resistance mechanisms were determined by biochemical assays. The esterases (α EST and β EST) and mixed function oxidase (MFO) activities were significantly higher in adults than in the larvae of the three resistant strains studied. The association of resistance level with the biochemical mechanism for each insecticide was established for each stage. The observed differences between larval and adult stages of Ae. aegypti in their levels of insecticide resistance and the biochemical mechanisms involved should be included as part of monitoring and surveillance activities in Ae. aegypti vector control programs.

  7. Thermodynamic secrets of multidrug resistance: A new take on transport mechanisms of secondary active antiporters.

    Science.gov (United States)

    Zhang, Xuejun C; Liu, Min; Lu, Guangyuan; Heng, Jie

    2018-03-01

    Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most-if not all-MDR transporters. © 2017 The Protein Society.

  8. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

    Science.gov (United States)

    Gorbunova, Vera; Hine, Christopher; Tian, Xiao; Ablaeva, Julia; Gudkov, Andrei V.; Nevo, Eviatar; Seluanov, Andrei

    2012-01-01

    Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground. PMID:23129611

  9. Insertion torque versus mechanical resistance of mini- implants inserted in different cortical thickness

    Directory of Open Access Journals (Sweden)

    Renata de Faria Santos

    2014-06-01

    Full Text Available OBJECTIVE: This study aimed to measure insertion torque, tip mechanical resistance to fracture and transmucosal neck of mini-implants (MI (Conexão Sistemas de PróteseT, as well as to analyze surface morphology. METHODS: Mechanical tests were carried out to measure the insertion torque of MIs in different cortical thicknesses, and tip mechanical resistance to fracture as well as transmucosal neck of MIs. Surface morphology was assessed by scanning electron microscopy (SEM before and after the mechanical tests. RESULTS: Values of mechanical resistance to fracture (22.14 N.cm and 54.95 N.cm were higher and statistically different (P 0.05 to torsional fracture in the tip of MI (22.14 N.cm when 3 mm cortical thickness (16.11 N.cm and dense bone (23.95 N.cm were used. Torsional fracture of the transmucosal neck (54.95 N.cm was higher and statistically different (P < 0.05 from insertion torsional strength in all tested situations. SEM analysis showed that the MIs had the same smooth surface when received from the manufacturer and after the mechanical tests were performed. Additionally, no significant marks resulting from the manufacturing process were observed. CONCLUSION: All mini-implants tested presented adequate surface morphology. The resistance of mini-implants to fracture safely allows placement in 1 and 2-mm cortical thickness. However, in 3-mm cortical thickness and dense bones, pre-drilling with a bur is recommended before insertion.

  10. A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations

    Directory of Open Access Journals (Sweden)

    Hong-Li Liu

    2017-08-01

    Full Text Available Hydroxyflutamide (HF, an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR. However, a drug resistance problem appears after about one year’s treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA method have been carried out to analyze the interaction mechanism between HF and wild-type (WT/mutant ARs. The obtained results indicate that AR helix 12 (H12 plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12. When H12 closes to the AR ligand-binding domain (LBD like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per-residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF.

  11. Structural Studies of Bacterial Enzymes and their Relation to Antibiotic Resistance Mechanisms - Final Paper

    Energy Technology Data Exchange (ETDEWEB)

    Maltz, Lauren [SLAC National Accelerator Lab., Menlo Park, CA (United States)

    2015-08-27

    By using protein crystallography and X-ray diffraction, structures of bacterial enzymes were solved to gain a better understanding of how enzymatic modification acts as an antibacterial resistance mechanism. Aminoglycoside phosphotransferases (APHs) are one of three aminoglycoside modifying enzymes that confer resistance to the aminoglycoside antibiotics via enzymatic modification, rendering many drugs obsolete. Specifically, the APH(2”) family vary in their substrate specificities and also in their preference for the phosphate donor (ADP versus GDP). By solving the structures of members of the APH(2”) family of enzymes, we can see how domain movements are important to their substrate specificity. Our structure of the ternary complex of APH(2”)-IIIa with GDP and kanamycin, when compared to the known structures of APH(2”)-IVa, reveals that there are real physical differences between these two enzymes, a structural finding that explains why the two enzymes differ in their preferences for certain aminoglycosides. Another important group of bacterial resistance enzymes are the Class D β- lactamases. Oxacillinase carbapenemases (OXAs) are part of this enzyme class and have begun to confer resistance to ‘last resort’ drugs, most notably carbapenems. Our structure of OXA-143 shows that the conformational flexibility of a conserved hydrophobic residue in the active site (Val130) serves to control the entry of a transient water molecule responsible for a key step in the enzyme’s mechanism. Our results provide insight into the structural mechanisms of these two different enzymes

  12. Mechanism by which arylamineN-acetyltransferase 1 ablation causes insulin resistance in mice.

    Science.gov (United States)

    Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper; Chukijrungroat, Natsasi; Petersen, Kitt Falk; Shulman, Gerald I

    2017-12-26

    A single-nucleotide polymorphism in the human arylamine N -acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle triglyceride (TAG) and diacylglycerol (DAG) content, which was associated with increased PKCε activation in liver and increased PKCθ activation in skeletal muscle. Nat1 KO mice also displayed reduced whole-body energy expenditure and reduced mitochondrial oxygen consumption in white adipose tissue, brown adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid deposition, insulin resistance, and type 2 diabetes. Copyright © 2017 the Author(s). Published by PNAS.

  13. Will the Amaranthus tuberculatus Resistance Mechanism to PPO-Inhibiting Herbicides Evolve in Other Amaranthus Species?

    Directory of Open Access Journals (Sweden)

    Chance W. Riggins

    2012-01-01

    Full Text Available Resistance to herbicides that inhibit protoporphyrinogen oxidase (PPO has been slow to evolve and, to date, is confirmed for only four weed species. Two of these species are members of the genus Amaranthus L. Previous research has demonstrated that PPO-inhibitor resistance in A. tuberculatus (Moq. Sauer, the first weed to have evolved this type of resistance, involves a unique codon deletion in the PPX2 gene. Our hypothesis is that A. tuberculatus may have been predisposed to evolving this resistance mechanism due to the presence of a repetitive motif at the mutation site and that lack of this motif in other amaranth species is why PPO-inhibitor resistance has not become more common despite strong herbicide selection pressure. Here we investigate inter- and intraspecific variability of the PPX2 gene—specifically exon 9, which includes the mutation site—in ten amaranth species via sequencing and a PCR-RFLP assay. Few polymorphisms were observed in this region of the gene, and intraspecific variation was observed only in A. quitensis. However, sequencing revealed two distinct repeat patterns encompassing the mutation site. Most notably, A. palmeri S. Watson possesses the same repetitive motif found in A. tuberculatus. We thus predict that A. palmeri will evolve resistance to PPO inhibitors via the same PPX2 codon deletion that evolved in A. tuberculatus.

  14. The length of pre-existing fissures effects on the mechanical properties of cracked red sandstone and strength design in engineering.

    Science.gov (United States)

    Wu, Jiangyu; Feng, Meimei; Yu, Bangyong; Han, Guansheng

    2018-01-01

    It is important to study the mechanical properties of cracked rock to understand the engineering behavior of cracked rock mass. Consequently, the influence of the length of pre-existing fissures on the strength, deformation, acoustic emission (AE) and failure characteristics of cracked rock specimen was analyzed, and the optimal selection of strength parameter in engineering design was discussed. The results show that the strength parameters (stress of dilatancy onset and uniaxial compressive strength) and deformation parameters (axial strain and circumferential strain at dilatancy onset and peak point) of cracked rock specimen decrease with the increase of the number of pre-existing fissures, and the relations which can use the negative exponential function to fit. Compared with the intact rock specimens, the different degrees of stress drop phenomena were produced in the process of cracked rock specimens when the stress exceeds the dilatancy onset. At this moment, the cracked rock specimens with the existence of stress drop are not instantaneous failure, but the circumferential strain, volumetric strain and AE signals increase burstingly. And the yield platform was presented in the cracked rock specimen with the length of pre-existing fissure more than 23mm, the yield failure was gradually conducted around the inner tip of pre-existing fissure, the development of original fissures and new cracks was evolved fully in rock. However, the time of dilatancy onset is always ahead of the the time of that point with the existence of stress drop. It indicates that the stress of dilatancy onset can be as the parameter of strength design in rock engineering, which can effectively prevent the large deformation of rock. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Testing the permeability and corrosion resistance of micro-mechanically interlocked joints

    DEFF Research Database (Denmark)

    Byskov-Nielsen, Jeppe; Holm, Allan Hjarbæk; Højsholt, Rune

    2011-01-01

    Micro-mechanical interlocking (MMI) can be applied to create new and interesting composite materials. We have employed laser structuring to achieve MMI between stainless steel and plastic with extremely high joint strength. However, the water permeability and corrosion resistance of the joint must...... be taken in order not to degrade the corrosion resistance of the sample to an unacceptable level....... is conducted. The permeability seems to be consistent with the Hagen–Poiseuille equation independent of the laser structuring technique and is orders of magnitudes larger than the diffusion rate through the plastic. Two different types of corrosion tests have been undertaken, and we show that care must...

  16. BIOCHEMICAL MECHANISMS OF RESISTANCE TO p-NITROCHLOROBENZENE OF KARST CAVES MICROORGANISMS.

    Science.gov (United States)

    Suslova, O S; Rokitko, P V; Bondar, K M; Golubenko, O O; Tashyrev, A B

    2015-01-01

    The biochemical mechanisms of resistance to persistent organic xenobiotic p-nitrochlorobenzene (NCB) of bacterial strains isolated from two cave clays ecosystems-Mushkarova Yama (Podolia, Ukraine) and Kuybyshevskaya (Western Caucasus, Abkhazia) have been established It has been determined that chemoorganotrophic karst caves strains could interact with NCB and transform it reducing the nitro group withformation of p-chloroaniline (ClA) followed by further destruction of NCB aromatic ring. This explained high resistance of caves strains to NCB. The studied strains could potentially be used in wastewater treatment from nitrochloraromatic compounds.

  17. Change from lung adenocarcinoma to small cell lung cancer as a mechanism of resistance to afatinib.

    Science.gov (United States)

    Manca, Paolo; Russano, Marco; Pantano, Francesco; Tonini, Giuseppe; Santini, Daniele

    2017-08-29

    We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.

  18. Study on the mechanism of wheat mutants resistance to bi-polaris sorokiniana

    International Nuclear Information System (INIS)

    Sun Guangzu; Wang Guangjin; Tang Fenglan; Liu Lijun; Li Zhongjie

    1992-01-01

    The activities and band number of peroxidase (POD), superoxide dismutase (SOD) and phenylalanine aminolyase (PAL) in plant tissue have been studied after treatment with phytotoxin produced from Bi polaris sorokiniana. The results showed that the activity and band number of these enzymes have been changed markedly. The change in degree of activity for mutants was more than that of the parent, and coincident with the ability of resistance to disease. The authors considered that the toxin tolerance ability and inducibility of SOD and POD by toxin might be one of resistance mechanism of wheat mutant against Bipolaris sorokiniana

  19. Biochemical mechanisms of resistance to p-nitrochlorobenzene of karst caves microorganisms

    Directory of Open Access Journals (Sweden)

    O. S. Suslova

    2015-08-01

    Full Text Available The biochemical mechanisms of resistance to persistent organic xenobiotic p-nitrochlorobenzene (NCB of bacterial strains isolated from two cave clays ecosystems – Mushkarova Yama (Podolia, Ukraine and Kuybyshevskaya (Western Caucasus, Abkhazia have been established. It has been determined that chemoorganotrophic karst caves strains could interact with NCB and transform it reducing the nitro group with formation of p-chloroaniline (ClA followed by further destruction of NCB aromatic ring. This explained high resistance of caves strains to NCB. The studied strains could potentially be used in wastewater treatment from nitrochloraromatic compounds.

  20. Alkali-Resistant Mechanism of a Hollandite DeNOx Catalyst.

    Science.gov (United States)

    Hu, Pingping; Huang, Zhiwei; Gu, Xiao; Xu, Fei; Gao, Jiayi; Wang, Yue; Chen, Yaxin; Tang, Xingfu

    2015-06-02

    A thorough understanding of the deactivation mechanism by alkalis is of great importance for rationally designing improved alkali-resistant deNOx catalysts, but a traditional ion-exchange mechanism cannot often accurately describe the nature of the deactivation, thus hampering the development of superior catalysts. Here, we establish a new exchange-coordination mechanism on the basis of the exhaustive study on the strong alkali resistance of a hollandite manganese oxide (HMO) catalyst. A combination of isothermal adsorption measurements of ammonia with X-ray absorption near-edge structure spectra and X-ray photoelectron spectra reveals that alkali metal ions first react with protons from Brønsted acid sites of HMO via the ion exchange. Synchrotron X-ray diffraction patterns and extended X-ray absorption fine structure spectra coupled with theoretical calculations demonstrate that the exchanged alkali metal ions are subsequently stabilized at size-suitable cavities in the HMO pores via a coordination model with an energy savings. This exchange-coordination mechanism not only gives a wholly convincing explanation for the intrinsic nature of the deactivation of the reported catalysts by alkalis but also provides a strategy for rationally designing improved alkali-resistant deNOx catalysts in general.

  1. The use of high-throughput sequencing to investigate an outbreak of glycopeptide-resistant Enterococcus faecium with a novel quinupristin-dalfopristin resistance mechanism.

    Science.gov (United States)

    Shaw, Timothy D; Fairley, D J; Schneiders, T; Pathiraja, M; Hill, R L R; Werner, G; Elborn, J S; McMullan, R

    2018-02-24

    High-throughput sequencing (HTS) has successfully identified novel resistance genes in enterococci and determined clonal relatedness in outbreak analysis. We report the use of HTS to investigate two concurrent outbreaks of glycopeptide-resistant Enterococcus faecium (GRE) with an uncharacterised resistance mechanism to quinupristin-dalfopristin (QD). Seven QD-resistant and five QD-susceptible GRE isolates from a two-centre outbreak were studied. HTS was performed to identify genes or predicted proteins that were associated with the QD-resistant phenotype. MLST and SNP typing on HTS data was used to determine clonal relatedness. Comparative genomic analysis confirmed this GRE outbreak involved two distinct clones (ST80 and ST192). HTS confirmed the absence of known QD resistance genes, suggesting a novel mechanism was conferring resistance. Genomic analysis identified two significant genetic determinants with explanatory power for the high level of QD resistance in the ST80 QD-resistant clone: an additional 56aa leader sequence at the N-terminus of the lsaE gene and a transposon containing seven genes encoding proteins with possible drug or drug-target modification activities. However, HTS was unable to conclusively determine the QD resistance mechanism and did not reveal any genetic basis for QD resistance in the ST192 clone. This study highlights the usefulness of HTS in deciphering the degree of relatedness in two concurrent GRE outbreaks. Although HTS was able to reveal some genetic candidates for uncharacterised QD resistance, this study demonstrates the limitations of HTS as a tool for identifying putative determinants of resistance to QD.

  2. Thiamethoxam resistance selected in the western flower thrips Frankliniella occidentalis (Thysanoptera: Thripidae): cross-resistance patterns, possible biochemical mechanisms and fitness costs analysis.

    Science.gov (United States)

    Gao, Cong-Fen; Ma, Shao-Zhi; Shan, Cai-Hui; Wu, Shun-Fan

    2014-09-01

    The western flower thrips (WFT) Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), an important pest of various crops in the world, has invaded China since 2003. To understand the risks and to determine possible mechanisms of resistance to thiamethoxam in WFT, a resistant strain was selected under the laboratory conditions. Cross-resistance and the possible biochemical resistance mechanisms were investigated in this study. A 15.1-fold thiamethoxam-resistant WFT strain (TH-R) was established after selection for 55 generations. Compared with the susceptible strain (TH-S), the selected TH-R strain showed extremely high level cross-resistance to imidaclothiz (392.1-fold) and low level cross-resistance to dinotefuran (5.7-fold), acetamiprid (2.9-fold) and emamectin benzoate (2.1-fold), respectively. No cross-resistance to other fourteen insecticides was detected. Synergism tests showed that piperonyl butoxide (PBO) and triphenyl phosphate (TPP) produced a high synergism of thiamethoxam effects in the TH-R strain (2.6- and 2.6-fold respectively). However, diethyl maleate (DEM) did not act synergistically with thiamethoxam. Biochemical assays showed that mixed function oxidase (MFO) activities and carboxylesterase (CarE) activity of the TH-R strain were 2.8- and 1.5-fold higher than that of the TH-S strain, respectively. When compared with the TH-S strain, the TH-R strain had a relative fitness of 0.64. The results show that WFT develops resistance to thiamethoxam after continuous application and thiamethoxam resistance had considerable fitness costs in the WFT. It appears that enhanced metabolism mediated by cytochrome P450 monooxygenases and CarE was a major mechanism for thiamethoxam resistance in the WFT. The use of cross-resistance insecticides, including imidaclothiz and dinotefuran, should be avoided for sustainable resistance management. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Towards mechanisms-guided resistivity-based monitoring of damage evolution in laminated composites

    KAUST Repository

    Lubineau, Gilles

    2013-04-05

    A convenient health monitoring technique for detecting degradation in laminated composite is to monitor the change of electrical resistance along multiple conduction paths within the structure. Yet, the relations between the global modification of resistivity and the exact underlying damage map is still unclear that makes diffcult to interpret these nondestructive-testing results. The challenge is then to be able to reconstruct from these global observation the underlying damage map. This is even more diffcult due to the numerous underlying damage mechanisms that can take place either at the inter laminar of intra laminar level. This paper intends to provide some preliminary insights about strategies to recover the damage state based only on global measurements. We focus here on transverse cracking detection. We introduce the homogenization process that defines at the meso scale an equivalent homogeneous ply that is energetically equivalent to the cracked one. This can be used as a first tool to reconstruct damage maps based on global resistivity measurements.

  4. Control mechanisms of mutability: Studies on the (radiation-resistant) mutant rar-2 of Drosophila melanogaster

    International Nuclear Information System (INIS)

    Rudolph, P.

    1981-01-01

    The author attempts a quantitative description of the resistance factor of the 2nd chromosome (rar-2) on the mutation rate after irradiation, an explanation of the mechanism of action via an analysis of induced numerical aberration, and an analysis of the genetic position of this factor and its delimination with the aid of phenotypically visible markers. A comparison of the two strains ROeI 0 and ROeI 40 was to help to investigate possible modifications of the resistance factor in the strain ROeI 40 , obtained by further selection from ROeI 0 . There was no difference between the two strains as far as the effects of the resistance factor rar-2 were concerned. (orig./MG) [de

  5. Proteomic Analysis Reveals Resistance Mechanism Against Chlorpyrifos in Frankliniella occidentalis (Thysanoptera: Thripidae).

    Science.gov (United States)

    Yan, Dan-Kan; Hu, Min; Tang, Yun-Xia; Fan, Jia-Qin

    2015-08-01

    The western flower thrips is an economically important worldwide pest of many crops, and chlorpyrifos has been used to control western flower thrips for many years. To develop a better resistance-management strategy, a chlorpyrifos-resistant strain of western flower thrips (WFT-chl) was selected in the laboratory. More than 39-fold resistance was achieved after selected by chlorpyrifos for 19 generations in comparison with the susceptible strain (WFT-S). Proteome of western flower thrips (WFT-S and WFT-chl) was investigated using a quantitative proteomics approach with isobaric tag for relative and absolute quantification technique and liquid chromatography-tandem mass spectrometry technologies. According to the functional analysis, 773 proteins identified were grouped into 10 categories of molecular functions and 706 proteins were presented in 213 kinds of pathways. Comparing the proteome of WFT-chl with that of WFT-S, a total of eight proteins were found up-regulated and three down-regulated. The results from functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that the differentially expressed protein functions in binding, catalyzing, transporting, and enzyme regulation were most important in resistance development. A list of proteins functioning in biological processes of metabolism, biological regulation, and response to stimulus was found in WFT-chl, suggesting that they are possibly the major components of the resistance mechanism to chlorpyrifos in western flower thrips. Notably, several novel potential resistance-related proteins were identified such as ribosomal protein, Vg (vitellogenin), and MACT (muscle actin), which can be used to improve our understanding of the resistance mechanisms in western flower thrips. This study provided the first comprehensive view of the complicated resistance mechanism employed by WFT-S and WFT-chl through the isobaric tag for relative and absolute quantification coupled

  6. A Systemic Review of Resistance Mechanisms and Ongoing Clinical Trials in ALK-rearranged Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Khashayar eEsfahani

    2014-07-01

    Full Text Available The identification of oncogenic driver driver mutations in non-small cell lung cancer has led to a paradigm shift and the development of specific molecular treatments. Tumors harboring a rearranged EML4-ALK fusion oncogene are highly sensitive to therapy with ALK-targeted inhibitors. Crizotinib is the first approved treatment for advanced lung tumors containing this genetic abnormality. In this mini review, we discuss the existing data on crizotinib as well as ongoing trials involving this medication. A brief overview of the known resistance mechanisms to criztotinib will also be presented followed by a summary of the ongoing trials involving next-generation ALK inhibitors or other targeted therapies in patients with ALK+ NSCLC.

  7. The effect of carbon content on mechanical properties, failure and corrosion resistance of deposited chromium metal

    Directory of Open Access Journals (Sweden)

    Леонід Кімович Лещинськiй

    2017-06-01

    Full Text Available It has been shown that if choosing a metal composition for surfacing rolls and rollers of continuous casting machines, both the carbon impact on the mechanical and functional properties and the critical values of the chromium concentration, which determine the corrosion resistance of the metal with regard to electrochemical corrosion theory, should be considered as well. The paper studied the effect of chromium and carbon steel the X5-X12 type on the structure, technological strength, mechanical properties, fracturing resistance and corrosion resistance of the weld metal. The composition of chromium tool steels (deposited metal (X5-used for the rolls of hot rolling mills and (X12-used for continuous casting machines rollers correspond to these values. The impact of carbon on the properties of the deposited metal containing chromium was considered by comparing the data for both types of the deposited metal. It was found that for both types of the deposited metal (X5 and X12, the limiting value of the carbon content, providing an optimal combination of strength, ductility, failure resistance is the same. If the carbon content is more than the limiting value – (0,25% the technological strength and failure resistance of the deposited metal significantly reduce. With increasing carbon content from 0,18 to 0,25% the martensite structure has a mixed morphology – lath and plate. The strength and toughness of the deposited metal grow. Of particular interest is simultaneous increase in the specific work of failure resulted from crack inhibition at the boundary with far less solid and more ductile ferrite. As for the 5% chromium metal, the X12 type composition with 0,25% C, is borderline. With a further increase in the carbon content of the metal both ductility and failure resistance sharply decrease and with 0,40% C the growth rate of fatigue crack increases by almost 1,5 times

  8. Use and Misuse of Antimicrobial Drugs in Poultry and Livestock: Mechanisms of Antimicrobial Resistance

    Directory of Open Access Journals (Sweden)

    Toni Poole* and Cynthia Sheffield

    2013-07-01

    Full Text Available Food safety begins on the farm with management practices that contribute to an abundant, safe, and affordable food supply. To attain this goal antimicrobials have been used in all stages of food animal production in the United States and elsewhere around the world at one time or another. Among food–production animals antimicrobials are used for growth promotion, disease prophylaxis or disease treatment, and are generally administered to the entire flock or herd. Over many decades bacteria have become resistant to multiple antimicrobial classes in a cumulative manner. Bacteria exhibit a number of well characterized mechanisms of resistance to antimicrobials that include: 1 modification of the antimicrobial; 2 alteration of the drug target; 3 decreased access of drug to target; and 4 implementation of an alternative metabolic pathway not affected by the drug. The mechanisms of resistance are complex and depend on the type of bacterium involved (e.g. Gram–positive or Gram–negative and the class of drug. Some bacterial species have accumulated resistance to nearly all antimicrobial classes due to a combination of intrinsic and acquired processes. This has and will continue to lead to clinical failures of antimicrobial treatment in both human and animal medicine.

  9. Mechanisms of resistance to linalool in Salmonella Senftenberg and their role in survival on basil.

    Science.gov (United States)

    Kalily, Emmanuel; Hollander, Amit; Korin, Ben; Cymerman, Itamar; Yaron, Sima

    2016-11-01

    Fresh produce contaminated with human pathogens raises vital and ecological questions about bacterial survival strategies. Such occurrence was basil harboring Salmonella enterica serovar Senftenberg that caused an outbreak in 2007. This host was unanticipated due to its production of antibacterial substances, including linalool. We show that linalool perforates bacterial membranes, resulting in increased permeability and leakage of vital molecules. It also inhibits cell motility and causes bacterial aggregation. Linalool-resistance was investigated by identification and characterization of S. Senftenberg mutants that perform altered resistance. Resistance mechanisms include selective permeability, regulated efflux/influx and chemotaxis-controlled motility. Moreover, survival of S. Senftenberg on basil leaves was substantially affected by McpL, a putative chemotaxis-related receptor, and RfaG, a component of the lipopolysaccharide production pathway, both have a role in resistance to linalool. Results reveal that adaptation to linalool occurs in nature by concurrent mechanisms. This adaption raises concerns about pathogens adaptation to new hosts including antimicrobial-compound-producing plants. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

  10. Characterization of Microstructure and Mechanical Properties of Resistance Spot Welded DP600 Steel

    Directory of Open Access Journals (Sweden)

    Ali Ramazani

    2015-09-01

    Full Text Available Resistance spot welding (RSW as a predominant welding technique used for joining steels in automotive applications needs to be studied carefully in order to improve the mechanical properties of the spot welds. The objectives of the present work are to characterize the resistance spot weldment of DP600 sheet steels. The mechanical properties of the welded joints were evaluated using tensile-shear and cross-tensile tests. The time-temperature evolution during the welding cycle was measured. The microstructures observed in different sites of the welds were correlated to thermal history recorded by thermocouples in the corresponding areas. It was found that cracks initiated in the periphery region of weld nuggets with a martensitic microstructure and a pull-out failure mode was observed. It was also concluded that tempering during RSW was the main reason for hardness decrease in HAZ.

  11. Ester-free Thiol-X Resins: New Materials with Enhanced Mechanical Behavior and Solvent Resistance.

    Science.gov (United States)

    Podgórski, Maciej; Becka, Eftalda; Chatani, Shunsuke; Claudino, Mauro; Bowman, Christopher N

    A series of thiol-Michael and radical thiol-ene network polymers were successfully prepared from ester-free as well as ester-containing monomer formulations. Polymerization reaction rates, dynamic mechanical analysis, and solvent resistance experiments were performed and compared between compositions with varied ester loading. The incorporation of ester-free alkyl thiol, vinyl sulfone and allylic monomers significantly improved the mechanical properties when compared with commercial, mercaptopropionate-based thiol-ene or thiol-Michael networks. For polymers with no hydrolytically degradable esters, glass transition temperatures (T g 's) as high as 100 °C were achieved. Importantly, solvent resistance tests demonstrated enhanced stability of ester-free formulations over PETMP-based polymers, especially in concentrated basic solutions. Kinetic analysis showed that glassy step-growth polymers are readily formed at ambient conditions with conversions reaching 80% and higher.

  12. Signaling Mechanisms Underlying Resistance Responses: What Have We Learned, and How Is It Being Applied?

    Science.gov (United States)

    Kachroo, Aardra; Vincelli, Paul; Kachroo, Pradeep

    2017-12-01

    Plants have evolved highly specific mechanisms to resist pathogens including preformed barriers and the induction of elaborate signaling pathways. Induced signaling requires recognition of the pathogen either via conserved pathogen-derived factors or specific pathogen-encoded proteins called effectors. Recognition of these factors by host encoded receptor proteins can result in the elicitation of different tiers of resistance at the site of pathogen infection. In addition, plants induce a type of systemic immunity which is effective at the whole plant level and protects against a broad spectrum of pathogens. Advances in our understanding of pathogen-recognition mechanisms, identification of the underlying molecular components, and their significant conservation across diverse plant species has enabled the development of novel strategies to combat plant diseases. This review discusses key advances in plant defense signaling that have been adapted or have the potential to be adapted for plant protection against microbial diseases.

  13. Molecular Mechanisms of Trastuzumab Resistance in HER2 Over expressing Breast Cancer

    International Nuclear Information System (INIS)

    Fiszman, G.L.; Jasnis, M.A.

    2011-01-01

    The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase over expressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, up regulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities

  14. Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance.

    Science.gov (United States)

    Ramamoorthy, Sivapriya; Cidlowski, John A

    2013-01-01

    Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of the GR. The molecular mechanisms that regulate glucocorticoid action highlight the dynamic nature of hormone signaling and provide novel insights into genomic glucocorticoid actions and glucocorticoid sensitivity. Although glucocorticoids are highly effective for therapeutic purposes, long-term and/or high-dose glucocorticoid administration often leads to reduced glucocorticoid sensitivity or resistance. Here, we summarize our current understanding of the mechanisms that modulate glucocorticoid sensitivity and resistance with a focus on GR-mediated signaling. Copyright © 2013 S. Karger AG, Basel.

  15. RNA interference as a resistance mechanism against crop parasites in Africa: a 'Trojan horse' approach.

    Science.gov (United States)

    Runo, Steven; Alakonya, Amos; Machuka, Jesse; Sinha, Neelima

    2011-02-01

    Biological crop pests cause serious economic losses. In Africa, the most prevalent parasites are insect pests, plant pathogenic root-knot nematodes, viruses and parasitic plants. African smallholder farmers struggle to overcome these parasitic constraints to agricultural production. Crop losses and the host range of these parasites have continued to increase in spite of the use of widely advocated control methods. A sustainable method to overcome biological pests in Africa would be to develop crop germplasm resistant to parasites. This is achievable using either genetic modification (GM) or a non-GM approach. However, there is a paucity of resistant genes available for introduction. Additionally, the biological processes underpinning host parasite resistance are not sufficiently well understood. The authors review a technology platform for using RNA-mediated interference (RNAi) as bioengineered resistance to important crop parasites in Africa. To achieve acquired resistance, a host crop is stably transformed with a transgene that encodes a hairpin RNA targeting essential parasitic genes. The RNAi sequence is chosen in such a way that it shares no homology with the host's genes, so it remains 'inactive' until parasitism. Upon parasitism, the RNAi sequence enters the parasite and post-transcriptional gene silencing (PTGS) mechanisms are activated, leading to the death of the parasite. Copyright © 2010 Society of Chemical Industry.

  16. Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase.

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    Jérémie Piton

    Full Text Available Mycobacterium tuberculosis DNA gyrase, an indispensable nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and is hence the sole target for quinolone action, a crucial drug active against multidrug-resistant tuberculosis. To understand at an atomic level the quinolone resistance mechanism, which emerges in extensively drug resistant tuberculosis, we performed combined functional, biophysical and structural studies of the two individual domains constituting the catalytic DNA gyrase reaction core, namely the Toprim and the breakage-reunion domains. This allowed us to produce a model of the catalytic reaction core in complex with DNA and a quinolone molecule, identifying original mechanistic properties of quinolone binding and clarifying the relationships between amino acid mutations and resistance phenotype of M. tuberculosis DNA gyrase. These results are compatible with our previous studies on quinolone resistance. Interestingly, the structure of the entire breakage-reunion domain revealed a new interaction, in which the Quinolone-Binding Pocket (QBP is blocked by the N-terminal helix of a symmetry-related molecule. This interaction provides useful starting points for designing peptide based inhibitors that target DNA gyrase to prevent its binding to DNA.

  17. Evaluation of the Mechanical Properties of Gray Cast Iron Using Electrical Resistivity Measurement

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    Bieroński M.

    2016-12-01

    Full Text Available In this paper an attempt to determine the relationship between the electrical resistivity and the tensile strength and hardness of cast iron of carbon equivalent in the range from 3.93% to 4.48%. Tests were performed on the gray cast iron for 12 different melts with different chemical composition. From one melt poured 6 samples. Based on the study of mechanical and electro-resistive determined variation characteristics of tensile strength, hardness and resistivity as a function of the carbon equivalent. Then, regression equations were developed as power functions describing the relationship between the resistivity of castings and their tensile strength and hardness. It was found a high level of regression equations to measuring points, particularly with regard to the relationship Rm=f(ρ. The obtained preliminary results indicate the possibility of application of the method of the resistance to rapid diagnostic casts on the production line, when we are dealing with repeatable production, in this case non variable geometry of the product for which it has been determinated before a regression equation.

  18. Bypass mechanisms of resistance to tyrosine kinase inhibition in chronic myelogenous leukaemia.

    Science.gov (United States)

    Marfe, Gabriella; Di Stefano, Carla

    2014-06-01

    Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patients can now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significant proportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiple molecular mechanisms of resistance have been identified and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain. The second is activation of alternative molecules that maintain the signalling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

  19. Mechanism of multidrug resistance of human small cell lung cancer cell line H446/VP.

    Science.gov (United States)

    Wang, Yan-Ling; Yan, Yun-Li; Zhou, Na-Jing; Han, Shuo; Zhao, Jun-Xia; Cao, Cui-Li; Lü, Yu-Hong

    2010-11-01

    Small cell lung cancer (SCLC) is the most aggressive form of lung cancer. This study aimed to investigate the mechanism of human small cell lung cancer cell line resistance to etoposide (VP-16), H446/VP. The cell viability was measured by MTT assay. Immunocytochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting methods were used to detect the multidrug resistance gene (MDR1), bcl-2, bax and the topoisomerase II (Topo II) expressions in H446 and H446/VP cells after treated with or without VP-16. The 50% inhibition concentration (IC50) of VP-16 on H446 cells was 49 mg/L, and 836 mg/L was for H446/VP cells. The expressions of MDR1 and bcl-2 were up-regulated, while the amounts of bax and Topo II were reduced in H446/VP cells. After treated with 49 mg/L of VP-16, it showed that the drug could significantly inhibit bcl-2 and Topo II expressions, and increase bax expression in H446 cells compared with that of H446/VP cells. The H446/VP cell was stably resistant to VP-16. The decreased expression of Topo II was correlated with the H446/VP multidrug resistance. The elevated expressions of MDR1, and the altered apoptotic pathways also played an important role in VP-16 induced multidrug resistance of SCLC.

  20. Virulence factors and mechanisms of antimicrobial resistance in Shigella strains from periurban areas of Lima (Peru).

    Science.gov (United States)

    Lluque, Angela; Mosquito, Susan; Gomes, Cláudia; Riveros, Maribel; Durand, David; Tilley, Drake H; Bernal, María; Prada, Ana; Ochoa, Theresa J; Ruiz, Joaquim

    2015-01-01

    The study was aimed to describe the serotype, mechanisms of antimicrobial resistance, and virulence determinants in Shigella spp. isolated from Peruvian children. Eighty three Shigella spp. were serogrouped and serotyped being established the antibiotic susceptibility. The presence of 12 virulence factors (VF) and integrase 1 and 2, along with commonly found antibiotic resistance genes was established by PCR. S. flexneri was the most relevant serogroup (55 isolates, 66%), with serotype 2a most frequently detected (27 of 55, 49%), followed by S. boydii and S. sonnei at 12 isolates each (14%) and S. dysenteriae (four isolates, 5%). Fifty isolates (60%) were multi-drug resistant (MDR) including 100% of S. sonnei and 64% of S. flexneri. Resistance levels were high to trimethoprim-sulfamethoxazole (86%), tetracycline (74%), ampicillin (67%), and chloramphenicol (65%). Six isolates showed decreased azithromycin susceptibility. No isolate was resistant to nalidixic acid, ciprofloxacin, nitrofurantoin, or ceftriaxone. The most frequent resistance genes were sul2 (95%), tet(B) (92%), cat (80%), dfrA1 (47%), blaOXA-1like (40%), with intl1 and intl2 detected in 51 and 52% of the isolates, respectively. Thirty-one different VF profiles were observed, being the ipaH (100%), sen (77%), virA and icsA (75%) genes the most frequently found. Differences in the prevalence of VF were observed between species with S. flexneri isolates, particularly serotype 2a, possessing high numbers of VF. In conclusion, this study highlights the high heterogeneity of Shigella VF and resistance genes, and prevalence of MDR organisms within this geographic region. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Diversity of Molecular Mechanisms Conferring Carbapenem Resistance to Pseudomonas aeruginosa Isolates from Saudi Arabia

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    Mohamed H. Al-Agamy

    2016-01-01

    Full Text Available Background. This study described various molecular and epidemiological characters determining antibiotic resistance patterns in Pseudomonas aeruginosa isolates. Methods. A total of 34 carbapenem-resistant P. aeruginosa clinical isolates were isolated from samples collected at a tertiary hospital in Riyadh, Saudi Arabia, from January to December 2011. Susceptibility testing, serotyping, molecular characterization of carbapenem resistance, and pulsed-field gel electrophoresis (PFGE were performed. Results. All isolates were resistant to ceftazidime, and more than half were highly resistant (minimum inhibitory concentration (MIC > 256 mg/L. Fifteen isolates had MIC values ≥64 mg/L for any of the carbapenems examined. Vietnamese extended-spectrum β-lactamase (VEB-1 (n=16/34 and oxacillinase (OXA-10 (n=14/34 were the most prevalent extended-spectrum β-lactamase and penicillinase, respectively. Verona imipenemase (VIM-1, VIM-2, VIM-4, VIM-11, and VIM-28 and imipenemase (IMP-7 variants were found in metallo-β-lactamase producers. A decrease in outer membrane porin gene (oprD expression was seen in nine isolates, and an increase in efflux pump gene (MexAB expression was detected in five isolates. Six serotypes (O:1, O:4, O:7, O:10, O:11, and O:15 were found among the 34 isolates. The predominant serotype was O:11 (16 isolates, followed by O:15 (nine isolates. PFGE analysis of the 34 carbapenem-resistant P. aeruginosa isolates revealed 14 different pulsotypes. Conclusions. These results revealed diverse mechanisms conferring carbapenem resistance to P. aeruginosa isolates from Saudi Arabia.

  2. Contribution of different mechanisms to the resistance to fluoroquinolones in clinical isolates of Salmonella enterica

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    Abeer Ahmed Rushdy

    Full Text Available OBJECTIVES: To study the potential factors include gene mutation, efflux pump and alteration of permeability associated with quinolone-resistance of Salmonella enterica strains isolated from patients with acute gastroenteritis and to evaluate the degree of synergistic activity of efflux pump inhibitors when combined with ciprofloxacin against resistant isolates. METHODS: Antimicrobial resistance patterns of fifty-eight Salmonella isolates were tested. Five isolates were selected to study the mechanism of resistance associated with quinolone group, including mutation in topoisomerase-encoding gene, altered cell permeability, and expression of an active efflux system. In addition, the combination between antibiotics and efflux pump inhibitors to overcome the microbial resistance was evaluated. RESULTS: Five Salmonella isolates totally resistant to all quinolones were studied. All isolates showed alterations in outer membrane proteins including disappearance of some or all of these proteins (Omp-A, Omp-C, Omp-D and Omp-F. Minimum inhibitory concentration values of ciprofloxacin were determined in the presence/absence of the efflux pump inhibitors: carbonyl cyanide m-chlorophenylhydrazone, norepinephrin and trimethoprim. Minimum inhibitory concentration values for two of the isolates were 2-4 fold lower with the addition of efflux pump inhibitors. All five Salmonella isolates were amplified for gyrA and parC genes and only two isolates were sequenced. S. Enteritidis 22 had double mutations at codon 83 and 87 in addition to three mutations at parC at codons 67, 76 and 80 whereas S. Typhimurium 57 had three mutations at codons 83, 87 and 119, but no mutations at parC. CONCLUSIONS: Efflux pump inhibitors may inhibit the major AcrAB-TolC in Salmonella efflux systems which are the major efflux pumps responsible for multidrug resistance in Gramnegative clinical isolates.

  3. Characterization of ceftazidime resistance mechanisms in clinical isolates of Burkholderia pseudomallei from Australia.

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    Derek S Sarovich

    Full Text Available Burkholderia pseudomallei is a gram-negative bacterium that causes the serious human disease, melioidosis. There is no vaccine against melioidosis and it can be fatal if not treated with a specific antibiotic regimen, which typically includes the third-generation cephalosporin, ceftazidime (CAZ. There have been several resistance mechanisms described for B. pseudomallei, of which the best described are amino acid changes that alter substrate specificity in the highly conserved class A β-lactamase, PenA. In the current study, we sequenced penA from isolates sequentially derived from two melioidosis patients with wild-type (1.5 µg/mL and, subsequently, resistant (16 or ≥256 µg/mL CAZ phenotypes. We identified two single-nucleotide polymorphisms (SNPs that directly increased CAZ hydrolysis. One SNP caused an amino acid substitution (C69Y near the active site of PenA, whereas a second novel SNP was found within the penA promoter region. In both instances, the CAZ resistance phenotype corresponded directly with the SNP genotype. Interestingly, these SNPs appeared after infection and under selection from CAZ chemotherapy. Through heterologous cloning and expression, and subsequent allelic exchange in the native bacterium, we confirmed the role of penA in generating both low-level and high-level CAZ resistance in these clinical isolates. Similar to previous studies, the amino acid substitution altered substrate specificity to other β-lactams, suggesting a potential fitness cost associated with this mutation, a finding that could be exploited to improve therapeutic outcomes in patients harboring CAZ resistant B. pseudomallei. Our study is the first to functionally characterize CAZ resistance in clinical isolates of B. pseudomallei and to provide proven and clinically relevant signatures for monitoring the development of antibiotic resistance in this important pathogen.

  4. Etiopathogenesis of Nonalcoholic Steatohepatitis: Role of Obesity, Insulin Resistance and Mechanisms of Hepatotoxicity

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    Praveen Guturu

    2012-01-01

    Full Text Available Incidence of nonalcoholic fatty liver disease is increasing with an estimated prevalence of 20–30% in developed nations. This is leading to increased incidence of chronic liver disease, cirrhosis, and hepatocellular cancer. It is critical to understand the etiology and pathogenesis of any disease to create therapeutic targets and develop new treatments. In this paper we discuss the etiology and pathogenesis of nonalcoholic steatohepatitis with special focus on obesity, role of insulin resistance, and molecular mechanisms of hepatotoxicity.

  5. Whole-genome sequencing reveals the mechanisms for evolution of streptomycin resistance in Lactobacillus plantarum.

    Science.gov (United States)

    Zhang, Fuxin; Gao, Jiayuan; Wang, Bini; Huo, Dongxue; Wang, Zhaoxia; Zhang, Jiachao; Shao, Yuyu

    2018-04-01

    In this research, we investigated the evolution of streptomycin resistance in Lactobacillus plantarum ATCC14917, which was passaged in medium containing a gradually increasing concentration of streptomycin. After 25 d, the minimum inhibitory concentration (MIC) of L. plantarum ATCC14917 had reached 131,072 µg/mL, which was 8,192-fold higher than the MIC of the original parent isolate. The highly resistant L. plantarum ATCC14917 isolate was then passaged in antibiotic-free medium to determine the stability of resistance. The MIC value of the L. plantarum ATCC14917 isolate decreased to 2,048 µg/mL after 35 d but remained constant thereafter, indicating that resistance was irreversible even in the absence of selection pressure. Whole-genome sequencing of parent isolates, control isolates, and isolates following passage was used to study the resistance mechanism of L. plantarum ATCC14917 to streptomycin and adaptation in the presence and absence of selection pressure. Five mutated genes (single nucleotide polymorphisms and structural variants) were verified in highly resistant L. plantarum ATCC14917 isolates, which were related to ribosomal protein S12, LPXTG-motif cell wall anchor domain protein, LrgA family protein, Ser/Thr phosphatase family protein, and a hypothetical protein that may correlate with resistance to streptomycin. After passage in streptomycin-free medium, only the mutant gene encoding ribosomal protein S12 remained; the other 4 mutant genes had reverted to the wild type as found in the parent isolate. Although the MIC value of L. plantarum ATCC14917 was reduced in the absence of selection pressure, it remained 128-fold higher than the MIC value of the parent isolate, indicating that ribosomal protein S12 may play an important role in streptomycin resistance. Using the mobile elements database, we demonstrated that streptomycin resistance-related genes in L. plantarum ATCC14917 were not located on mobile elements. This research offers a way of

  6. EXPERIMENTAL VERIFICATION OF THE MECHANICAL RESISTANCE OF FORENSIC MARKING BY MEANS SYNTHETIC DNA

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    Marek HÜTTER

    2017-06-01

    Full Text Available This article deals with experimental verification of resistance of forensic identification marks (microdots in combination with artificial DNA to property. It is considered mechanical abrasion from potential offender to remove or damage readability of marking and following identification. The aim of this work is to test the hypothesis that forensic marking can be completely removed by the process of mechanical abrasion without causing damages to a protected object. To fulfill this purpose it was designed and built a test equipment, where experiments were carried out to confirm or refute the above mentioned hypothesis.

  7. Alpha prime effect on mechanical properties and corrosion resistance of UR 52N+ duplex stainless steel

    International Nuclear Information System (INIS)

    Fontes, Talita Filier

    2009-01-01

    Alpha prime phase leads to decreased corrosion resistance and mechanical properties losses of duplex stainless steels. In this work mechanical and electrochemical tests were performed in duplex stainless steel UR 52N+ aged at 475 degree C for various periods in order to determine the sensibility of these tests to alpha prime presence. Hardness tests showed a gradual increase in its values; on the other hand, impact tests revealed that the material aged for 12h losses about 80% of energy absorption capacity of the solution annealed sample. Notwithstanding cyclic polarization tests showed that significant changes are only noted for aging times greater than 96h. (author)

  8. Resisting force characteristics of a mechanical snubber and its restraint effect on beam deformation

    International Nuclear Information System (INIS)

    Ohmata, Kenichiro

    1987-01-01

    A mechanical snubber is used to restrain piping systems in nuclear power plants during an earthquake. It has nonlinearities in both load (or exciting amplitude) and frequency response, so it will be very difficult to analyze the resisting force characteristics of the mechanical snubber theoretically. In this report, the equation of motion of the mechanical snubber is derived and digital simulations of snubber dynamic characteristics over a frequency range are carried out using the Continuous System Simulation Language (CSSL). Also, the restraint effect of the mechanical snubber applied to a simple beam is discussed both numerically and experimentally. The beam is replaced by a lumped mass system and CSSL is used to perform the digital simulations. (author)

  9. Effect of Pre-existing Nano Sized Precipitates on Microstructure and Mechanical Property of Al-0.2wt% Sc Highly Deformed by ARB Process

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    Ehsan Borhani

    2014-06-01

    Full Text Available The effect of pre-existing nano sized precipitates on the mechanisms and rate of grain refinement has been investigated during the severe plastic deformation. A binary Al–0.2Sc alloy, containing coherent Al3Sc particles, of 3.62 nm in diameter has been deformed by accumulative roll bonding up to 10 cycles. The resulting deformed structures were quantitatively analyzed using electron backscattered diffraction and transmission electron microscope techniques, and the results have been compared to those obtained from a solution treated Al–0.2Sc alloy, deformed up to same accumulative roll bonding cycles. The fraction of high-angle grain boundaries and grain size in all materials was increased and decreased gradually with increasing equivalent strain, respectively. However, the Aged-ARB alloy had relatively higher fraction of high-angle grain boundaries and smaller grain size than those of ST-ARB specimens at the same accumulative roll bonding cycles. It was found in an Al-0.2%Sc alloy that starting microstructures significantly affect the formation of ultrafine grains during severe plastic deformation. It was shown that the small Al3Sc precipitates are more effective on microstructural evolution during accumulative roll bonding process. Existence of fine precipitates in the starting material greatly accelerated the microstructure refinement. In this regards some unique phenomena, including softening during severe plastic deformation and dissolution of pre-existing Al3Sc, were observed.

  10. Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania.

    Science.gov (United States)

    Gazanion, Élodie; Fernández-Prada, Christopher; Papadopoulou, Barbara; Leprohon, Philippe; Ouellette, Marc

    2016-05-24

    Innovative strategies are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. Here we develop a sensitive method, which we term Cosmid Sequencing (or "Cos-Seq"), based on functional cloning coupled to next-generation sequencing. Cos-Seq identified >60 loci in the Leishmania genome that were enriched via drug selection with methotrexate and five major antileishmanials (antimony, miltefosine, paromomycin, amphotericin B, and pentamidine). Functional validation highlighted both known and previously unidentified drug targets and resistance genes, including novel roles for phosphatases in resistance to methotrexate and antimony, for ergosterol and phospholipid metabolism genes in resistance to miltefosine, and for hypothetical proteins in resistance to paromomycin, amphothericin B, and pentamidine. Several genes/loci were also found to confer resistance to two or more antileishmanials. This screening method will expedite the discovery of drug targets and resistance mechanisms and is easily adaptable to other microorganisms.

  11. Classical and quantum mechanical behaviour in the low-field magneto-resistance in open quantum dots

    International Nuclear Information System (INIS)

    Brunner, R.

    2005-09-01

    Electronic transport through open dots has received much attention in recent years. An interesting aspect of this research focuses on the use of such low-dimensional systems to probe the connection between semi-classical physics and quantum mechanics. The purpose of this thesis is to understand the transport properties in a ballistic open quantum dot and dot arrays and to find clear evidence that, although the system is open, still discrete energy states are present. This is achieved by using a classical model calculation and performing DC and microwave experiments in the single open quantum dot and 3-dot array. By comparing the magneto-resistance obtained from the experiment with the calculated magneto-resistance the confining potential of the open quantum dot is found to be a soft parabolic potential. Peaks in the low-field magneto-resistance are attributed to backscattering events in the open dot. At certain magnetic fields classically calculated trajectories are obtained which are backscattered. As a consequence the magneto-resistance is raised. As a consequence of a stability analysis by calculating the Poincare section and estimating the Lyapunov exponent, the single open quantum dot is identified as an integrable system. In the case of an open quantum dot array the symmetry of the single dot is broken. Depending on the magnetic field, the open quantum dot array is characterized as an integrable system or a nonintegrable system with mixed phase space. The mixed phase space exists of chaotic and quasi-periodic trajectories. The quasi-periodic trajectories are attributed to Kolmogorov-Arnol'd-Moser (KAM) islands. These islands are completely decoupled from the surrounding and therefore classically inaccessible. We argue that the closed orbits which generate a series of delta functions in the density of states might be associated with discrete energy states in the open quantum dot. To search for discrete energy states in the open quantum dot microwave

  12. Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data

    OpenAIRE

    Oikonomou, O.; Sarrou, S.; Papagiannitsis, C. C.; Georgiadou, S.; Mantzarlis, K.; Zakynthinos, E.; Dalekos, G. N.; Petinaki, E.

    2015-01-01

    Background Colistin-resistant/carbapenem-resistant Acinetobacter baumannii is a significant challenge for antibiotic treatment and infection control policies. Since 2012, in Central Greece an increase of colistin/pan- resistant A. baumannii has occurred, indicating the need for further analysis. Methods A total of 86 colistin-resistant/carbapenem-resistant out of 1228 A. baumannii clinical isolates, consecutively collected between 2012 and 2014 in a tertiary Greek hospital of Central Greece, ...

  13. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

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    Juan D Unciti-Broceta

    2015-06-01

    Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

  14. Auxinic herbicides, mechanisms of action, and weed resistance: A look into recent plant science advances

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    Pedro Jacob Christoffoleti

    2015-08-01

    Full Text Available Auxin governs dynamic cellular processes involved at several stages of plant growth and development. In this review, we discuss the mechanisms employed by auxin in light of recent scientific advances, with a focus on synthetic auxins as herbicides and synthetic auxin resistance mechanisms. Two auxin receptors were reported. The plasma membrane receptor ABP1 (Auxin Binding Protein 1 alters the structure and arrangement of actin filaments and microtubules, leading to plant epinasty and reducing peroxisomes and mitochondria mobility in the cell environment. The second auxin receptor is the gene transcription pathway regulated by the SCFTir/AFB ubiquitination complex, which destroys transcription repressor proteins that interrupt Auxin Response Factor (ARF activation. As a result mRNA related with Abscisic Acid (ABA and ethylene are transcribed, producing high quantities of theses hormones. Their associated action leads to high production of Reactive Oxygen Species (ROS, leading to tissue and plant death. Recently, another ubiquitination pathway which is described as a new auxin signaling route is the F-box protein S-Phase Kinase-Associated Protein 2A (SKP2A. It is active in cell division regulation and there is evidence that auxin herbicides can deregulate the SKP2A pathway, which leads to severe defects in plant development. In this discussion, we propose that SFCSKP2A auxin binding site alteration could be a new auxinic herbicide resistance mechanism, a concept which may contribute to the current progress in plant biology in its quest to clarify the many questions that still surround auxin herbicide mechanisms of action and the mechanisms of weed resistance.

  15. Mechanisms of antimicrobial resistant Salmonella enterica transmission associated with starling-livestock interactions.

    Science.gov (United States)

    Carlson, James C; Hyatt, Doreene R; Ellis, Jeremy W; Pipkin, David R; Mangan, Anna M; Russell, Michael; Bolte, Denise S; Engeman, Richard M; DeLiberto, Thomas J; Linz, George M

    2015-08-31

    Bird-livestock interactions have been implicated as potential sources for bacteria within concentrated animal feeding operations (CAFO). European starlings (Sturnus vulgaris) in particular are known to contaminate cattle feed and water with Salmonella enterica through their fecal waste. We propose that fecal waste is not the only mechanisms through which starlings introduce S. enterica to CAFO. The goal of this study was to assess if starlings can mechanically move S. enterica. We define mechanical movement as the transportation of media containing S. enterica, on the exterior of starlings within CAFO. We collected 100 starlings and obtained external wash and gastrointestinal tract (GI) samples. We also collected 100 samples from animal pens. Within each pen we collected one cattle fecal, feed, and water trough sample. Isolates from all S. enterica positive samples were subjected to antimicrobial susceptibility testing. All sample types, including 17% of external starling wash samples, contained S. enterica. All sample types had at least one antimicrobial resistant (AMR) isolate and starling GI samples harbored multidrug resistant S. enterica. The serotypes isolated from the starling external wash samples were all found in the farm environment and 11.8% (2/17) of isolates from positive starling external wash samples were resistant to at least one class of antibiotics. This study provides evidence of a potential mechanism of wildlife introduced microbial contamination in CAFO. Mechanical movement of microbiological hazards, by starlings, should be considered a potential source of bacteria that is of concern to veterinary, environmental and public health. Published by Elsevier B.V.

  16. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

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    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  17. Unravelling of a mechanism of resistance to colistin in Klebsiella pneumoniae using atomic force microscopy.

    Science.gov (United States)

    Formosa, C; Herold, M; Vidaillac, C; Duval, R E; Dague, E

    2015-08-01

    In this study we focused on the mechanism of colistin resistance in Klebsiella pneumoniae. We used two strains of K. pneumoniae: a colistin-susceptible strain (K. pneumoniae ATCC 700603, KpATCC) and its colistin-resistant derivative (KpATCCm, MIC of colistin 16 mg/L). We performed a genotypic analysis based on the expression of genes involved in LPS synthesis and L-Ara4N moiety addition. We also explored the status of the mgrB gene. Then, a phenotypic analysis was performed using atomic force microscopy (AFM). The Young modulus was extracted from force curves fitted using the Hertz model, and stiffness values were extracted from force curves fitted using the Hooke model. We failed to observe any variation in the expression of genes implicated in LPS synthesis or L-Ara4N moiety addition in KpATCCm, in the absence of colistin or under colistin pressure (versus KpATCC). This led us to identify an insertional inactivation/mutation in the mgrB gene of KpATCCm. In addition, morphology results obtained by AFM showed that colistin removed the capsule from the susceptible strain, but not from the resistant strain. Nanomechanical data on the resistant strain showed that colistin increased the Young modulus of the capsule. Extend force curves recorded on top of the cells allowed us to make the following hypothesis about the nanoarchitecture of the capsule of the two strains: KpATCC has a soft capsule consisting of one layer, whereas the KpATCCm capsule is harder and organized in several layers. We hypothesize that capsular polysaccharides might be implicated in the mechanism of colistin resistance in K. pneumoniae, depending on its genotype. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues.

    Directory of Open Access Journals (Sweden)

    Geoffrey D Coxon

    Full Text Available Defining the pharmacological target(s of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61 or HadC (at Val85, Lys157 or Thr123, which are components of the β-hydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.

  19. Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

    Science.gov (United States)

    Shen, Jianan; He, Qianjun; Gao, Yu; Shi, Jianlin; Li, Yaping

    2011-10-01

    Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC50 of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

  20. Metabolic and Behavioral Mechanisms of Indoxacarb Resistance in Sitophilus zeamais (Coleoptera: Curculionidae).

    Science.gov (United States)

    Haddi, Khalid; Mendonça, Larine P; Dos Santos, Milaine F; Guedes, Raul Narciso C; Oliveira, Eugênio E

    2015-02-01

    The control of the most important pest of stored maize, the weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), is mainly achieved with the use of pyrethroid insecticides. However, the intensive use of these compounds has led to the selection of resistant populations and has compromised the control efficacy of this insect pest. Here, the toxicity of indoxacarb for a potential use in the control of S. zeamais was assessed on 13 Brazilian populations. Concentration-mortality bioassays, in the presence of synergists (piperonyl butoxide, triphenyl phosphate, and diethyl maleate), were used to assess potential metabolic-based indoxacarb resistance mechanisms. We also assessed the behavioral (locomotory) responses of these populations to indoxacarb exposure. The results showed significant differences between the populations (LD50 values ranged from 0.06 to 13.99 mg a.i/kg of grains), resulting in resistance ratios of >200-fold between the least (Canarana-MT) and the most (Espirito Santo do Pinhal-SP) susceptible populations. The results obtained with synergized indoxacarb suggest the involvement of esterases and glutathione-S-transferases on indoxacarb action, and also suggest the involvement of cytochrome P450-dependent monooxygenases as a potential indoxacarb resistance mechanism in Brazilian populations of S. zeamais. Although indoxacarb-induced behavioral avoidance varied among populations, some resistant populations (e.g., Canarana-MT) were able to reduce exposure to indoxacarb by spending more time in the nontreated areas. Collectively, our findings indicate that the behavioral (locomotory) and physiological responses of these insects may compromise the control efficacy of oxadiazine insecticides (e.g., indoxacarb) in Brazilian populations of S. zeamais. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Quantitative proteomics as a tool to identify resistance mechanisms in erlotinib-resistant subclones of the non-small cell lung cancer cell line HCC827

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine

    Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as approximately 70% of patients show significant tumor regression when treated (Santarpia et. al., 2013). However, all patients relapse due to development of acquired resistance...... line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively), and performed comparative quantitative proteomic analysis of these and the parental HCC827 cell line. The resistant subclones were examined both in absence and presence...... the identification of novel resistance mechanisms. We identified 2875 cytoplasmic proteins present in all 4 cell lines. Of these 87, 56 and 23 are upregulated >1.5 fold; and 117, 72 and 32 are downregulated >1.5 fold, respectively, in the 3 resistant clones compared to the parental cell line. By network analysis, we...

  2. Characterization resistance mechanisms in faba bean (Vicia faba against broomrape species (Orobanche and Phelipanche spp.

    Directory of Open Access Journals (Sweden)

    Diego Rubiales

    2016-11-01

    Full Text Available Faba bean (Vicia faba production in Mediterranean and Near East agriculture is severely constrained by broomrape infection. The most widely distributed broomrape species affecting faba bean is Orobanche crenata, although O. foetida and Phelipanche aegyptiaca are of local importance. Only moderately resistant cultivars are available to farmers. Rizotrons studies allowed the dissection of resistance components in faba bean accessions against the very infective species O. crenata, O. foetida var. broteri and P. aegyptiaca, and to the inappropriate P. ramosa and O. foetida var. foetida. Results confirm that some levels of incomplete resistance are available, resulting in a reduced number of broomrape tubercles successfully formed per faba bean plant. Interestingly, the intermediate levels of resistance of cv. Baraca were operative against all broomrape populations and species studied, confirming previous reports on the stability of resistance of Baraca in field trials in different countries. Low induction of seed germination played a major role in the resistance against the inappropriate O. foetida var. foetida but not against the also inappropriate P. ramosa, neither to the infective species O. crenata, O. foetida var. broteri or P. aegyptiaca. Negative tropism of germinated seeds with radicles growing away from faba bean roots was marked for both inappropriate species but was not observed in any of the infective species. Also, a proportion of radicles that had successfully contacted faba bean roots became necrotic, failing in starting tubercle development, particularly frequent for the two inappropriate species. Such necrosis was significant also on radicles contacting resistant faba bean accessions, being particularly relevant for Spanish O. crenata population, and lower although still significant in some accessions against Syrian O. crenata and P. aegytiaca, suggesting that this might also be an operative mechanism to be selected and further

  3. Characterization of Resistance Mechanisms in Faba Bean (Vicia faba) against Broomrape Species (Orobanche and Phelipanche spp.)

    Science.gov (United States)

    Rubiales, Diego; Rojas-Molina, Maria M.; Sillero, Josefina C.

    2016-01-01

    Faba bean (Vicia faba) production in Mediterranean and Near East agriculture is severely constrained by broomrape infection. The most widely distributed broomrape species affecting faba bean is Orobanche crenata, although O. foetida and Phelipanche aegyptiaca are of local importance. Only moderately resistant cultivars are available to farmers. Rizotrons studies allowed the dissection of resistance components in faba bean accessions against the very infective species O. crenata, O. foetida var. broteri and P. aegyptiaca, and to the inappropriate P. ramosa and O. foetida var. foetida. Results confirm that some levels of incomplete resistance are available, resulting in a reduced number of broomrape tubercles successfully formed per faba bean plant. Interestingly, the intermediate levels of resistance of cv. Baraca were operative against all broomrape populations and species studied, confirming previous reports on the stability of resistance of Baraca in field trials in different countries. Low induction of seed germination played a major role in the resistance against the inappropriate O. foetida var. foetida but not against the also inappropriate P. ramosa, neither to the infective species O. crenata, O. foetida var. broteri, or P. aegyptiaca. Negative tropism of germinated seeds with radicles growing away from faba bean roots was marked for both inappropriate species but was not observed in any of the infective species. Also, a proportion of radicles that had successfully contacted faba bean roots became necrotic, failing in starting tubercle development, particularly frequent for the two inappropriate species. Such necrosis was significant also on radicles contacting resistant faba bean accessions, being particularly relevant for Spanish O. crenata population, and lower although still significant in some accessions against Syrian O. crenata and P. aegyptiaca, suggesting that this might also be an operative mechanism to be selected and further exploited in faba

  4. Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds

    International Nuclear Information System (INIS)

    Crochiere, Marsha; Kashyap, Trinayan; Kalid, Ori; Shechter, Sharon; Klebanov, Boris; Senapedis, William; Saint-Martin, Jean-Richard; Landesman, Yosef

    2015-01-01

    Exportin 1 (XPO1) is a well-characterized nuclear export protein whose expression is up-regulated in many types of cancers and functions to transport key tumor suppressor proteins (TSPs) from the nucleus. Karyopharm Therapeutics has developed a series of small-molecule Selective Inhibitor of Nuclear Export (SINE) compounds, which have been shown to block XPO1 function both in vitro and in vivo. The drug candidate, selinexor (KPT-330), is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors. The present study sought to decipher the mechanisms that render cells either sensitive or resistant to treatment with SINE compounds, represented by KPT-185, an early analogue of KPT-330. Using the human fibrosarcoma HT1080 cell line, resistance to SINE was acquired over a period of 10 months of constant incubation with increasing concentration of KPT-185. Cell viability was assayed by MTT. Immunofluorescence was used to compare nuclear export of TSPs. Fluorescence activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), and immunoblots were used to measure effects on cell cycle, gene expression, and cell death. RNA from naïve and drug treated parental and resistant cells was analyzed by Affymetrix microarrays. Treatment of HT1080 cells with gradually increasing concentrations of SINE resulted in > 100 fold decrease in sensitivity to SINE cytotoxicity. Resistant cells displayed prolonged cell cycle, reduced nuclear accumulation of TSPs, and similar changes in protein expression compared to parental cells, however the magnitude of the protein expression changes were more significant in parental cells. Microarray analyses comparing parental to resistant cells indicate that a number of key signaling pathways were altered in resistant cells including expression changes in genes involved in adhesion, apoptosis, and inflammation. While the patterns of changes in transcription following drug treatment are similar in parental

  5. Modeling of the bacterial mechanism of methicillin-resistance by a systems biology approach.

    Directory of Open Access Journals (Sweden)

    Ida Autiero

    Full Text Available BACKGROUND: A microorganism is a complex biological system able to preserve its functional features against external perturbations and the ability of the living systems to oppose to these external perturbations is defined "robustness". The antibiotic resistance, developed by different bacteria strains, is a clear example of robustness and of ability of the bacterial system to acquire a particular functional behaviour in response to environmental changes. In this work we have modeled the whole mechanism essential to the methicillin-resistance through a systems biology approach. The methicillin is a beta-lactamic antibiotic that act by inhibiting the penicillin-binding proteins (PBPs. These PBPs are involved in the synthesis of peptidoglycans, essential mesh-like polymers that surround cellular enzymes and are crucial for the bacterium survival. METHODOLOGY: The network of genes, mRNA, proteins and metabolites was created using CellDesigner program and the data of molecular interactions are stored in Systems Biology Markup Language (SBML. To simulate the dynamic behaviour of this biochemical network, the kinetic equations were associated with each reaction. CONCLUSIONS: Our model simulates the mechanism of the inactivation of the PBP by methicillin, as well as the expression of PBP2a isoform, the regulation of the SCCmec elements (SCC: staphylococcal cassette chromosome and the synthesis of peptidoglycan by PBP2a. The obtained results by our integrated approach show that the model describes correctly the whole phenomenon of the methicillin resistance and is able to respond to the external perturbations in the same way of the real cell. Therefore, this model can be useful to develop new therapeutic approaches for the methicillin control and to understand the general mechanism regarding the cellular resistance to some antibiotics.

  6. Inheritance, Realized Heritability, and Biochemical Mechanisms of Malathion Resistance in Bactrocera dorsalis (Diptera: Tephritidae).

    Science.gov (United States)

    Wang, Luo-Luo; Feng, Zi-Jiao; Li, Ting; Lu, Xue-Ping; Zhao, Jia-Jia; Niu, Jin-Zhi; Smagghe, Guy; Wang, Jin-Jun

    2016-02-01

    To better characterize the resistance development and therefore establish effective pest management strategies, this study was undertaken to investigate the inheritance mode and biochemical mechanisms of malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel), which is one of the most notorious pests in the world. After 22 generations of selection with malathion, the malathion-resistant (MR) strain of B. dorsalis developed a 34-fold resistance compared with a laboratory susceptible strain [malathion-susceptible (MS)]. Bioassay results showed that there was no significant difference between the LD50 values of malathion against the progenies from both reciprocal crosses (F(1)-SR and F(1)-RS). The degree of dominance values (D) was calculated as 0.39 and 0.32 for F(1)-RS and F(1)-SR, respectively. The logarithm dosage-probit mortality lines of the F(2) generation and progeny from the backcross showed no clear plateaus of mortality across a range of doses. In addition, Chi-square analysis revealed significant differences between the mortality data and the theoretical expectations. The realized heritability (h(2)) value was 0.16 in the laboratory-selected resistant strain of B. dorsalis. Enzymatic activities identified significant changes of carboxylesterases, cytochrome P450 (general oxidases), and glutathione S-transferases in MR compared with the MS strain of B. dorsalis. Taken together, this study revealed for the first time that malathion resistance in B. dorsalis follows an autosomal, incompletely dominant, and polygenic mode of inheritance and is closely associated with significantly elevated activities of three major detoxification enzymes. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Influence of Brazilian vegetable oils on mechanical resistence of hair fiber

    Directory of Open Access Journals (Sweden)

    Maria Valéria Velasco

    2015-02-01

    Full Text Available Associating the global trend of incorporating active compounds and plants in cosmetic formulations and the vast Brazilian biodiversity, the present work aimed to study the incorporation of Brazilian vegetable oils in hair conditioner formulations, evaluating the mechanical resistance of hair fibers. The following oils were incorporated into base formulations at 5.0 % (w/w: babassu, buriti, andiroba and pequi. The formulations were applied to samples of Caucasian hair, followed by several washing steps, then the evaluation of mechanical strength. It was found that there was no statistically significant difference in mechanical resistance between samples treated with oils and the control between the first and seventh wash cycles. This fact can be explained by the possible low penetration of oils into the cortex, a region responsible for the mechanical properties of the hair fiber, since the grease composition disfavors its diffusion. The common effects of vegetable oils on the cuticle, such as filling in cracks or cavities, lubrication, and increased protein hydrophobicity cannot be excluded. The oils tested in this work were not able to raise or protect hair tresses. However, additional studies are required in order to establish the effects of oil treatments, particularly in damaged hair.

  8. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria.

    Science.gov (United States)

    Hall, Clayton W; Mah, Thien-Fah

    2017-05-01

    Biofilms are surface-attached groups of microbial cells encased in an extracellular matrix that are significantly less susceptible to antimicrobial agents than non-adherent, planktonic cells. Biofilm-based infections are, as a result, extremely difficult to cure. A wide range of molecular mechanisms contribute to the high degree of recalcitrance that is characteristic of biofilm communities. These mechanisms include, among others, interaction of antimicrobials with biofilm matrix components, reduced growth rates and the various actions of specific genetic determinants of antibiotic resistance and tolerance. Alone, each of these mechanisms only partially accounts for the increased antimicrobial recalcitrance observed in biofilms. Acting in concert, however, these defences help to ensure the survival of biofilm cells in the face of even the most aggressive antimicrobial treatment regimens. This review summarises both historical and recent scientific data in support of the known biofilm resistance and tolerance mechanisms. Additionally, suggestions for future work in the field are provided. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Wear Resistance and Mechanical Behaviour of Epoxy/Mollusk Shell Biocomposites developed for Structural Applications

    Directory of Open Access Journals (Sweden)

    I.O. Oladele

    2016-09-01

    Full Text Available Epoxy resin is one of the strongest commercially exploitable thermosetting polymers in the polymer family; however its expensive nature in comparison with other thermosetting polymers such as vinylester and polyester limits its applications as a structural material. Inexpensive fillers on the other hand, especially those derived from agro-industrial wastes are very important in reducing the overall cost of polymer composites and furthermore influential in enhancing some of their engineering properties. In the present study, the wear resistance and mechanical behaviour of epoxy polymer matrix filled with <75 and 75 μm calcined particles of African land snail shells have been comparatively investigated. The wear resistance and the mechanical behaviour of the composites were studied via Taber Abraser and INSTRON universal testing machine. Also, the elemental constituents of the calcined snail shell and the epoxy biocomposites were characterized by X-Ray Fluorescence Spectroscopy and Scanning Electron Microscopy/Energy Dispersion Spectroscopy. From the experimental results, it was observed that, at the highest filler loading, smaller particle size presented a biocomposite with significant enhancement in wear and mechanical properties. However, it was also observed that increase in particle size showed no significant enhancement in the mechanical properties of the biocomposites.

  10. Overview on mechanisms of acetic acid resistance in acetic acid bacteria.

    Science.gov (United States)

    Wang, Bin; Shao, Yanchun; Chen, Fusheng

    2015-02-01

    Acetic acid bacteria (AAB) are a group of gram-negative or gram-variable bacteria which possess an obligate aerobic property with oxygen as the terminal electron acceptor, meanwhile transform ethanol and sugar to corresponding aldehydes, ketones and organic acids. Since the first genus Acetobacter of AAB was established in 1898, 16 AAB genera have been recorded so far. As the main producer of a world-wide condiment, vinegar, AAB have evolved an elegant adaptive system that enables them to survive and produce a high concentration of acetic acid. Some researches and reviews focused on mechanisms of acid resistance in enteric bacteria and made the mechanisms thoroughly understood, while a few investigations did in AAB. As the related technologies with proteome, transcriptome and genome were rapidly developed and applied to AAB research, some plausible mechanisms conferring acetic acid resistance in some AAB strains have been published. In this review, the related mechanisms of AAB against acetic acid with acetic acid assimilation, transportation systems, cell morphology and membrane compositions, adaptation response, and fermentation conditions will be described. Finally, a framework for future research for anti-acid AAB will be provided.

  11. Identifyng mechanisms of resistance to chemotherapy in osteosarcoma tumor stem cells

    OpenAIRE

    Oliveira, Vitor Emanuel Bucete

    2011-01-01

    Introdução: A teoria das células estaminais tumorais propõe que os tumores estão hierarquicamente organizados, onde existe uma pequena subpopulação de células com características de células estaminas (CSCs) responsáveis pela iniciação e manutenção do crescimento tumoral e pela resistência à quimioterapia. Com este trabalho, pretendemos estudar a sensibilidade das CSCs isoladas a partir de uma linha celular humana de osteossarcoma (MNNG/HOS) à doxorrubicina (DOX) e identificar os possíveis mec...

  12. Label-free SRM-based relative quantification of antibiotic resistance mechanisms in Pseudomonas aeruginosa clinical isolates

    Directory of Open Access Journals (Sweden)

    Yannick eCharretier

    2015-02-01

    Full Text Available Both acquired and intrinsic mechanisms play a crucial role in Pseudomonas aeruginosa antibiotic resistance. Many clinically relevant resistance mechanisms result from changes in gene expression, namely multidrug efflux pump overproduction, AmpC beta-lactamase induction or derepression, and inactivation or repression of the carbapenem-specific porin OprD. Changes in gene expression are usually assessed using reverse-transcription quantitative real-time PCR (RT-qPCR assays. Here, we evaluated label-free Selected Reaction Monitoring (SRM-based mass spectrometry to directly quantify proteins involved in antibiotic resistance. We evaluated the label-free SRM using a defined set of P. aeruginosa isolates with known resistance mechanisms and compared it against RT-qPCR. Referring to efflux systems, we found a more robust relative quantification of antibiotic resistance mechanisms by SRM than RT-qPCR. The SRM-based approach was applied to a set of clinical P. aeruginosa isolates to detect antibiotic resistance proteins. This multiplexed SRM-based approach is a rapid and reliable method for the simultaneous detection and quantification of resistance mechanisms and we demonstrate its relevance for antibiotic resistance prediction.

  13. Label-free SRM-based relative quantification of antibiotic resistance mechanisms in Pseudomonas aeruginosa clinical isolates.

    Science.gov (United States)

    Charretier, Yannick; Köhler, Thilo; Cecchini, Tiphaine; Bardet, Chloé; Cherkaoui, Abdessalam; Llanes, Catherine; Bogaerts, Pierre; Chatellier, Sonia; Charrier, Jean-Philippe; Schrenzel, Jacques

    2015-01-01

    Both acquired and intrinsic mechanisms play a crucial role in Pseudomonas aeruginosa antibiotic resistance. Many clinically relevant resistance mechanisms result from changes in gene expression, namely multidrug efflux pump overproduction, AmpC β-lactamase induction or derepression, and inactivation or repression of the carbapenem-specific porin OprD. Changes in gene expression are usually assessed using reverse-transcription quantitative real-time PCR (RT-qPCR) assays. Here, we evaluated label-free Selected Reaction Monitoring (SRM)-based mass spectrometry to directly quantify proteins involved in antibiotic resistance. We evaluated the label-free SRM using a defined set of P. aeruginosa isolates with known resistance mechanisms and compared it with RT-qPCR. Referring to efflux systems, we found a more robust relative quantification of antibiotic resistance mechanisms by SRM than RT-qPCR. The SRM-based approach was applied to a set of clinical P. aeruginosa isolates to detect antibiotic resistance proteins. This multiplexed SRM-based approach is a rapid and reliable method for the simultaneous detection and quantification of resistance mechanisms and we demonstrate its relevance for antibiotic resistance prediction.

  14. Antibiotics Resistance in Rhizobium: Type, Process, Mechanism and Benefit for Agriculture.

    Science.gov (United States)

    Naamala, Judith; Jaiswal, Sanjay K; Dakora, Felix D

    2016-06-01

    The use of high-quality rhizobial inoculants on agricultural legumes has contributed substantially to the N economy of farming systems through inputs from biological nitrogen fixation (BNF). Large populations of symbiotically effective rhizobia should be available in the rhizosphere for symbiotic BNF with host plants. The rhizobial populations should also be able to compete and infect host plants. However, the rhizosphere comprises large populations of different microorganisms. Some of these microorganisms naturally produce antibiotics which are lethal to susceptible rhizobial populations in the soil. Therefore, intrinsic resistance to antibiotics is a desirable trait for the rhizobial population. It increases the rhizobia's chances of growth, multiplication and persistence in the soil. With a large population of rhizobia in the soil, infectivity of host plants and the subsequent BNF efficiency can be guaranteed. This review, therefore, puts together findings by various researchers on antibiotic resistance in bacteria with the main emphasis on rhizobia. It describes the different modes of action of different antibiotics, the types of antibiotic resistance exhibited by rhizobia, the mechanisms of acquisition of antibiotic resistance in rhizobia and the levels of tolerance of different rhizobial species to different antibiotics.

  15. Changes in cadmium accumulation as a mechanism for cadmium resistance in the least killifish Heterandria formosa

    International Nuclear Information System (INIS)

    Xie Lingtian; Klerks, Paul L.

    2004-01-01

    Evolution of resistance to heavy metals may involve complex changes at the physiological level. We report here on research into changes in cadmium uptake and accumulation as mechanisms underlying the increased resistance to Cd in laboratory lines of the least killifish, Heterandria formosa. We compared Cd accumulation between three control lines and three lines selected successfully for an increased Cd-resistance. Individuals of the Cd-adapted lines had a lower short-term (2 h) uptake of Cd than those of the control lines. A time-series experiment showed that selection-line fish had a lower rate of Cd accumulation than fish from the control lines during the first 14 h of exposure to 6 mg/l of Cd. At the 14 h time point, Cd accumulation in the control-line fish approached lethal levels, while Cd levels in selection-line fish from this point on increased at a slower rate than in the initial 14 h. Overall, the relatively small changes in uptake and accumulation patterns caused lethal body burdens in the fish from the selection lines to be reached at more than twice the exposure duration at which this occurred in fish from the control lines. Lethal Cd levels appeared to be the same in control- and selection-line fish. Our results suggest that reduced uptake and accumulation of Cd accounted for approximately two-third of the increased resistance in the Cd-adapted lines

  16. Structural Insights into the Fluoroquinolone Resistance Mechanism of Shigella flexneri DNA Gyrase and Topoisomerase IV.

    Science.gov (United States)

    Tamanna; Ramana, Jayashree

    2016-07-01

    Traveler's diarrhea (TD) is an important public health concern that can result from a variety of intestinal pathogens, including bacteria, parasites, and virus. A number of antibiotics are being used to cure TD, but due to widespread use of these antibiotics, the pathogens are becoming resistant to them. In this work, we performed docking studies of DNA gyraseA (GyrA) and topoisomerase IV (ParC) of Shigella flexneri and their mutants with two different fluoroquinolones, ciprofloxacin and norfloxacin, to understand their resistance mechanism at the structural level. S. flexneri strains with mutations at serine 83 to leucine and aspartic acid 87 to glutamate or asparagine of GyrA and that of serine 80 to isoleucine in ParC have decreased susceptibility to fluoroquinolones. This analysis revealed that interaction of ciprofloxacin/norfloxacin with all the mutants was weaker than the interaction of ciprofloxacin/norfloxacin with the wild type. This study highlights the importance of aspartic acid and serine in GyrA and that of serine in ParC, forming bonds with ciprofloxacin/norfloxacin, which may play a crucial role in antibiotic resistance. This work corelates very well with the experimental outcomes and gives a good explanation for fluoroquinolone resistance in S. flexneri.

  17. Transcriptional Network Analysis Reveals Drought Resistance Mechanisms of AP2/ERF Transgenic Rice

    Directory of Open Access Journals (Sweden)

    Hongryul Ahn

    2017-06-01

    Full Text Available This study was designed to investigate at the molecular level how a transgenic version of rice “Nipponbare” obtained a drought-resistant phenotype. Using multi-omics sequencing data, we compared wild-type rice (WT and a transgenic version (erf71 that had obtained a drought-resistant phenotype by overexpressing OsERF71, a member of the AP2/ERF transcription factor (TF family. A comprehensive bioinformatics analysis pipeline, including TF networks and a cascade tree, was developed for the analysis of multi-omics data. The results of the analysis showed that the presence of OsERF71 at the source of the network controlled global gene expression levels in a specific manner to make erf71 survive longer than WT. Our analysis of the time-series transcriptome data suggests that erf71 diverted more energy to survival-critical mechanisms related to translation, oxidative response, and DNA replication, while further suppressing energy-consuming mechanisms, such as photosynthesis. To support this hypothesis further, we measured the net photosynthesis level under physiological conditions, which confirmed the further suppression of photosynthesis in erf71. In summary, our work presents a comprehensive snapshot of transcriptional modification in transgenic rice and shows how this induced the plants to acquire a drought-resistant phenotype.

  18. Physiological and metabolic responses as function of the mechanical load in resistance exercise.

    Science.gov (United States)

    Buitrago, Sebastian; Wirtz, Nicolas; Flenker, Ulrich; Kleinöder, Heinz

    2014-03-01

    The present study aimed to investigate the relationship between the mechanical load during resistance exercise and the elicited physiological responses. Ten resistance-trained healthy male subjects performed 1 set of resistance exercise each at 55%, 70%, and 85% of 1 repetition maximum for as many repetitions as possible and in 4 training modes: 4-1-4-1 (4 s concentric, 1 s isometric, 4 s eccentric, and 1 s isometric successive actions), 2-1-2-1, 1-1-1-1, and explosive (maximum velocity concentric). Mean concentric power and total concentric work were determined. Oxygen uptake (V̇O2) was measured during exercise and for 30 min post exercise. Total volume of consumed oxygen (O2 consumed) and excess post-exercise oxygen consumption (EPOC) were calculated. Maximum blood lactate concentration (LAmax) was also determined. V̇O2 exhibited a linear dependency on mean concentric power. Mean concentric power did not have a detectable effect on EPOC and LAmax. An augmentation of total concentric work resulted in significant linear increase of O2 consumed and EPOC. Total concentric work caused a significant increase in LAmax. In general, a higher mechanical load induced a larger physiological response. An increase in mean concentric power elicited higher aerobic energy turnover rates. However, a higher extent of total concentric work augments total energy cost covered by oxidative and (or) glycolytic pathways.

  19. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.

    Science.gov (United States)

    Nicolaides, Nicolas; Lamprokostopoulou, Agaristi; Sertedaki, Amalia; Charmandari, Evangelia

    2016-01-01

    Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

  20. Role of resveratrol in the management of insulin resistance and related conditions: Mechanism of action.

    Science.gov (United States)

    Abbasi Oshaghi, Ebrahim; Goodarzi, Mohammad Taghi; Higgins, Victoria; Adeli, Khosrow

    2017-06-01

    Resveratrol (RES), a well-known antioxidant, is present in numerous plant species and, as a result, is easily obtained through dietary intake of plant-based foods and beverages. Several studies suggest that RES has anti-carcinogenic, anti-microbial, and anti-viral effects. It may also have beneficial metabolic properties that result in mitigation of insulin resistance (IR) and related metabolic abnormalities, including dyslipidemia, hyperglycemia, and hyperinsulinemia through regulation of gene expression or the activity of rate-limiting enzymes. A large body of evidence supports the beneficial effects of RES in the management and treatment of IR, type 2 diabetes, and related complications through a multitude of mechanisms. This review article focuses on the mechanisms of action of RES, the mechanisms leading to improved insulin sensitivity, and its clinical role in the management and treatment of type 2 diabetes.

  1. Colistin in Pig Production: Chemistry, Mechanism of Antibacterial Action, Microbial Resistance Emergence, and One Health Perspectives

    Science.gov (United States)

    Rhouma, Mohamed; Beaudry, Francis; Thériault, William; Letellier, Ann

    2016-01-01

    , veterinarians, and other scientific health and environmental professionals. This review is an update on the chemistry of colistin, its applications and antibacterial mechanism of action, and on Enterobacteriaceae resistance to colistin in pigs. We also detail and discuss the One Health approach and propose guidelines for colistin resistance management. PMID:27891118

  2. Colistin in pig production: Chemistry, Mechanism of antibacterial action, Microbial resistance emergence, and One Health Perspectives

    Directory of Open Access Journals (Sweden)

    Mohamed Rhouma

    2016-11-01

    cooperation between physicians, veterinarians, and other scientific health and environmental professionals. This review is an update on the chemistry of colistin, its applications and antibacterial mechanism of action, and on Enterobacteriaceae resistance to colistin in pigs. We also detail and discuss the One Health approach and propose guidelines for colistin resistance management.

  3. Pseudomonas aeruginosa carbapenem resistance mechanisms in Spain: impact on the activity of imipenem, meropenem and doripenem.

    Science.gov (United States)

    Riera, Elena; Cabot, Gabriel; Mulet, Xavier; García-Castillo, María; del Campo, Rosa; Juan, Carlos; Cantón, Rafael; Oliver, Antonio

    2011-09-01

    To investigate the mechanisms of carbapenem resistance in the 175 Pseudomonas aeruginosa isolates (39%; 175/448) showing non-susceptibility (European Committee on Antimicrobial Susceptibility Testing breakpoints) to imipenem (35%), meropenem (33%) and/or doripenem (33%) recovered in 2008-09 from 16 Spanish hospitals during the Comparative Activity of Carbapenem Testing (COMPACT) surveillance study. MICs (Etest), clonal relatedness (PFGE) and metallo-β-lactamase (MBL) production (Etest-MBL, PCR and sequencing) were determined. Mutation-driven resistance was studied in 60 non-MBL producers according to the doripenem MICs (15 isolates from each of four MIC groups: ≤ 1, 2-4, 8-16 and ≥ 32 mg/L). The expression of ampC, mexB, mexY, mexD and mexF was determined by real-time reverse transcription-PCR and the presence of mutations in oprD by PCR and sequencing. Isogenic mutants expressing combinations of mutation-driven carbapenem resistance were constructed. Twelve (6.9%) isolates were MBL (VIM-20, VIM-2 or VIM-13) producers and all showed high-level resistance (MIC 32 mg/L) to all three carbapenems. Regarding mutation-driven resistance, all but 1 of the 60 isolates were non-susceptible (MIC >32 mg/L) to imipenem, linked to oprD inactivation. In addition, 50% of the isolates overexpressed ampC, 33% mexY, 32% mexB and 15% mexF, while none overexpressed mexD. Increasing prevalence of ampC overexpression correlated with increasing doripenem MICs (≤ 1, 13%; 2-4, 53%; 8-16, 60%; and ≥ 32, 73%) while overexpression of efflux pumps correlated only with moderate resistance. Doripenem showed slightly higher activity than meropenem against isolates overexpressing ampC, especially mexB or mexY. The analysis of a collection of isogenic laboratory mutants supported this finding. Although the prevalence of MBL producers is increasing, mutation-driven resistance is still more frequent in Spain. Imipenem resistance was driven by OprD inactivation, while additional AmpC and

  4. Detection of knockdown resistance (kdr mutations in Anopheles gambiae: a comparison of two new high-throughput assays with existing methods

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    Ball Amanda

    2007-08-01

    Full Text Available Abstract Background Knockdown resistance (kdr is a well-characterized mechanism of resistance to pyrethroid insecticides in many insect species and is caused by point mutations of the pyrethroid target site the para-type sodium channel. The presence of kdr mutations in Anopheles gambiae, the most important malaria vector in Africa, has been monitored using a variety of molecular techniques. However, there are few reports comparing the performance of these different assays. In this study, two new high-throughput assays were developed and compared with four established techniques. Methods Fluorescence-based assays based on 1 TaqMan probes and 2 high resolution melt (HRM analysis were developed to detect kdr alleles in An. gambiae. Four previously reported techniques for kdr detection, Allele Specific Polymerase Chain Reaction (AS-PCR, Heated Oligonucleotide Ligation Assay (HOLA, Sequence Specific Oligonucleotide Probe – Enzyme-Linked ImmunoSorbent Assay (SSOP-ELISA and PCR-Dot Blot were also optimized. The sensitivity and specificity of all six assays was then compared in a blind genotyping trial of 96 single insect samples that included a variety of kdr genotypes and African Anopheline species. The relative merits of each assay was assessed based on the performance in the genotyping trial, the length/difficulty of each protocol, cost (both capital outlay and consumable cost, and safety (requirement for hazardous chemicals. Results The real-time TaqMan assay was both the most sensitive (with the lowest number of failed reactions and the most specific (with the lowest number of incorrect scores. Adapting the TaqMan assay to use a PCR machine and endpoint measurement with a fluorimeter showed a slight reduction in sensitivity and specificity. HRM initially gave promising results but was more sensitive to both DNA quality and quantity and consequently showed a higher rate of failure and incorrect scores. The sensitivity and specificity of AS

  5. Fracture resistance curves and toughening mechanisms in polymer based dental composites

    DEFF Research Database (Denmark)

    De Souza, J.A.; Goutianos, Stergios; Skovgaard, M.

    2011-01-01

    The fracture resistance (R-curve behaviour) of two commercial dental composites (Filtek Z350® and Concept Advanced®) were studied using Double Cantilever Beam sandwich specimens loaded with pure bending moments to obtain stable crack growth. The experiments were conducted in an environmental...... displayed distinctly different R-curve behaviours. The difference was related to different toughening mechanisms as the two composites had markedly different microstructures. Contrary to common experience, the composite with the finer microstructure (smaller particles), the Concept Advanced®, showed...... significantly higher fracture resistance than the composite with the coarser microstructure. The fracture properties were related to the flexural strength of the dental composites. The method, thus, can provide useful insight into how the microstructure enhances toughness, which is necessary for the future...

  6. Testing the permeability and corrosion resistance of micro-mechanically interlocked joints

    Science.gov (United States)

    Byskov-Nielsen, Jeppe; Holm, Allan H.; Højsholt, Rune; Sá, Pedro; Balling, Peter

    2011-09-01

    Micro-mechanical interlocking (MMI) can be applied to create new and interesting composite materials. We have employed laser structuring to achieve MMI between stainless steel and plastic with extremely high joint strength. However, the water permeability and corrosion resistance of the joint must be examined. For many industrially relevant applications it is important to keep water away from certain parts and to prevent the sample from corroding. A thorough study of the permeability of the interconnected samples at different temperatures and after employing different laser-structuring techniques is conducted. The permeability seems to be consistent with the Hagen-Poiseuille equation independent of the laser structuring technique and is orders of magnitudes larger than the diffusion rate through the plastic. Two different types of corrosion tests have been undertaken, and we show that care must be taken in order not to degrade the corrosion resistance of the sample to an unacceptable level.

  7. Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients

    DEFF Research Database (Denmark)

    Jalal, S; Ciofu, O; Høiby, Niels

    2000-01-01

    in parC or mexR. Six isolates had mutations in efflux pumps without gyrA mutations. The average number of mutations was higher in isolates from 1997 than in those from 1994. The results also suggested that efflux resistance mechanisms are more common in isolates from CF patients than in strains from...... urine and wounds from non-CF patients, in which mutations in gyrA and parC dominate (S. Jalal and B. Wretlind, Microb. Drug Resist. 4:257-261, 1998)....... with the same PFGE or ribotyping patterns in 1997 as in 1994, and ciprofloxacin had a two- to fourfold higher MIC for the isolates collected in 1997 than those from 1994. Genomic DNA was amplified for gyrA, parC, mexR, and nfxB by PCR and sequenced. Eleven isolates had mutations in gyrA, seven isolates had...

  8. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system.

    Science.gov (United States)

    Kibria, Golam; Hatakeyama, Hiroto; Harashima, Hideyoshi

    2014-01-01

    Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.

  9. Supramolecular Cationic Assemblies against Multidrug-Resistant Microorganisms: Activity and Mechanism of Action

    Directory of Open Access Journals (Sweden)

    Letícia Dias de Melo Carrasco

    2015-03-01

    Full Text Available The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium chloride (PDDA polymer as the outer NP layer shows a remarkable activity against these organisms. The mechanism of cell death involves bacterial membrane lysis as determined from the leakage of inner phosphorylated compounds and possibly disassembly of the NP with the appearance of multilayered fibers made of the NP components and the biopolymers withdrawn from the cell wall. The NPs display broad-spectrum activity against MDR microorganisms, including Gram-negative and Gram-positive bacteria and yeast.

  10. Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat.

    Science.gov (United States)

    Costa-Lourenço, Ana Paula Ramalho da; Barros Dos Santos, Késia Thaís; Moreira, Beatriz Meurer; Fracalanzza, Sergio Eduardo Longo; Bonelli, Raquel Regina

    Neisseria gonorrhoeae is the agent of gonorrhea, a sexually transmitted infection with an estimate from The World Health Organization of 78 million new cases in people aged 15-49 worldwide during 2012. If left untreated, complications may include pelvic inflammatory disease and infertility. Antimicrobial treatment is usually effective; however, resistance has emerged successively through various molecular mechanisms for all the regularly used therapeutic agents throughout decades. Detection of antimicrobial susceptibility is currently the most critical aspect for N. gonorrhoeae surveillance, however poorly structured health systems pose difficulties. In this review, we compiled data from worldwide reports regarding epidemiology and antimicrobial resistance in N. gonorrhoeae, and highlight the relevance of the implementation of surveillance networks to establish policies for gonorrhea treatment. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  11. Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat

    Directory of Open Access Journals (Sweden)

    Ana Paula Ramalho da Costa-Lourenço

    Full Text Available ABSTRACT Neisseria gonorrhoeae is the agent of gonorrhea, a sexually transmitted infection with an estimate from The World Health Organization of 78 million new cases in people aged 15-49 worldwide during 2012. If left untreated, complications may include pelvic inflammatory disease and infertility. Antimicrobial treatment is usually effective; however, resistance has emerged successively through various molecular mechanisms for all the regularly used therapeutic agents throughout decades. Detection of antimicrobial susceptibility is currently the most critical aspect for N. gonorrhoeae surveillance, however poorly structured health systems pose difficulties. In this review, we compiled data from worldwide reports regarding epidemiology and antimicrobial resistance in N. gonorrhoeae, and highlight the relevance of the implementation of surveillance networks to establish policies for gonorrhea treatment.

  12. Molecular epidemiology, antimicrobial susceptibilities and resistance mechanisms of Streptococcus pyogenes isolates resistant to erythromycin and tetracycline in Spain (1994–2006

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    Rubio-López Virginia

    2012-09-01

    Full Text Available Abstract Background Group A Streptococcus (GAS causes human diseases ranging in severity from uncomplicated pharyngitis to life-threatening necrotizing fasciitis and shows high rates of macrolide resistance in several countries. Our goal is to identify antimicrobial resistance in Spanish GAS isolates collected between 1994 and 2006 and to determine the molecular epidemiology (emm/T typing and PFGE and resistance mechanisms of those resistant to erythromycin and tetracycline. Results Two hundred ninety-five out of 898 isolates (32.8% were erythromycin resistant, with the predominance of emm4T4, emm75T25, and emm28T28, accounting the 67.1% of the 21 emm/T types. Spread of emm4T4, emm75T25 and emm28T28 resistant clones caused high rates of macrolide resistance. The distribution of the phenotypes was M (76.9%, cMLSB (20.3%, iMLSB (2.7% with the involvement of the erythromycin resistance genes mef(A (89.5%, msr(D (81.7%, erm(B (37.3% and erm(A (35.9%. Sixty-one isolates were tetracycline resistant, with the main representation of the emm77T28 among 20 emm/T types. To note, the combination of tet(M and tet(O tetracycline resistance genes were similar to tet(M alone reaching values close to 40%. Resistance to both antibiotics was detected in 19 isolates of 7 emm/T types, being emm11T11 and the cMLSB phenotype the most frequent ones. erm(B and tet(M were present in almost all the strains, while erm(A, mef(A, msr(D and tet(O appeared in less than half of them. Conclusions Spanish GAS were highly resistant to macrolides meanwhile showed minor resistance rate to tetracycline. A remarkable correlation between antimicrobial resistance and emm/T type was noticed. Clonal spread of emm4T4, emm75T25 and emm28T28 was the main responsable for macrolide resistance where as that emm77T28 clones were it to tetraclycline resistance. A wide variety of macrolide resistance genes were responsible for three macrolide resistance phenotypes.

  13. Mechanisms of therapeutic resistance in cancer (stem cells with emphasis on thyroid cancer cells.

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    Sabine eHombach-Klonisch

    2014-03-01

    Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.

  14. Insecticide Resistance Mechanisms in the Green Peach Aphid Myzus persicae (Hemiptera: Aphididae) II: Costs and Benefits

    Science.gov (United States)

    Silva, Andrea X.; Bacigalupe, Leonardo D.; Luna-Rudloff, Manuela; Figueroa, Christian C.

    2012-01-01

    Background Among herbivorous insects that have exploited agro-ecosystems, the peach-potato aphid, Myzus persicae, is recognized as one of the most important agricultural pests worldwide. Uses over 400 plant species and has evolved different insecticides resistance mechanisms. As M. persicae feeds upon a huge diversity of hosts, it has been exposed to a wide variety of plant allelochemicals, which probably have promoted a wide range of detoxification systems. Methodology/Principal Findings In this work we (i) evaluated whether insecticide resistance mutations (IRM) in M. persicae can give an advantage in terms of reproductive fitness when aphids face two hosts, pepper (Capsicum annuum) a suitable host and radish (Raphanus sativus) the unfavorable host and (ii) examined the transcriptional expression of six genes that are known to be up-regulated in response to insecticides. Our results show a significant interaction between host and IRM on the intrinsic rate of increase (rm). Susceptible genotypes (not carrying insensitivity mutations) had a higher rm on pepper, and the transcriptional levels of five genes increased on radish. The rm relationship was reversed on the unfavorable host; genotypes with multiple IRM exhibited higher rm, without altering the transcriptional levels of the studied genes. Genotypes with one IRM kept a similar rm on both hosts, but they increased the transcriptional levels of two genes. Conclusions/Significance Although we have studied only nine genotypes, overall our results are in agreement with the general idea that allelochemical detoxification systems could constitute a pre-adaptation for the development of insecticide resistance. Genotypes carrying IRM exhibited a higher rm than susceptible genotypes on radish, the more unfavorable host. Susceptible genotypes should be able to tolerate the defended host by up-regulating some metabolic genes that are also responding to insecticides. Hence, our results suggest that the trade-off among