Of the transporters involved in fluconazole resistancein medically important fungi, CDR1 and CDR2 are the most studied. Despite their high degree of amino acid similarity, there are functional differences between the two. Mutants of CDR2 retain a wild-type level of resistance to fluconazole; however, in a double mutant (DCDR1/DCDR2) the strain is more susceptible to fluconazole than either single mutant . Other differences in function have been identified, suggesting that the two ABC transporters have separate, but overlapping, roles in the fungus . In addition, there is allelic variation of the genes. Comparison of the CDR2 alleles uncovered two point mutations in equal frequency of an allele in transmembrane helix 12 that were involved in substrate binding and function . Most strains were heterozygous for these CDR2 genes, and further phylogenetic analysis suggested that as many as 33 codon changes between the two alleles may be selectively advantageous . Differences in transmembrane domains are significant, as evidence builds that they are responsible for substrate specificity. Most ABC trans- porters have been demonstrated to have multiple substrates; thus, it is postulated that substrate binding does not occur in a specific active site, but rather in an active pocket able to accommodate a variety of structurally different compounds [74,75]. Several amino acids are conserved among these transmembrane helices of fluconazole PDR transporters, where the most conserved helices are 6 and 12.
When writing Nzikitanza, in spring 2012, I had just witnessed the launch of some Canadian military aircrafts from Trapani Airport, a civilian airport in Sicily: the aircrafts headed towards Libya, as part of the NATO Operation Unified Protector. In the same period, the project of constructing the MUOS, a military communications satellite system owned by the US Navy, near the town of Niscemi, was reaching its final stages. This in turn triggered the organized resistance of various groups of Sicilian citizens, who founded the NO MUOS committee (LA LOTA, 2012).
Abstract: Multidrug resistance of cancer cells and pathogenic microorganisms leading to the treatment failure of some forms of cancer or life-threatening bacterial or fungal infections is often caused by the overexpression of multidrug efflux pumps belonging to the ATP-binding cassette transporters superfamily. The multidrug resistance of fungal cells often involves the overexpression of efflux pumps belonging to the pleiotropic drug resistance (PDR) family of ABC transporters. Possibly the best-studied fungal PDR transporter is the multidrug resistance transporter Pdr5p of Saccharomyces cerevisiae. Some research groups have been searching for new inhibitors of these efflux pumps in order to alleviate resistance. Natural products are a great source for the discovery of new compounds with biological activity. Propolis is a complex resinous material collected by honeybees from exudates and buds of certain plant sources and this material is thought to serve as a defense substance for bee hives. Propolis is widely used in traditional medicine and is reported to have a broad spectrum of pharmacological properties. Literature reported some biological functionalities of propolis, such as antibacterial, antiviral, fungicidal, anti- inflammatory and anti-carcinogenic activities. The chemical composition of propolis is qualitatively and quantitatively variable. Components isolated from methanolic extract of red Brazilian propolis (Alagoas, Northeast of Brazil) are isoflavonoids (including pterocarpans, isoflavans, isoflavones), flavanones and polyprenylated benzophenones. In this work we demonstrated the effects of five different isolated compounds on the ATPase activity of Pdr5p. Out of all five substances tested, only BRP-1 was able to completely abolish the enzymatic activity while others worked as positive modulators of the enzyme activity. BRP-1also inhibited the efflux of Rhodamine 6G from yeast cells overexpressing Pdr5p. Taken together, these results demonstrate that Brazilian propolis could be a source of promising compounds that can alleviate the MDR phenomenon, particularly in some fungi, where it could be used as an adjuvant for the treatment with azoles.
6 recent studies have reported that these CA-MRSA strains have acquired additional resistance determinants [138, 200]. More recently, new MRSA clones that are not related to contemporary CA-MRSA or HA-MRSA clones have emerged among livestock, being designated livestock-associated MRSA (LA-MRSA) . Among these, a particular clone (ST398) was first detected in pig farmers and later found to be prevalent among pigs and in other food-producing animals like cattle and poultry . Reports of the occurrence of this LA-MRSA clone in livestock have arisen from several countries, including cases of animal-to-person transmission . This transmission was found to occur mainly in people in close contact with animals, like pig farmers and slaughterhouse workers, but these strains were found to be poor colonizers of humans and it was proposed that their carriage results from continued exposure rather than stable colonization . Furthermore, they appear not to be associated with a high infectious risk for humans . A recent study revealed a likely human ancestral origin for this clonal lineage as MSSA that experienced a human-to-livestock jump followed by host adaptation to livestock and acquisition of additional resistance determinants . Of particular interest is the identification of new resistance determinants in these LA-MRSA strains [98, 221]. These findings highlight the potential role of S. aureus as a zoonotic pathogen and of animals as reservoirs for new MRSA strains [72, 172]. These LA-MRSA strains may also act as a reservoir for the emergence and dissemination of new resistance genes. Similarly, reports on the occurrence of MRSA strains in a variety of food samples like meat products, milk, fish and other food products have been published, but information is still scarce to support the role of MRSA as a potential food-borne pathogen [5, 222].
It is widely known that the exposure of plants to certain stresses can induce a state of sensitization in the whole plant; characterized by faster and stronger acti- vation of cellular defenses upon invasion. This state is known as a priming of defense (Conrath, 2009; Goellner and Conrath, 2008; Jung et al., 2009; Pastor et al., 2013). Priming inducers can be divided into synthetic or natural compounds. Synthetic compounds are those that cannot be found or rarely occur in nature, such as Aciben- zolar-S-methyl (ASM, syn. benzothiadiazol BTH) and 2.6-dichloroisonicotinic acid (INA). On the other hand, the group of natural inducers includes substances which are synthetized by the plant in response to stress signals such as SA, JA or azelaic acid (Jung et al., 2009) and other natural compounds that are not derived or related to plant defensive pathways, such as hexanoic acid (Hx) (Aranega- Bou et al., 2014). These compounds have the advantage of being easily found in nature such as chitin from crus- taceous exoskeletons (Xing et al., 2015) or laminarin from algae (Aziz et al., 2003). Application of these resistancein- ducers, either synthetic or natural, can protect the plants against a broad spectrum of diseases caused either by fungi or bacteria, such as brown spot caused by Alternaria alternata Keissl or citrus canker caused by Xanthomonas citri (Hasse) (Conrath, 2009; Jakab et al., 2001; Llorens et al., 2013; Llorens et al., 2015), including a number of crop diseases that are difficult to control through conventional management disease strategies (Li et al., 2015). However, despite the positive results these compounds have shown in model plants and herbaceous crops, only a few of them have been tested in woody plants.
I can say this with firsthand experience not only in the realm of puppetry but in my work in UNIMA, where often we constantly try to push or to confirm agendas seen by the modern north countries perspec- tives, to the working of centuries old traditions of other communities, eg the preparations of the congress in Chengdu, or for that matter the creation of national centers and representatives in countries who do not work in the ways we understand or want them to... this is a bitter pill to swallow but we must come to terms with it, and in the bargain find a democratic bridge which helps to make our work progress, and in so at times giving up unfortunately what we see as best practices.
by the host such as enzymes and immunoglobulins (key proteins of the host acquired immune system) . This extraordinary level of precision is species and tissue specific, depending on the bacterial adhesin that is brought into play. The latter can be witnessed in several strains of enteropathogenic Escherichia coli, which express adhesins that only adhere to the intestinal epithelium of humans and pigs . Minding the fact that a sole bacterial pathogen may express a vast array of virulence-associated adherence mechanisms, and that VFs implicated in adhesion to the host may play other roles in pathogenicity as well, the part a specific adhesin plays in the infection process of the host can be strikingly difficult to ascertain . Regardless of the previous hindrance, two principal adhesin groups shall be approached as archetypes of typical host-pathogen adhesion mechanisms, the first being the type IV pili (T4P) multi-functional adhesins. Structurally speaking, type IV pili adhesins can be construed as polymeric molecular complexes, composed of thousands upon thousands of pilin protein subunits, which together compose utterly thin filaments, named pilus, that stand a few microns in length . Type IV pili have been credited with several virulence related traits, including surface migration, biofilm (groups of bacteria stuck together being usually attached to surfaces) production, adhesion, avoidance of host immunological responses, signaling between individual cells, DNA transformation and the attachment of bacteriophages . Concerning type IV pili adhesion properties to the host-cell epithelium, one can expose as an example that the expression of the type IV pili complex is required in the commencing stages of infection undertaken by the pathogenic species of Neisseria spp. (a wide genus of bacteria that thrive in the mucosal surfaces of several animals) in order for it to be capable of attachment to human epithelial cells . The pilus receptor has
Since the initial report by Sanglard et al. more than ten years ago , many studies have shown that the major mechanism of resistance to the widely used antifungal agent ﬂuconazole in clinical C. albicans isolates is the constitutive overexpression of efﬂux pumps, which actively transport this drug and other toxic substances out of the cell, thereby conferring multidrug resistance. It is well established that mutations in trans-regulatory factors are responsible for the upregulation of genes encoding efﬂux pumps in drug- resistant C. albicans isolates [24,32]; however, until recently the identity of these regulators has remained elusive. Two main factors, namely 1) the discovery of a cis-regulatory element in the promoters of CDR1 and CDR2 with features that are typical of binding sites of zinc cluster transcription factors, and 2) the observation that homozygosity at the mating type locus was linked with the development of azole resistancein certain clinical strains, led Coste et al. to exploit the available C. albicans genome sequence information to systematically search for candidate transcription factors that might regulate the expression of these efﬂux pumps. This strategy resulted in the identiﬁcation of the zinc cluster transcription factor TAC1, which is located near the mating type locus, as the major regulator of CDR1 and CDR2 . In contrast, no obvious criteria for a similar in silico search for a regulator of MDR1, the other efﬂux pump that mediates drug resistancein many clinical C. albicans isolates, were evident. Promoter deletion analyses performed by several research groups have identiﬁed three different activating regions in the MDR1 promoter, two of which contain binding sites for the transcription factors Cap1p and Mcm1p [19,20,25,26]. However, each of these regions could be individually deleted from the full-length MDR1 promoter without abrogating its constitutive activation in MDR1 overexpressing C. albicans isolates, which suggested that a transcription factor other than Cap1p or Mcm1p causes the upregulation of MDR1 in drug-resistant strains. Assuming that a common mechanism might be responsible for the constitutive MDR1 upregulation in such strains, we compared the alterations in gene expression that occurred in three different MDR1 over- expressing, drug-resistant C. albicans isolates. This approach led to the identiﬁcation of MRR1, a zinc cluster transcription factor that was moderately upregulated in all three resistant isolates as compared with matched, drug-susceptible isolates, suggesting that this transcription factor might contribute to MDR1 overexpression and/or drug resistance. A role of MRR1 in ﬂuconazole resistance would not have been easily inferred from genetic analysis of commonly used C. albicans laboratory
The pieces here discussed, like many others, have a hierarchical structure. This means that they are composed of bigger related segments that are also decomposable in smaller segments. The results of the experiments that we have already done lead us to conclude that the system has a strong tendency to first identify the longest segments existing in one piece, i.e., to do the higher-level segmentation. The question of how to continue a first segmentation, in order to identify smaller segments, still is an open problem in our work. One obvious possibility consists in the application of the same process of segmentation to the segments already identified. However, this approach can, in some situations, be fruitless because the existing segments may not be composed of related sub-segments. As an example, suppose that one piece has the structure A + B + A and that A = a + b and B = c + b. If we try to analyse the two segments independently we will be unable to identify segments a, b and c, because a is not related to b, which is not related to c. A human analyst would have no problems with this approach because he/she can always take a look to other segments while working on a specific segment, in order to identify common sub-segments. Based on this idea, we sketched an approach that consists in the application of the segmentation process again to the entire piece, but now imposing the following restrictions: only segments that fall within the previously identified segments can be generated; individuals that use more notes than the ones used in the previous segmentation (with a higher second term in the fitness function), or that use a equal or fewer number of segments, are strongly penalized. We applied this approach to the piece «Be m’anperdout…» using, as previously identified segments, the ones corresponding to ADF3 ([0, 41]) and ADF6 ([84, 141]) in Figure 5. Also, individuals with less than 4 segments and using more than 100 notes from the original music were strongly penalized. In Figure 7 we show two of the best individuals that resulted from these experiments. The first one has an error of 4 notes and uses 66 notes from the original music, which corresponds to a fitness value of 86. The second one has no error and uses 78 notes from the original music, thus having a fitness value of 78. Although both individuals are similar to the segmentation done by Ruwet, the first one is closer to it. This is one of the cases where the best individual, from the point of view of a human analyst, has a worst fitness value. In this case, this happens due to the errors
En este sentido, teniendo especialmente en cuenta que el ente ha sido dota- do de potestades que corresponden en primer término a las jurisdicciones locales, señalamos que, en el caso de la Ciudad, los arts. 8° y 26 a 31 de su Constitución establecen derechos de los habitantes y, como contracara de ello, competencias am- bientales en cabeza de las autoridades porteñas que, como tales, son de cumpli- miento obligatorio, improrrogable e irrenunciable. Incluso, indicamos que el mismo texto constitucional reiere a su carácter indelegable. Por esta razón, consideramos que resulta trascendental que la Ciudad participe en igualdad de condiciones en la elaboración de las decisiones de la ACUMAR, pues sólo de esta manera la adhesión a la Ley 26.168 resultaría compatible con su Constitución.
There have recently been significant increases in the prevalence of systemic invasive fungal infections. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. Combination drug thera- pies have become one of the most widely used and effective strategies to alleviate this problem. Amiodarone (AMD) is classically used for the treatment of atrial fibrillation and is the drug of choice for patients with arrhythmia. Recent studies have shown broad antifungal activity of the drug when administered in combination with fluconazole (FLC). In the present study, we in- duced resistance to fluconazole in six strains of Candida tropicalis and evaluated potential synergism between fluconazole and amiodarone. The evaluation of drug interaction was determined by calculating the fractional inhibitory concentration and by performing flow cytometry. We conclude that amiodarone, when administered in combination with fluconazole, exhibits activ- ity against strains of C. tropicalis that are resistant to fluconazole, which most likely occurs via changes in the integrity of the yeast cell membrane and the generation of oxidative stress, mitochondrial dysfunction, and DNA damage that could lead to cell death by apoptosis.
Esta comprensión de la relación entre la investigación formativa y la investigación en sentido estricto llevó a varias instituciones que no tenían conformados grupos de investigación a iniciar sus sistemas de investigación con grupos de semilleros, apoyados institucionalmente que en el mediano plazo se convirtieran en grupos y dieran los frutos de la investigación en sentido estricto. Desde aquí es posible que exista el semillero antes que el grupo de investigación, siendo el primero el origen del segundo; así como también se observa en propuestas de semillero, donde el semillero es una parte fundamental del grupo, espacio de formación que va más allá de los proyectos, donde cada estudiante está vinculado a procesos de investigación e incluso él mismo puede proponerlos; pero la formación no se agota en los proyectos, incluye las actitudes y el desarrollo de habilidades. Bajo esta premisa tienden a ser semilleros con ciclos de formación más amplios y que pocas veces se asemejan a clases o cursos pues estos son de corta duración y alta rotación de estudiantes lo cual no permite la formación del sujeto investigador como se espera.
Often, new service versions are replications of a previous version that have additional or modified elements. New versions are named differently (by using some naming convention), and their description is stored in the registry as a new entry. Juric et al.  propose extensions to WSDL and UDDI for service versioning. The approach addresses run-time and development-time versioning. Efficiency at the code level is addressed by allowing multiple versions of a service to refer to the same codebase. Additionally, notifications about new and deprecated versions are communicated to consumers. Traceability support is provided to track changes. This academic research promotes the reuse of services and keeps the complexity of a service registry manageable.
Ernst M. Kussul received his M.S. in mechanics from Leningrad Polytechnic Institute, Russia. He received the Ph.D. in mathematical logic and programming from the Institute of Cybernetics of the Ukrainian Academy of Sciences. In 1967 he joined the Institute of Cybernetics of Ukrainian Academy of Sciences as a junior researcher, from 1976 as a senior researcher, and from 1982 as a leading researcher. In 1982 he received the D. Sci. degree in artificial neural networks from the Institute of Cybernetics of the Ukrainian Academy of Sciences. From 1988 to 1998 he was head of the department of neural networks in the International Research and Training Center of UNESCO/IIP of Information Technologies and Systems. Since 1998 he is Researcher level “C” and the head of the Laboratory of Micromechanics and Mechatronics in UNAM, Mexico. He has published over 140 scientific papers, authored and coauthored 2 books; he is author of 11 patents. He participated in international projects INTAS, ISF. He is laureate of the Prize of the Government of Ukraine in Science and Techniques in 1997. He is a member of the Mexican Academy of Technology. He is a member of IEEE. His present research interests are micromechanics, mechatronics, neural networks, and pattern recognition.
In the present study it has been observed that in absence of acquired resistant determinants (carbapenemases), overexpression of MexAB-OprM efflux pumps was responsible for merope- nem resistancein clinical isolates of P. aeruginosa in this geographical region of the world. This study also establishes the fact that combination of factors might be responsible to induce over- expression of MexAB-OprM and despite expression of different components of MexAB-OprM in a heterlogous host E. coli, the components failed to enhance meropenem resistancein both host and in non host. In spite of being a well characterized mechanism of resistance, MexA- B-OprM mediated mechanism is often neglected and diagnostic laboratories are yet to incor- porate a phenotypic tool for their detection in routine practice. Thus, equal importance should be given for diagnosis of intrinsic resistance mechanism so as to minimize treatment failure. As meropenem could not enhance mexA transcriptions significantly, there might be a possibility that the increase in expression of efflux pump genes does not mediated by single antibiotic but rather by a combination of antipseudomonal drugs which are used during treatments. The study emphasizes early detection of this intrinsic resistance mechanism improving the selection of proper therapeutic options.
La primera línea, subraya la importancia de la participación ciudadana con los diferentes grupos de interés para la apropiación del conocimiento. Esta relación es el primer paso para que se pueda dar la transferencia y el intercambio de conocimiento señalado en el tercer aspecto. La segunda línea de acción es la comunicación, la cual es considerada como un elemento de mediación entre la ciencia, la tecnología y la sociedad, apunta a la articulación de actores, siendo el ideal el cambiar el imaginario social que se tiene sobre la ciencia y la tecnología, como elementos ajenos a la cotidianidad para ser visto como “una actividad humana en estrecha relación con nuestro medio, con nuestros problemas y nuestra capacidad de resolverlos” (p.31). Este elemento fue identificado desde la declaración de Caracas de 1960. Finalmente gestión para la apropiación del conocimiento es la cuarta línea planteada, la cual busca.
INCLUSION CRITERIA: Senile/ pre senile cataract, including mature and immature cataract, well dilated pupil. Informed consent obtained in every case, with age group ranging from 40 years to70 years. Preoperative visual acuity assessed in all 140 patients, nasolacrimal duct patency noted, intraocular pressure estimated with Goldmann Applanation Tonometer. Blood pressure recorded, urine sugar strip test was done. Fundus examination was done with indirect ophthalmoscope by using 20D lens and 90D lenses wherever possible. Using Bausch Lomb Keratometer and non- immersion contact type A-scan Biometry IOL power was calculated by using SRK II formula.
reported the expression of endothelial NOS (eNOS) and inducible NOS (iNOS), but not neuronal NOS, in rat mesangial cells . The eNOS and iNOS expressed in mesangial cells may be responsible for NO productions induced by G protein coupled receptor agonists and inflammatory stimulators, respectively [29,30]. The expression of iNOS in mesangial cells in response to inflammatory stimulators has been shown to be inhibited by conjugated-LA . All three isoforms of NOS were detected in the kidney homogenates and the expression of NOS proteins was downregulated in aged ZSF1 fatty rats, which was associated with enhanced renal peroxynitrite and other structural and functional abnormalities . The importance of NOS in the pathogenesis of diabetic nephropathy has clearly evidenced by studies from animal models and diabetic patients. However, in HM cells the LA- induced peroxynitrite generation was not inhibited by N G -nitro-L- arginine (0.1–1 mM) or L-N G -monomethyl arginine (0.5 mM) (data not shown), indicating that the LA responsive NO, a required substrate for peroxynitrite generation, was produced in an L-arginine independent manner. Mitochondrial complex III has been shown to possess nitrite reductase activity and is responsible for NO generation in the mitochondria by an L- arginine independent manner [32–34]. Thus the NO involved inLA responsive peroxynitrite generation was more likely to be produced from the nitrite conversion by mitochondrial complex III in HM cells (as depicted in Figure 8). The inhibition of LA responsive peroxynitrite generation by the complex I blocker (rotenone) or complex III blockers (antimycin A or myxothiazol) suggested that complexes I and III may be responsible for the generation of either superoxide or NO, which are the two primary substrates required to form peroxynitrite.
This work stems from a the series of experiments made by Klippel and Montello (2004, 2007) that attempted to understand how people encode turn directions. Klippel and Montello asked people to classify 122 types of turns, ranging from the sharp left to the sharp right. The items appeared in a disorgani- zed way on a screen and people had to move them to the right in order to form as many groups as they wanted. The results showed that people encode turn direc- tions in a complex way, for there is no symmetry between the upper and lower sides of the horizontal axis, nor between the right and left side of the vertical axis. With the objective of expanding Klippel and Montello´s indings, this pa- per presents and investigation on how people encode linear misalignments. To date, this is a rather unexplored area, although recent research has shown that spa- tial discontinuations heavily affect how space is explored by people (HILLIER, 1996; CONROY-DALTON, 2003; WERNER; SCHINDLER, 2004; MORA, 2007; CARLSON et al., 2010). Hillier, for example, has suggested that minor spatial discontinuations of space that might dificult for people to infer global properties of spatial systems might cause the emergence of “urban ghettos”, whe- re no person apart from residents passes through. Conroy-Dalton, showed that by slightly moving the pieces of a virtual world (without changing any other feature of it), the entire structure of exploration became less structured and unpredictable (CONROY-DALTON, 2003). Werner and Schindler (2004) and Mora (2007), showed that slight spatial misalignments affect, respectively, wayinding perfor- mance in buildings. Finally, a recent paper by Carlson and colleagues (2010) suggest that wayinding behavior depend, to a great extent, in the existence of continuous visual access to incoming spaces.