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Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily  [PDF]
Sanath Kumar,Mun Mun Mukherjee,Manuel F. Varela
International Journal of Bacteriology , 2013, DOI: 10.1155/2013/204141
Abstract: Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS. 1. Introduction Drug and multidrug resistant bacterial pathogens that are causative agents of infectious disease constitute a serious public health concern. Bacterial multidrug efflux pump systems of the major facilitator superfamily (MFS) and resistance-nodulation-cell division (RND) superfamily represent common mechanisms for bacterial resistance to antimicrobial agents. As such these bacterial transporters make suitable targets for modulation in order to restore the clinical efficacy of relevant chemotherapeutic antibacterial agents. Here, we briefly review the drug transporter systems of the MFS (and to a lesser extent the RND superfamily) and discuss their modulation via regulation of expression and efflux pump transport inhibition. 2. Bacteria and Pathogenesis Bacteria are unicellular, microscopic living organisms that are rod shaped, ball shaped, or spiral shaped when observed under the microscope. Most bacteria are not harmful; rather, they aid in food preparation and digestion, compete with pathogens, provide vitamins to the body, are useful for basic and applied research purposes, and are important in biotechnology. However, less than one percent of the bacteria of different types are responsible for causing bacterial infections. Bacterial cells are capable of quickly reproducing and releasing chemicals and toxins; pathogenic bacteria can cause damage to cells and tissues in the body and cause clinical disease. Some of the common diseases and infections caused by pathogenic strains of bacteria include food poisoning caused by Escherichia coli and Salmonella [1–6], gastritis and ulcers caused by Helicobacter pylori [7], the sexually transmitted disease gonorrhea caused by Neisseria gonorrhoeae [8], meningitis caused by N. meningitides [9], skin infections like boils, cellulitis,
Roles of Major Facilitator Superfamily Transporters in Phosphate Response in Drosophila  [PDF]
Clemens Bergwitz, Matthew D. Rasmussen, Charles DeRobertis, Mark J. Wee, Sumi Sinha, Hway H. Chen, Joanne Huang, Norbert Perrimon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031730
Abstract: The major facilitator superfamily (MFS) transporter Pho84 and the type III transporter Pho89 are responsible for metabolic effects of inorganic phosphate in yeast. While the Pho89 ortholog Pit1 was also shown to be involved in phosphate-activated MAPK in mammalian cells, it is currently unknown, whether orthologs of Pho84 have a role in phosphate-sensing in metazoan species. We show here that the activation of MAPK by phosphate observed in mammals is conserved in Drosophila cells, and used this assay to characterize the roles of putative phosphate transporters. Surprisingly, while we found that RNAi-mediated knockdown of the fly Pho89 ortholog dPit had little effect on the activation of MAPK in Drosophila S2R+ cells by phosphate, two Pho84/SLC17A1–9 MFS orthologs (MFS10 and MFS13) specifically inhibited this response. Further, using a Xenopus oocyte assay, we show that MSF13 mediates uptake of [33P]-orthophosphate in a sodium-dependent fashion. Consistent with a role in phosphate physiology, MSF13 is expressed highest in the Drosophila crop, midgut, Malpighian tubule, and hindgut. Altogether, our findings provide the first evidence that Pho84 orthologs mediate cellular effects of phosphate in metazoan cells. Finally, while phosphate is essential for Drosophila larval development, loss of MFS13 activity is compatible with viability indicating redundancy at the levels of the transporters.
Integration of Evolutionary Features for the Identification of Functionally Important Residues in Major Facilitator Superfamily Transporters  [PDF]
Jouhyun Jeon,Jae-Seong Yang,Sanguk Kim
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000522
Abstract: The identification of functionally important residues is an important challenge for understanding the molecular mechanisms of proteins. Membrane protein transporters operate two-state allosteric conformational changes using functionally important cooperative residues that mediate long-range communication from the substrate binding site to the translocation pathway. In this study, we identified functionally important cooperative residues of membrane protein transporters by integrating sequence conservation and co-evolutionary information. A newly derived evolutionary feature, the co-evolutionary coupling number, was introduced to measure the connectivity of co-evolving residue pairs and was integrated with the sequence conservation score. We tested this method on three Major Facilitator Superfamily (MFS) transporters, LacY, GlpT, and EmrD. MFS transporters are an important family of membrane protein transporters, which utilize diverse substrates, catalyze different modes of transport using unique combinations of functional residues, and have enough characterized functional residues to validate the performance of our method. We found that the conserved cores of evolutionarily coupled residues are involved in specific substrate recognition and translocation of MFS transporters. Furthermore, a subset of the residues forms an interaction network connecting functional sites in the protein structure. We also confirmed that our method is effective on other membrane protein transporters. Our results provide insight into the location of functional residues important for the molecular mechanisms of membrane protein transporters.
Basic Residues R260 and K357 Affect the Conformational Dynamics of the Major Facilitator Superfamily Multidrug Transporter LmrP  [PDF]
Wei Wang, Hendrik W. van Veen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038715
Abstract: Secondary-active multidrug transporters can confer resistance on cells to pharmaceuticals by mediating their extrusion away from intracellular targets via substrate/H+(Na+) antiport. While the interactions of catalytic carboxylates in these transporters with coupling ions and substrates (drugs) have been studied in some detail, the functional importance of basic residues has received much less attention. The only two basic residues R260 and K357 in transmembrane helices in the Major Facilitator Superfamily transporter LmrP from Lactococcus lactis are present on the outer surface of the protein, where they are exposed to the phospholipid head group region of the outer leaflet (R260) and inner leaflet (K357) of the cytoplasmic membrane. Although our observations on the proton-motive force dependence and kinetics of substrate transport, and substrate-dependent proton transport demonstrate that K357A and R260A mutants are affected in ethidium-proton and benzalkonium-proton antiport compared to wildtype LmrP, our findings suggest that R260 and K357 are not directly involved in the binding of substrates or the translocation of protons. Secondary-active multidrug transporters are thought to operate by a mechanism in which binding sites for substrates are alternately exposed to each face of the membrane. Disulfide crosslinking experiments were performed with a double cysteine mutant of LmrP that reports the substrate-stimulated transition from the outward-facing state to the inward-facing state with high substrate-binding affinity. In the experiments, the R260A and K357A mutations were found to influence the dynamics of these major protein conformations in the transport cycle, potentially by removing the interactions of R260 and K357 with phospholipids and/or other residues in LmrP. The R260A and K357A mutations therefore modify the maximum rate at which the transport cycle can operate and, as the transitions between conformational states are differently affected by components of the proton-motive force, the mutations also influence the energetics of transport.
Major Facilitator Superfamily Domain-Containing Protein 2a (MFSD2A) Has Roles in Body Growth, Motor Function, and Lipid Metabolism  [PDF]
Justin H. Berger, Maureen J. Charron, David L. Silver
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050629
Abstract: The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα), where PPARα upregulates genes encoding the biochemical pathway for β-oxidation of fatty acids and ketogenesis. As part of an effort to identify and characterize nutritionally regulated genes that play physiological roles in the adaptation to fasting, we identified Major facilitator superfamily domain-containing protein 2a (Mfsd2a) as a fasting-induced gene regulated by both PPARα and glucagon signaling in the liver. MFSD2A is a cell-surface protein homologous to bacterial sodium-melibiose transporters. Hepatic expression and turnover of MFSD2A is acutely regulated by fasting/refeeding, but expression in the brain is constitutive. Relative to wildtype mice, gene-targeted Mfsd2a knockout mice are smaller, leaner, and have decreased serum, liver and brown adipose triglycerides. Mfsd2a knockout mice have normal liver lipid metabolism but increased whole body energy expenditure, likely due to increased β-oxidation in brown adipose tissue and significantly increased voluntary movement, but surprisingly exhibited a form of ataxia. Together, these results indicate that MFSD2A is a nutritionally regulated gene that plays myriad roles in body growth and development, motor function, and lipid metabolism. Moreover, these data suggest that the ligand(s) that are transported by MFSD2A play important roles in these physiological processes and await future identification.
BC4707 Is a Major Facilitator Superfamily Multidrug Resistance Transport Protein from Bacillus cereus Implicated in Fluoroquinolone Tolerance  [PDF]
Roger Simm, Aniko V?r?s, Jaakko V. Ekman, Marianne S?dring, Ingerid Nes, Jasmin K. Kroeger, Massoud Saidijam, Kim E. Bettaney, Peter J. F. Henderson, Mirja Salkinoja-Salonen, Anne-Brit Kolst?
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036720
Abstract: Transcriptional profiling highlighted a subset of genes encoding putative multidrug transporters in the pathogen Bacillus cereus that were up-regulated during stress produced by bile salts. One of these multidrug transporters (BC4707) was selected for investigation. Functional characterization of the BC4707 protein in Escherichia coli revealed a role in the energized efflux of xenobiotics. Phenotypic analyses after inactivation of the gene bc4707 in Bacillus cereus ATCC14579 suggested a more specific, but modest role in the efflux of norfloxacin. In addition to this, transcriptional analyses showed that BC4707 is also expressed during growth of B. cereus under non-stressful conditions where it may have a role in the normal physiology of the bacteria. Altogether, the results indicate that bc4707, which is part of the core genome of the B. cereus group of bacteria, encodes a multidrug resistance efflux protein that is likely involved in maintaining intracellular homeostasis during growth of the bacteria.
The BBN Manifesto  [PDF]
Terry P. Walker
Physics , 1996, DOI: 10.1016/S0375-9474(97)00299-6
Abstract: In this manifesto I review the status of standard BBN in light of recent observational data (e.g., QSO deuterium and Izotov etal. helium-4).
The OverRelational Manifesto  [PDF]
Evgeniy Grigoriev
Computer Science , 2006,
Abstract: The OverRelational Manifesto (below ORM) proposes a possible approach to creation of data storage systems of the next generation. ORM starts from the requirement that information in a relational database is represented by a set of relation values. Accordingly, it is assumed that the information about any entity of an enterprise must also be represented as a set of relation values (the ORM main requirement). A system of types is introduced, which allows one to fulfill the main requirement. The data are represented in the form of complex objects, and the state of any object is described as a set of relation values. Emphasize that the types describing the objects are encapsulated, inherited, and polymorphic. Then, it is shown that the data represented as a set of such objects may also be represented as a set of relational values defined on the set of scalar domains (dual data representation). In the general case, any class is associated with a set of relation variables (R-variables) each one containing some data about all objects of this class existing in the system. One of the key points is the fact that the usage of complex (from the user's viewpoint) refined names of R-variables and their attributes makes it possible to preserve the semantics of complex data structures represented in the form of a set of relation values. The most important part of the data storage system created on the approach proposed is an object-oriented translator operating over a relational DBMS. The expressiveness of such a system is comparable with that of OO programming languages.
Dmytri Kleiner, Manifesto telecomunista
Maria Chiara Pievatolo
Bollettino Telematico di Filosofia Politica , 2011,
Abstract: Liberamente scaricabile presso telekommunisten.net, The Telekommunist Manifesto è un tentativo di riformulare il Manifesto del partito comunista per l’età della rete. Chi lavora in rete – ha sostenuto Kevin Kelly – adotta modi di produzione sociali e paritari, al di là dello stato e del mercato, che sembrano approssimarsi al socialismo. Dmytri Kleiner, sviluppatore e [...]
SPECIAL REPORT: The Communist Manifesto - A Hnuder and Fifty Years After
Frank Pascual
Kasarinlan : Philippine Journal of Third World Studies , 2000,
Abstract: For more than 150 years, the Communist Manifesto of Karl Marx and Friedrich Engels has provided an analysis of the evolution of bourgeois society from the ruins of feudal society, an outline of the inherent contradictions of the capitalist system, and a prediction of the inevitable capitalist crisis leading to the system’s eventual defeat. The Manifesto has projected the triumph of socialism and the proletariat’s coming to power through a socialist revolution. Its analysis has been borne out by the recurring crisis of capitalism as well as the experience of the proletariat in its struggle for socialism in the intervening 150 years since it was written. It continues to be borne out by the most recent economic and political developments. Moreover, it continues to illumine the path of the proletariat in its struggle for socialism. The process described in the Manifesto is ongoing. Hence, the document is as applicable today as it was 150 years ago.

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