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1
Sekhwal, Manoj Kumar, Vinay Sharma, and Renu Sarin. "Identification of MFS proteins in sorghum using semantic similarity." Theory in Biosciences 132, no. 2 (January 9, 2013): 105–13. http://dx.doi.org/10.1007/s12064-012-0174-z.
2
Xiao, Qingjie, Mengxue Xu, Weiwei Wang, Tingting Wu, Weizhe Zhang, Wenming Qin, and Bo Sun. "Utilization of AlphaFold2 to Predict MFS Protein Conformations after Selective Mutation." International Journal of Molecular Sciences 23, no. 13 (June 29, 2022): 7235. http://dx.doi.org/10.3390/ijms23137235.
Анотація:
The major facilitator superfamily (MFS) is the largest secondary transporter family and is responsible for transporting a broad range of substrates across the biomembrane. These proteins are involved in a series of conformational changes during substrate transport. To decipher the transport mechanism, it is necessary to obtain structures of these different conformations. At present, great progress has been made in predicting protein structure based on coevolutionary information. In this study, AlphaFold2 was used to predict different conformational structures for 69 MFS transporters of E. coli after the selective mutation of residues at the interface between the N- and C-terminal domains. The predicted structures for these mutants had small RMSD values when compared to structures obtained using X-ray crystallography, which indicates that AlphaFold2 predicts the structure of MSF transporters with high accuracy. In addition, different conformations of other transporter family proteins have been successfully predicted based on mutation methods. This study provides a structural basis to study the transporting mechanism of the MFS transporters and a method to probe dynamic conformation changes of transporter family proteins when performing their function.
3
Ditty, Jayna L., and Caroline S. Harwood. "Conserved Cytoplasmic Loops Are Important for both the Transport and Chemotaxis Functions of PcaK, a Protein fromPseudomonas putida with 12 Membrane-Spanning Regions." Journal of Bacteriology 181, no. 16 (August 15, 1999): 5068–74. http://dx.doi.org/10.1128/jb.181.16.5068-5074.1999.
Анотація:
ABSTRACT Chemotaxis to the aromatic acid 4-hydroxybenzoate (4-HBA) byPseudomonas putida is mediated by PcaK, a membrane-bound protein that also functions as a 4-HBA transporter. PcaK belongs to the major facilitator superfamily (MFS) of transport proteins, none of which have so far been implicated in chemotaxis. Work with two well-studied MFS transporters, LacY (the lactose permease) and TetA (a tetracycline efflux protein), has revealed two stretches of amino acids located between the second and third (2-3 loop) and the eighth and ninth (8-9 loop) transmembrane regions that are required for substrate transport. These sequences are conserved among most MFS transporters, including PcaK. To determine if PcaK has functional requirements similar to those of other MFS transport proteins and to analyze the relationship between the transport and chemotaxis functions of PcaK, we generated strains with mutations in amino acid residues located in the 2-3 and 8-9 loops of PcaK. The mutant proteins were analyzed in 4-HBA transport and chemotaxis assays. Cells expressing mutant PcaK proteins had a range of phenotypes. Some transported at wild-type levels, while others were partially or completely defective in 4-HBA transport. An aspartate residue in the 8-9 loop that has no counterpart in LacY and TetA, but is conserved among members of the aromatic acid/H+ symporter family of the MFS, was found to be critical for 4-HBA transport. These results indicate that conserved amino acids in the 2-3 and 8-9 loops of PcaK are required for 4-HBA transport. Amino acid changes that decreased 4-HBA transport also caused a decrease in 4-HBA chemotaxis, but the effect on chemotaxis was sometimes slightly more severe. The requirement of PcaK for both 4-HBA transport and chemotaxis demonstrates that P. putida has a chemoreceptor that differs from the classical chemoreceptors described for Escherichia coli and Salmonella typhimurium.
4
Severson, Aaron F., and Bruce Bowerman. "Myosin and the PAR proteins polarize microfilament-dependent forces that shape and position mitotic spindles in Caenorhabditis elegans." Journal of Cell Biology 161, no. 1 (April 14, 2003): 21–26. http://dx.doi.org/10.1083/jcb.200210171.
Анотація:
In Caenorhabditis elegans, the partitioning proteins (PARs), microfilaments (MFs), dynein, dynactin, and a nonmuscle myosin II all localize to the cortex of early embryonic cells. Both the PARs and the actomyosin cytoskeleton are required to polarize the anterior-posterior (a-p) body axis in one-cell zygotes, but it remains unknown how MFs influence embryonic polarity. Here we show that MFs are required for the cortical localization of PAR-2 and PAR-3. Furthermore, we show that PAR polarity regulates MF-dependent cortical forces applied to astral microtubules (MTs). These forces, which appear to be mediated by dynein and dynactin, produce changes in the shape and orientation of mitotic spindles. Unlike MFs, dynein, and dynactin, myosin II is not required for the production of these forces. Instead, myosin influences embryonic polarity by limiting PAR-3 to the anterior cortex. This in turn produces asymmetry in the forces applied to MTs at each pole and allows PAR-2 to accumulate in the posterior cortex of a one-cell zygote and maintain asymmetry.
5
Rizal, S., Masrukhin, H. A. Nugroho, and S. Saputra. "Detection of major facilitator superfamily (MFS) transporter in Enterobacteriaceae isolated from chicken." IOP Conference Series: Earth and Environmental Science 1107, no. 1 (December 1, 2022): 012050. http://dx.doi.org/10.1088/1755-1315/1107/1/012050.
Анотація:
Abstract A major facilitator superfamily (MFS) transporter is an active secondary transport system that uses a chemiosmotic ion gradient to transport small molecules. MFS is part of the efflux pump group of proteins and is responsible for releasing toxic compounds and contributing to the antimicrobial resistance mechanisms. In this study, we aimed to detect MFS genes from a collection of Enterobacteriaceae (n=60) isolated from cloacal swabs of chickens. After DNA extraction and amplification, only four isolates (6.7%) were regarded positive for MFS genes and subjected to Sanger dideoxy sequencing. A BlastX search in GenBank® showed that four positive samples with approximate length 300 bp were identified as MSF transporter from Klebsiella pneumoniae with a similarity of 97-98%. This finding warrants further study to confirm both phenotypic and genotypic resistance profiles that correlate with bacterial multidrug efflux pump mechanism.
6
Varela, Manuel F., Anely Ortiz-Alegria, Manjusha Lekshmi, Jerusha Stephen, and Sanath Kumar. "Functional Roles of the Conserved Amino Acid Sequence Motif C, the Antiporter Motif, in Membrane Transporters of the Major Facilitator Superfamily." Biology 12, no. 10 (October 16, 2023): 1336. http://dx.doi.org/10.3390/biology12101336.
Анотація:
The biological membrane surrounding all living cells forms a hydrophobic barrier to the passage of biologically important molecules. Integral membrane proteins called transporters circumvent the cellular barrier and transport molecules across the cell membrane. These molecular transporters enable the uptake and exit of molecules for cell growth and homeostasis. One important collection of related transporters is the major facilitator superfamily (MFS). This large group of proteins harbors passive and secondary active transporters. The transporters of the MFS consist of uniporters, symporters, and antiporters, which share similarities in structures, predicted mechanism of transport, and highly conserved amino acid sequence motifs. In particular, the antiporter motif, called motif C, is found primarily in antiporters of the MFS. The antiporter motif’s molecular elements mediate conformational changes and other molecular physiological roles during substrate transport across the membrane. This review article traces the history of the antiporter motif. It summarizes the physiological evidence reported that supports these biological roles.
7
Zhang, Jialan, Yingbao Liu, Li Li, and Mengxiang Gao. "iTRAQ-Based Quantitative Proteomic Analysis Reveals Changes in Metabolite Biosynthesis in Monascus purpureus in Response to a Low-Frequency Magnetic Field." Toxins 10, no. 11 (October 29, 2018): 440. http://dx.doi.org/10.3390/toxins10110440.
Анотація:
Background: Low-frequency magnetic fields (LF-MFs) dampen the citrinin output by Monascus purpureus in fermentations. The influence of LF-MFs on biosynthesis by M. purpureus was evaluated at the protein level. Methods: Cultures were treated with a 1.6-mT MF from day 0 to day 2 of incubation, and secondary metabolite production was evaluated on the day 12 of incubation. All proteins were extracted from M. purpureus mycelia and subjected to isobaric tags for relative and absolute quantification (iTRAQ) labeling and subsequent liquid chromatography/mass spectrometry (LC-MS/MS) analysis on day 6 of fermentation. Results: There was no difference in biomass between the treated samples and the control. Citrinin production was 46.7% lower, and the yields of monacolin K and yellow, orange, and red pigment were 29.3%, 31.3%, 41.7%, and 40.3% higher, respectively, in the exposed samples compared to the control. Protein expression in M. purpureus under LF-MF treatment was quantified using iTRAQ technology. Of 2031 detected proteins, 205 were differentially expressed. The differentially-expressed proteins were subjected to Gene Ontology (GO) functional annotation and statistical analysis, which revealed that they mainly refer to biological metabolism, translation, antioxidant, transport and defense pathways. Among all the tagged proteins, emphasis was placed on the analysis of those involved in the synthesis of citrinin, pigment and monacolin K was emphasized. Conclusions: LF-MFs affected Monascus secondary metabolism at the protein level, and aggregate data for all the protein profiles in LF-MF-treated Monascus was obtained.
8
Vardy, Eyal, Sonia Steiner-Mordoch, and Shimon Schuldiner. "Characterization of Bacterial Drug Antiporters Homologous to Mammalian Neurotransmitter Transporters." Journal of Bacteriology 187, no. 21 (November 1, 2005): 7518–25. http://dx.doi.org/10.1128/jb.187.21.7518-7525.2005.
Анотація:
ABSTRACT Multidrug transporters are ubiquitous proteins, and, based on amino acid sequence similarities, they have been classified into several families. Here we characterize a cluster of archaeal and bacterial proteins from the major facilitator superfamily (MFS). One member of this family, the vesicular monoamine transporter (VMAT) was previously shown to remove both neurotransmitters and toxic compounds from the cytoplasm, thereby conferring resistance to their effects. A BLAST search of the available microbial genomes against the VMAT sequence yielded sequences of novel putative multidrug transporters. The new sequences along with VMAT form a distinct cluster within the dendrogram of the MFS, drug-proton antiporters. A comparison with other proteins in the family suggests the existence of a potential ion pair in the membrane domain. Three of these genes, from Mycobacterium smegmatis, Corynebacterium glutamicum, and Halobacterium salinarum, were cloned and functionally expressed in Escherichia coli. The proteins conferred resistance to fluoroquinolones and chloramphenicol (at concentrations two to four times greater than that of the control). Measurement of antibiotic accumulation in cells revealed proton motive force-dependent transport of those compounds.
9
Ginn, Samantha L., Melissa H. Brown, and Ronald A. Skurray. "The TetA(K) Tetracycline/H+ Antiporter from Staphylococcus aureus: Mutagenesis and Functional Analysis of Motif C." Journal of Bacteriology 182, no. 6 (March 15, 2000): 1492–98. http://dx.doi.org/10.1128/jb.182.6.1492-1498.2000.
Анотація:
ABSTRACT Conserved motif C, identified within members of the major facilitator superfamily (MFS) of transport proteins that mediate drug export, was examined in the tetracycline resistance efflux protein TetA(K) from Staphylococcus aureus; motif C is contained within transmembrane segment 5. Using site-directed mutagenesis, the importance of the conserved glycine (G151, G155, G159, and G160) and proline (P156) residues within this motif was investigated. Over 40 individual amino acid replacements were introduced; however, only alanine and serine substitutions for glycine at G151, G155, and G160 were found to retain significant levels of tetracycline resistance and transport activity in cells expressing mutant proteins. Notably, P156 and G159 appear to be crucial, as amino acid replacements at these positions either significantly reduced or abolished tetracycline/H+ activity. The highly conserved nature of motif C and its distribution throughout drug exporters imply that the residues of motif C play a similar role in all MFS proteins that function as antiporters.
10
Tortosa, Valentina, Maria Carmela Bonaccorsi di Patti, Federico Iacovelli, Andrea Pasquadibisceglie, Mattia Falconi, Giovanni Musci, and Fabio Polticelli. "Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism." International Journal of Molecular Sciences 21, no. 18 (September 16, 2020): 6785. http://dx.doi.org/10.3390/ijms21186785.
Анотація:
Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotrophic lateral sclerosis and Alzheimer’s disease. MFS transporters are also involved in multidrug resistance in bacteria and fungi. The structures of most MFS members, especially those of members with significant physiological relevance, are yet to be solved. The lack of structural and functional information impedes our detailed understanding, and thus the pharmacological targeting, of these transporters. To improve our knowledge on the mechanistic principles governing the function of MSF members, molecular dynamics (MD) simulations were performed on the inward-facing and outward-facing crystal structures of the human ferroportin homologue from the Gram-negative bacterium Bdellovibrio bacteriovorus (BdFpn). Several simulations with an excess of iron ions were also performed to explore the relationship between the protein’s dynamics and the ligand recognition mechanism. The results reinforce the existence of the alternating-access mechanism already described for other MFS members. In addition, the reorganization of salt bridges, some of which are conserved in several MFS members, appears to be a key molecular event facilitating the conformational change of the transporter.
11
Sharma, Suman, Atanu Banerjee, Alexis Moreno, Archana Kumari Redhu, Pierre Falson, and Rajendra Prasad. "Spontaneous Suppressors against Debilitating Transmembrane Mutants of CaMdr1 Disclose Novel Interdomain Communication via Signature Motifs of the Major Facilitator Superfamily." Journal of Fungi 8, no. 5 (May 22, 2022): 538. http://dx.doi.org/10.3390/jof8050538.
Анотація:
The Major Facilitator Superfamily (MFS) drug:H+ antiporter CaMdr1, from Candida albicans, is responsible for the efflux of structurally diverse antifungals. MFS members share a common fold of 12–14 transmembrane helices (TMHs) forming two N- and C-domains. Each domain is arranged in a pseudo-symmetric fold of two tandems of 3-TMHs that alternatively expose the drug-binding site towards the inside or the outside of the yeast to promote drug binding and release. MFS proteins show great diversity in primary structure and few conserved signature motifs, each thought to have a common function in the superfamily, although not yet clearly established. Here, we provide new information on these motifs by having screened a library of 64 drug transport-deficient mutants and their corresponding suppressors spontaneously addressing the deficiency. We found that five strains recovered the drug-resistance capacity by expressing CaMdr1 with a secondary mutation. The pairs of debilitating/rescuing residues are distributed either in the same TMH (T127ATMH1- > G140DTMH1) or 3-TMHs repeat (F216ATMH4- > G260ATMH5), at the hinge of 3-TMHs repeats tandems (R184ATMH3- > D235HTMH4, L480ATMH10- > A435TTMH9), and finally between the N- and C-domains (G230ATMH4- > P528HTMH12). Remarkably, most of these mutants belong to the different signature motifs, highlighting a mechanistic role and interplay thought to be conserved among MFS proteins. Results also point to the specific role of TMH11 in the interplay between the N- and C-domains in the inward- to outward-open conformational transition.
12
Panda, Siva Prasad, Mahamat Sami Adam Mahamat, Malikyahia Abdul Rasool, DSNBK Prasanth, Idris Adam Ismail, Moyed Abasher Ahmed Abasher, and Bikash Ranjan Jena. "Inhibitory effects of mixed flavonoid supplements on unraveled DSS-induced ulcerative colitis and arthritis." BioImpacts 13, no. 1 (December 31, 2022): 73–84. http://dx.doi.org/10.34172/bi.2022.23523.
Анотація:
Introduction: The mixed flavonoid supplement (MFS) [Trimethoxy Flavones (TMF) + epigallocatechin-3-gallate (EGCG)] can be used to suppress inflammatory ulcers as an ethical medicine in Ayurveda. The inflammation of the rectum and anal regions is mostly attributed to nuclear factor kappa beta (NF-κB) signaling. NF-κB stimulates the expression of matrix metalloproteinase (MMP9), inflammatory cytokines tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β). Although much research targeted the NF-κB and MMP9 signaling pathways, a subsequent investigation of target mediators in the inflammatory ulcer healing and NF-κB pathway has not been done. Methods: The docking studies of compounds TMF and EGCG were performed by applying PyRx and available software to understand ligand binding properties with the target proteins. The synergistic ulcer healing and anti-arthritic effects of MFS were elucidated using dextran sulfate sodium (DSS)-induced colon ulcer in Swiss albino rats. The colon mucosal injury was analyzed by colon ulcer index (CUI) and anorectic tissue microscopy. The IL-1β, tumor necrosis factor (TNF-α), and the pERK, MMP9, and NF-κB expressions in the colon tissue were determined by ELISA and Western blotting. RT-PCR determined the mRNA expression for inflammatory marker enzymes. Results: The docking studies revealed that EGCG and TMF had a good binding affinity with MMP9 (i.e., -6.8 and -6.0 Kcal/mol) and NF-kB (-9.4 and 8.3 kcal/mol). The high dose MFS better suppressed ulcerative colitis (UC) and associated arthritis with marked low-density pERK, MMP9, and NF-κB proteins. The CUI score and inflammatory mediator levels were suppressed with endogenous antioxidant levels in MFS treated rats. Conclusion: The MFS effectively unraveled anorectic tissue inflammation and associated arthritis by suppressing NF-κB-mediated MMP9 and cytokines.
13
Pao, Stephanie S., Ian T. Paulsen, and Milton H. Saier. "Major Facilitator Superfamily." Microbiology and Molecular Biology Reviews 62, no. 1 (March 1, 1998): 1–34. http://dx.doi.org/10.1128/mmbr.62.1.1-34.1998.
Анотація:
SUMMARY The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity. All homologous MFS protein sequences in the public databases as of January 1997 were identified on the basis of sequence similarity and shown to be homologous. Phylogenetic analyses revealed the occurrence of 17 distinct families within the MFS, each of which generally transports a single class of compounds. Compounds transported by MFS permeases include simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of organic and inorganic anions and cations. Protein members of some MFS families are found exclusively in bacteria or in eukaryotes, but others are found in bacteria, archaea, and eukaryotes. All permeases of the MFS possess either 12 or 14 putative or established transmembrane α-helical spanners, and evidence is presented substantiating the proposal that an internal tandem gene duplication event gave rise to a primordial MFS protein prior to divergence of the family members. All 17 families are shown to exhibit the common feature of a well-conserved motif present between transmembrane spanners 2 and 3. The analyses reported serve to characterize one of the largest and most diverse families of transport proteins found in living organisms.
14
Stephen, Jerusha, Fathima Salam, Manjusha Lekshmi, Sanath H. Kumar, and Manuel F. Varela. "The Major Facilitator Superfamily and Antimicrobial Resistance Efflux Pumps of the ESKAPEE Pathogen Staphylococcus aureus." Antibiotics 12, no. 2 (February 7, 2023): 343. http://dx.doi.org/10.3390/antibiotics12020343.
Анотація:
The ESKAPEE bacterial pathogen Staphylococcus aureus has posed a serious public health concern for centuries. Throughout its evolutionary course, S. aureus has developed strains with resistance to antimicrobial agents. The bacterial pathogen has acquired multidrug resistance, causing, in many cases, untreatable infectious diseases and raising serious public safety and healthcare concerns. Amongst the various mechanisms for antimicrobial resistance, integral membrane proteins that serve as secondary active transporters from the major facilitator superfamily constitute a chief system of multidrug resistance. These MFS transporters actively export structurally different antimicrobial agents from the cells of S. aureus. This review article discusses the S. aureus-specific MFS multidrug efflux pump systems from a molecular mechanistic perspective, paying particular attention to structure–function relationships, modulation of antimicrobial resistance mediated by MFS drug efflux pumps, and direction for future investigation.
15
Banerjee, Atanu, Jorgaq Pata, Suman Sharma, Brian C. Monk, Pierre Falson, and Rajendra Prasad. "Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters of Candida albicans." Journal of Fungi 7, no. 2 (January 20, 2021): 68. http://dx.doi.org/10.3390/jof7020068.
Анотація:
Multidrug resistance (MDR) transporters belonging to either the ATP-Binding Cassette (ABC) or Major Facilitator Superfamily (MFS) groups are major determinants of clinical drug resistance in fungi. The overproduction of these proteins enables the extrusion of incoming drugs at rates that prevent lethal effects. The promiscuity of these proteins is intriguing because they export a wide range of structurally unrelated molecules. Research in the last two decades has used multiple approaches to dissect the molecular basis of the polyspecificity of multidrug transporters. With large numbers of drug transporters potentially involved in clinical drug resistance in pathogenic yeasts, this review focuses on the drug transporters of the important pathogen Candida albicans. This organism harbors many such proteins, several of which have been shown to actively export antifungal drugs. Of these, the ABC protein CaCdr1 and the MFS protein CaMdr1 are the two most prominent and have thus been subjected to intense site-directed mutagenesis and suppressor genetics-based analysis. Numerous results point to a common theme underlying the strategy of promiscuity adopted by both CaCdr1 and CaMdr1. This review summarizes the body of research that has provided insight into how multidrug transporters function and deliver their remarkable polyspecificity.
16
Wisler, James W., Emily M. Harris, Michael Raisch, Lan Mao, Jihee Kim, Howard A. Rockman та Robert J. Lefkowitz. "The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome". American Journal of Physiology-Heart and Circulatory Physiology 309, № 9 (листопад 2015): H1516—H1527. http://dx.doi.org/10.1152/ajpheart.00291.2015.
Анотація:
Ang II type 1a receptor (AT1aR)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). β-Arrestin2 (βarr2) is known to mediate AT1aR-dependent MAPK activation, as well as proproliferative and profibrotic signaling in aortic vascular smooth muscle cells. Therefore, we investigated whether βarr2-dependent signaling contributes to TAA formation in MFS. We used a murine model of MFS [fibrillin ( Fbn)C1039G/+] to generate an MFS murine model in combination with genetic βarr2 deletion ( FbnC1039G/+/ βarr2−/−). FbnC1039G/+/ βarr2−/− mice displayed delayed aortic root dilation compared with FbnC1039G/+ mice. The mRNA and protein expression of several mediators of TAA formation, including matrix metalloproteinase (MMP)-2 and -9, was reduced in the aorta of FbnC1039G/+/ βarr2−/− mice relative to FbnC1039G/+ mice. Activation of ERK1/2 was also decreased in the aortas of FbnC1039G/+/ βarr2−/− mice compared with FbnC1039G/+ animals. Small interfering RNA targeting βarr2 inhibited angiotensin-stimulated expression of proaneurysmal signaling mediators in primary aortic root smooth muscle cells. Angiotensin-stimulated expression of the proaneurysmal signaling mediators MMP-2 and -9 was inhibited by blockade of ERK1/2 or the EGF receptor, whereas blockade of the transforming growth factor-β receptor had no effect. These results suggest that βarr2 contributes to TAA formation in MFS by regulating ERK1/2-dependent expression of proaneurysmal genes and proteins downstream of the AT1aR. Importantly, this demonstration of the unique signaling mechanism by which βarr2 contributes to aneurysm formation identifies multiple novel, potential therapeutic targets in MFS.
17
Aínsa, José A., Marian C. J. Blokpoel, Isabel Otal, Douglas B. Young, Koen A. L. De Smet, and Carlos Martín. "Molecular Cloning and Characterization of Tap, a Putative Multidrug Efflux Pump Present in Mycobacterium fortuitum and Mycobacterium tuberculosis." Journal of Bacteriology 180, no. 22 (November 15, 1998): 5836–43. http://dx.doi.org/10.1128/jb.180.22.5836-5843.1998.
Анотація:
ABSTRACT A recombinant plasmid isolated from a Mycobacterium fortuitum genomic library by selection for gentamicin and 2-N′-ethylnetilmicin resistance conferred low-level aminoglycoside and tetracycline resistance when introduced intoM. smegmatis. Further characterization of this plasmid allowed the identification of the M. fortuitum tap gene. A homologous gene in the M. tuberculosis H37Rv genome has been identified. The M. tuberculosis tap gene (Rv1258 in the annotated sequence of the M. tuberculosis genome) was cloned and conferred low-level resistance to tetracycline when introduced into M. smegmatis. The sequences of the putative Tap proteins showed 20 to 30% amino acid identity to membrane efflux pumps of the major facilitator superfamily (MFS), mainly tetracycline and macrolide efflux pumps, and to other proteins of unknown function but with similar antibiotic resistance patterns. Approximately 12 transmembrane regions and different sequence motifs characteristic of the MFS proteins also were detected. In the presence of the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP), the levels of resistance to antibiotics conferred by plasmids containing the tap genes were decreased. When tetracycline accumulation experiments were carried out with the M. fortuitum tap gene, the level of tetracycline accumulation was lower than that in control cells but was independent of the presence of CCCP. We conclude that the Tap proteins of the opportunistic organism M. fortuitum and the important pathogen M. tuberculosisare probably proton-dependent efflux pumps, although we cannot exclude the possibility that they act as regulatory proteins.
18
Jacquemier, Jocelyne, Christophe Ginestier, Jacques Rougemont, Valérie-Jeanne Bardou, Emmanuelle Charafe-Jauffret, Jeannine Geneix, José Adélaïde, et al. "Protein Expression Profiling Identifies Subclasses of Breast Cancer and Predicts Prognosis." Cancer Research 65, no. 3 (February 1, 2005): 767–79. http://dx.doi.org/10.1158/0008-5472.767.65.3.
Анотація:
Abstract Breast cancer is a heterogeneous disease whose evolution is difficult to predict by using classic histoclinical prognostic factors. Prognostic classification can benefit from molecular analyses such as large-scale expression profiling. Using immunohistochemistry on tissue microarrays, we have monitored the expression of 26 selected proteins in more than 1,600 cancer samples from 552 consecutive patients with early breast cancer. Both an unsupervised approach and a new supervised method were used to analyze these profiles. Hierarchical clustering identified relevant clusters of coexpressed proteins and clusters of tumors. We delineated protein clusters associated with the estrogen receptor and with proliferation. Tumor clusters correlated with several histoclinical features of samples, including 5-year metastasis-free survival (MFS), and with the recently proposed pathophysiologic taxonomy of disease. The supervised method identified a set of 21 proteins whose combined expression significantly correlated to MFS in a learning set of 368 patients (P < 0.0001) and in a validation set of 184 patients (P < 0.0001). Among the 552 patients, the 5-year MFS was 90% for patients classified in the “good-prognosis class” and 61% for those classified in the “poor-prognosis class” (P < 0.0001). This difference remained significant when the molecular grouping was applied according to lymph node or estrogen receptor status, as well as the type of adjuvant systemic therapy. In multivariate analysis, the 21-protein set was the strongest independent predictor of clinical outcome. These results show that protein expression profiling may be a clinically useful approach to assess breast cancer heterogeneity and prognosis in stage I, II, or III disease.
19
Valdivia Callejon, Irene, Lucia Buccioli, Jarl Bastianen, Jolien Schippers, Aline Verstraeten, Ilse Luyckx, Silke Peeters, et al. "Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome." International Journal of Molecular Sciences 25, no. 9 (May 4, 2024): 5025. http://dx.doi.org/10.3390/ijms25095025.
Анотація:
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
20
Asi, Azizah Mohd, and Mark S. P. Sansom. "Structural Quality and MD Simulations of Homology Models of Major Facilitator Superfamily (MFS) Transporter Proteins." Biophysical Journal 98, no. 3 (January 2010): 645a. http://dx.doi.org/10.1016/j.bpj.2009.12.3536.
21
Ye, Yanfang, Lichen Chen, Lishi Xiao, Wenlan Mo, Zhenghuai Zheng, and Zhiwei Huang. "Characterization and Mechanism Analysis of Sugar Transporter Protein Obtained from Monascus pilosus." Journal of Biobased Materials and Bioenergy 18, no. 3 (May 1, 2024): 395–403. http://dx.doi.org/10.1166/jbmb.2024.2392.
Анотація:
Sugar transporter protein family is very common among different organisms in nature and plays a key role in the transportation, absorption, and synthesis of secondary metabolites. To investigate the functional characteristics of sugar transporter proteins in Monascus pilosus, cDNA sequence of sugar transporter protein gene MpST collected from M. pilosus CICC 5045 was cloned in this research. Furthermore, bioinformatics methods and molecular docking techniques were applied to analyze MpST protein. The obtained results revealed that the coding region of MpST was 1677 bp in length, which coded 558 amino acids, and it was a stable protein. Phylogenetic tree analysis found a close relationship between MpST and two other proteins from M. purpureus (BDD61243.1 and TQB74099.1). Bioinformatics analyses indicated that this protein is a hydrophilic protein with 11 transmembrane domains and its functional domains were mainly consisted of the conserved domains of major facilitator superfamily (MFS) and sugar transporter proteins, suggesting that this protein belonged to MFS transporter protein family. Molecular docking results suggested that the receptor protein could spontaneously bind with high affinity to small molecular ligands such as galactose, raffinose, glucose, xylose, and maltose. From the above analyses, it was predicted that this protein might have good transport function for the above five sugars. This study lays the foundation for further in-depth research on the functions and applications of this protein.
22
Shang, Yan, Peiwen Lv, Dandan Su, Yaru Li, Yu Liang, Cuiqing Ma, and Chunyu Yang. "Evolutionary conservative analysis revealed novel functional sites in the efflux pump NorA of Staphylococcus aureus." Journal of Antimicrobial Chemotherapy 77, no. 3 (December 15, 2021): 675–81. http://dx.doi.org/10.1093/jac/dkab453.
Анотація:
Abstract Objectives The NorA antiporter of Staphylococcus aureus belongs to the major facilitator superfamily (MFS) and extrudes various kinds of drugs. With no structure available for this drug efflux pump, the aim of this study was to explore its important structural elements that contribute to substrate binding and drug transport. Methods Evolutionary conservative analyses were conducted on different compilations of NorA homologues to identify conservative motifs and residues. Site-directed mutations were constructed to verify the functional changes in NorA efflux capacities and the conformational changes were further measured by fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST) analysis. Results Besides Motif-A, Motif-B and Motif-C that were reported previously in MFS proteins, two other motifs, Motif-1 and Motif-2, were identified in NorA. Site-directed mutations of Motif-1 and Motif-2 as well as 11 predicted binding sites all caused remarkable reductions in drug resistance and efflux activity. Among these, mutant F16A/E222A/F303A/D307A showed an altered binding affinity for tetraphenylphosphonium chloride when measured by MST and Motif-1 mutant G114D/A117E/D118G/V119I and Motif-2 mutant Q325E/G326E/A328E/G330E displayed obvious conformational alterations when compared with the wild-type NorA in the FRET signal spectra. Conclusions The NorA structure agrees well with the typical structures of MFS proteins, with two newly identified motifs (Motif-1 and Motif-2) that are critical to the structural stability of NorA, and sites F16, E222, F303 and D307 are involved in substrate binding.
23
Parker, Sarah J., Aleksandr Stotland, Elena MacFarlane, Nicole Wilson, Amanda Orosco, Vidya Venkatraman, Kyle Madrid, Roberta Gottlieb, Harry C. Dietz та Jennifer E. Van Eyk. "Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice". American Journal of Physiology-Heart and Circulatory Physiology 315, № 5 (1 листопада 2018): H1112—H1126. http://dx.doi.org/10.1152/ajpheart.00089.2018.
Анотація:
The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-β-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-β activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of β3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that β3-integrin expression and activation modulated TGF-β-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-β signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by β3-integrin constitute a modulator of transforming growth factor-β-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.
24
Trent, Brandon J., Yuejin Liang, Yan Xing, Marisol Esqueda, Wei Yang, Nam-Hyuk Cho, Hong-Il Kim, et al. "Pulmonary inflammation and Tie2/Angiopoietin mediated vascular dysregulation during lethal Orientia tsutsugamushi infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.25. http://dx.doi.org/10.4049/jimmunol.202.supp.190.25.
Анотація:
Abstract Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of lung damage: 1) a significant increase of ICAM-1, VEGFR2, and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Evidence for neutrophil-mediated inflammation and tissue damage included in vitro infection and activation of neutrophils, lung accumulation of activated (CD63+)neutrophils, co-localization of lung bacteria with neutrophils, and co-localization of MPO+ neutrophils with Ang2+ ECs. At the onset of disease, pulmonary macrophages (MF) were polarized toward an M1-like phenotype, with limited detection of M2-like cells. Comparative studies of LPS- versus IL-4-primed MFs revealed extensive bacterial replication in M2-type MFs that preferentially expressed the IL-10 and SOCS1 genes. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection and highlights inflammatory biomarkers future therapeutic research for the control of this neglected tropical disease.
25
Pasqua, Grossi, Zennaro, Fanelli, Micheli, Barras, Colonna, and Prosseda. "The Varied Role of Efflux Pumps of the MFS Family in the Interplay of Bacteria with Animal and Plant Cells." Microorganisms 7, no. 9 (August 22, 2019): 285. http://dx.doi.org/10.3390/microorganisms7090285.
Анотація:
Efflux pumps represent an important and large group of transporter proteins found in all organisms. The importance of efflux pumps resides in their ability to extrude a wide range of antibiotics, resulting in the emergence of multidrug resistance in many bacteria. Besides antibiotics, multidrug efflux pumps can also extrude a large variety of compounds: Bacterial metabolites, plant-produced compounds, quorum-sensing molecules, and virulence factors. This versatility makes efflux pumps relevant players in interactions not only with other bacteria, but also with plant or animal cells. The multidrug efflux pumps belonging to the major facilitator superfamily (MFS) are widely distributed in microbial genomes and exhibit a large spectrum of substrate specificities. Multidrug MFS efflux pumps are present either as single-component transporters or as tripartite complexes. In this review, we will summarize how the multidrug MFS efflux pumps contribute to the interplay between bacteria and targeted host cells, with emphasis on their role in bacterial virulence, in the colonization of plant and animal host cells and in biofilm formation. We will also address the complexity of these interactions in the light of the underlying regulatory networks required for the effective activation of efflux pump genes.
26
Hepler, Peter K., Aline Valster, Tasha Molchan, and Jan W. Vos. "Roles for kinesin and myosin during cytokinesis." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 357, no. 1422 (June 29, 2002): 761–66. http://dx.doi.org/10.1098/rstb.2002.1093.
Анотація:
Cytokinesis in higher plants involves the phragmoplast, a complex cytoplasmic structure that consists of microtubules (MTs), microfilaments (MFs) and membrane elements. Both MTs and MFs are essential for cell plate formation, although it is not clear which motor proteins are involved. Some candidate processes for motor proteins include transport of Golgi vesicles to the plane of the cell plate and the spatiotemporal organization of the cytoskeletal elements in order to achieve proper deposition and alignment of the cell plate. We have focused on the kinesin–like calmodulin binding protein (KCBP) and, more broadly, on myosins. Using an antibody that constitutively activates KCBP, we find that this MT motor, which is minus–end directed, contributes to the organization of the spindle and phragmoplast MTs. It does not participate in vesicle transport; rather, because of the orientation of the phragmoplast MTs, it is supposed that plus–end kinesins fill this role. Myosins, on the other hand, based on their inhibition with 2,3–butanedione monoxime and 1–(5–iodonaphthalene–1–sulphonyl)–1H–hexahydro–1,4–diazepine (ML–7), are associated with the process of post–mitotic spindle/phragmoplast alignment and with late lateral expansion of the cell plate. They are also not the principal motors involved in vesicle transport.
27
Panwar, Sneh Lata, Ritu Pasrija, and Rajendra Prasad. "Membrane homoeostasis and multidrug resistance in yeast." Bioscience Reports 28, no. 4 (August 1, 2008): 217–28. http://dx.doi.org/10.1042/bsr20080071.
Анотація:
The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.
28
Madej, M. Gregor. "Function, Structure, and Evolution of the Major Facilitator Superfamily: The LacY Manifesto." Advances in Biology 2014 (September 18, 2014): 1–20. http://dx.doi.org/10.1155/2014/523591.
Анотація:
The major facilitator superfamily (MFS) is a diverse group of secondary transporters with members found in all kingdoms of life. A paradigm for MFS is the lactose permease (LacY) of Escherichia coli, which couples the stoichiometric translocation of a galactopyranoside and an H+ across the cytoplasmic membrane. LacY has been the test bed for the development of many methods applied for the analysis of transport proteins. X-ray structures of an inward-facing conformation and the most recent structure of an almost occluded conformation confirm many conclusions from previous studies. Although structure models are critical, they are insufficient to explain the catalysis of transport. The clues to understanding transport are based on the principles of enzyme kinetics. Secondary transport is a dynamic process—static snapshots of X-ray crystallography describe it only partially. However, without structural information, the underlying chemistry is virtually impossible to conclude. A large body of biochemical/biophysical data derived from systematic studies of site-directed mutants in LacY suggests residues critically involved in the catalysis, and a working model for the symport mechanism that involves alternating access of the binding site is presented. The general concepts derived from the bacterial LacY are examined for their relevance to other MFS transporters.
29
Perland, Emelie, Sonchita Bagchi, Axel Klaesson, and Robert Fredriksson. "Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression." Open Biology 7, no. 9 (September 2017): 170142. http://dx.doi.org/10.1098/rsob.170142.
Анотація:
Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6 L, 7, 8, 9, 10, 11, 12, 13A, 14A and 14B; SV2A, SV2B and SV2C; SVOP and SVOPL; SPNS1, SPNS2 and SPNS3; and UNC93A and UNC93B1. We studied their fundamental properties, and we also included CLN3, an atypical SLC not yet belonging to any protein family (Pfam) clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted atypical MFS transporter families (AMTF1-15). Hidden Markov models were used to identify orthologues from human to Drosophila melanogaster and Caenorhabditis elegans . Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLCs were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs.
30
Clegg, N. J., I. P. Whitehead, J. K. Brock, D. A. Sinclair, R. Mottus, G. Stromotich, M. J. Harrington, and T. A. Grigliatti. "A cytogenetic analysis of chromosomal region 31 of Drosophila melanogaster." Genetics 134, no. 1 (May 1, 1993): 221–30. http://dx.doi.org/10.1093/genetics/134.1.221.
Анотація:
Abstract Cytogenetic region 31 of the second chromosome of Drosophila melanogaster was screened for recessive lethal mutations. One hundred and thirty nine new recessive lethal alleles were isolated that fail to complement Df(2L)J2 (31A-32A). These new alleles, combined with preexisting mutations in the region, define 52 complementation groups, 35 of which have not previously been described. Among the new mutations were alleles of the cdc2 and mfs(2)31 genes. Six new deficiencies were also isolated and characterized identifying 16 deficiency subintervals within region 31. The new deficiencies were used to further localize three loci believed to encode non-histone chromosomal proteins. Suvar(2)1/Su(var)214, a dominant suppressor of position-effect variegation (PEV), maps to 31A-B, while the recessive suppressors of PEV mfs(2)31 and wdl were localized to regions 31E and 31F-32A, respectively. In addition, the cytological position of several mutations that interact with heterochromatin were more precisely defined.
31
Lin, S. I., C. Santi, E. Jobet, E. Lacut, N. El Kholti, W. M. Karlowski, J. L. Verdeil, et al. "Complex Regulation of Two Target Genes Encoding SPX-MFS Proteins by Rice miR827 in Response to Phosphate Starvation." Plant and Cell Physiology 51, no. 12 (November 9, 2010): 2119–31. http://dx.doi.org/10.1093/pcp/pcq170.
32
Floyd, Jody L., Kenneth P. Smith, Sanath H. Kumar, Jared T. Floyd, and Manuel F. Varela. "LmrS Is a Multidrug Efflux Pump of the Major Facilitator Superfamily from Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 54, no. 12 (September 20, 2010): 5406–12. http://dx.doi.org/10.1128/aac.00580-10.
Анотація:
ABSTRACT A multidrug efflux pump designated LmrS (lincomycin resistance protein of Staphylococcus aureus), belonging to the major facilitator superfamily (MFS) of transporters, was cloned, and the role of LmrS in antimicrobial efflux was evaluated. The highest relative increase in MIC, 16-fold, was observed for linezolid and tetraphenylphosphonium chloride (TPCL), followed by an 8-fold increase for sodium dodecyl sulfate (SDS), trimethoprim, and chloramphenicol. LmrS has 14 predicted membrane-spanning domains and is homologous to putative lincomycin resistance proteins of Bacillus spp., Lactobacillus spp., and Listeria spp.
33
Saletnik, Bogdan, Aneta Saletnik, Ewelina Słysz, Grzegorz Zaguła, Marcin Bajcar, Anna Puchalska-Sarna, and Czesław Puchalski. "The Static Magnetic Field Regulates the Structure, Biochemical Activity, and Gene Expression of Plants." Molecules 27, no. 18 (September 8, 2022): 5823. http://dx.doi.org/10.3390/molecules27185823.
Анотація:
The purpose of this paper is to review the scientific results and summarise the emerging topic of the effects of statistic magnetic field on the structure, biochemical activity, and gene expression of plants. The literature on the subject reports a wide range of possibilities regarding the use of the magnetic field to modify the properties of plant cells. MFs have a significant impact on the photosynthesis efficiency of the biomass and vigour accumulation indexes. Treating plants with SMFs accelerates the formation and accumulation of reactive oxygen species. At the same time, the influence of MFs causes the high activity of antioxidant enzymes, which reduces oxidative stress. SMFs have a strong influence on the shape of the cell and the structure of the cell membrane, thus increasing their permeability and influencing the various activities of the metabolic pathways. The use of magnetic treatments on plants causes a higher content of proteins, carbohydrates, soluble and reducing sugars, and in some cases, lipids and fatty acid composition and influences the uptake of macro- and microelements and different levels of gene expression. In this study, the effect of MFs was considered as a combination of MF intensity and time exposure, for different varieties and plant species. The following article shows the wide-ranging possibilities of applying magnetic fields to the dynamics of changes in the life processes and structures of plants. Thus far, the magnetic field is not widely used in agricultural practice. The current knowledge about the influence of MFs on plant cells is still insufficient. It is, therefore, necessary to carry out detailed research for a more in-depth understanding of the possibilities of modifying the properties of plant cells and achieving the desired effects by means of a magnetic field.
34
Pourali, Parastoo, Oldřich Benada, Miroslav Pátek, Eva Neuhöferová, Volha Dzmitruk, and Veronika Benson. "Response of Biological Gold Nanoparticles to Different pH Values: Is It Possible to Prepare Both Negatively and Positively Charged Nanoparticles?" Applied Sciences 11, no. 23 (December 6, 2021): 11559. http://dx.doi.org/10.3390/app112311559.
Анотація:
The mycelium-free supernatant (MFS) of a five-day-old culture medium of Fusarium oxysporum was used to synthesize gold nanoparticles (AuNPs). The experimental design of the study was to answer the question: can this production process of AuNPs be controllable like classical chemical or physical approaches? The process of producing AuNPs from 1 mM tetrachloroauric (III) acid trihydrate in MFS was monitored visually by color change at different pH values and quantified spectroscopically. The produced AuNPs were analyzed by transmission electron microscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The presence of capping agents was confirmed by Fourier transform infrared spectroscopy (FTIR). Two AuNP samples with acidic and alkaline pH were selected and adjusted with the pH gradient and analyzed. Finally, the size and zeta potential of all samples were determined. The results confirmed the presence of the proteins as capping agents on the surface of the AuNPs and confirmed the production of AuNPs at all pH values. All AuNP samples exhibited negative zeta potential, and this potential was higher at natural to alkaline pH values. The size distribution analysis showed that the size of AuNPs produced at alkaline pH was smaller than that at acidic pH. Since all samples had negative charge, we suspect that there were other molecules besides proteins that acted as capping agents on the surface of the AuNPs. We conclude that although the biological method of nanoparticle production is safe, green, and inexpensive, the ability to manipulate the nanoparticles to obtain both positive and negative charges is limited, curtailing their application in the medical field.
35
Manto, Mario, and Hiroshi Mitoma. "Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges—Editorial." Brain Sciences 13, no. 12 (November 24, 2023): 1626. http://dx.doi.org/10.3390/brainsci13121626.
Анотація:
The clinical category of immune-mediated cerebellar ataxias (IMCAs) has been established after 3 decades of clinical and experimental research. The cerebellum is particularly enriched in antigens (ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells) and is vulnerable to immune attacks. IMCAs include various disorders, including gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Other disorders such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen vascular disorders may also present with cerebellar symptoms when lesions are localized to cerebellar pathways. The triggers of autoimmunity are established in GA (gluten sensitivity), PIC and MFS (infections), PCD (malignancy), and OMS (infections or malignant tumors). Patients whose clinical profiles do not match those of classic types of IMCAs are now included in the spectrum of primary autoimmune cerebellar ataxia (PACA). Recent remarkable progress has clarified various characteristics of these etiologies and therapeutic strategies in terms of immunotherapies. However, it still remains to be elucidated as to how immune tolerance is broken, leading to autoimmune insults of the cerebellum, and the consecutive sequence of events occurring during cerebellar damage caused by antibody- or cell-mediated mechanisms. Antibodies may specifically target the cerebellar circuitry and impair synaptic mechanisms (synaptopathies). The present Special Issue aims to illuminate what is solved and what is unsolved in clinical practice and the pathophysiology of IMCAs. Immune ataxias now represent a genuine category of immune insults to the central nervous system (CNS).
36
Sharma, Monika, Raman Manoharlal, Suneet Shukla, Nidhi Puri, Tulika Prasad, Suresh V. Ambudkar, and Rajendra Prasad. "Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals." Antimicrobial Agents and Chemotherapy 53, no. 8 (May 26, 2009): 3256–65. http://dx.doi.org/10.1128/aac.01497-08.
Анотація:
ABSTRACT Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [125I]iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 μM). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC protein-expressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells.
37
Meena, Varsha, Shivani Sharma, Gazaldeep Kaur, Bhupinder Singh, and Ajay Kumar Pandey. "Diverse Functions of Plant Zinc-Induced Facilitator-like Transporter for Their Emerging Roles in Crop Trait Enhancement." Plants 11, no. 1 (December 30, 2021): 102. http://dx.doi.org/10.3390/plants11010102.
Анотація:
The major facilitator superfamily (MFS) is a large and diverse group of secondary transporters found across all kingdoms of life. Zinc-induced facilitator-like (ZIFL) transporters are the MFS family members that function as exporters driven by the antiporter-dependent processes. The presence of multiple ZIFL transporters was shown in various plant species, as well as in bryophytes. However, only a few ZIFLs have been functionally characterized in plants, and their localization has been suggested to be either on tonoplast or at the plasma membrane. A subset of the plant ZIFLs were eventually characterized as transporters due to their specialized role in phytosiderophores efflux and auxin homeostasis, and they were also proven to impart tolerance to micronutrient deficiency. The emerging functions of ZIFL proteins highlight their role in addressing important traits in crop species. This review aims to provide insight into and discuss the importance of plant ZIFL in various tissue-specific functions. Furthermore, a spotlight is placed on their role in mobilizing essential micronutrients, including iron and zinc, from the rhizosphere to support plant survival. In conclusion, in this paper, we discuss the functional redundancy of ZIFL transporters to understand their roles in developing specific traits in crop.
38
Fischer, Jana, Gunnar Kleinau, Anne Müller, Peter Kühnen, Denise Zwanziger, Anita Kinne, Maren Rehders, et al. "Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations." Journal of Molecular Endocrinology 54, no. 1 (February 2015): 39–50. http://dx.doi.org/10.1530/jme-14-0272.
Анотація:
The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural–mechanistical insights into MCT8.
39
Nagamura, Reina, Masahiro Fukuda, Akihiro Kawamoto, Kyoko Matoba, Naoshi Dohmae, Ryuichiro Ishitani, Junichi Takagi, and Osamu Nureki. "Structural basis for oligomerization of the prokaryotic peptide transporter PepTSo2." Acta Crystallographica Section F Structural Biology Communications 75, no. 5 (April 24, 2019): 348–58. http://dx.doi.org/10.1107/s2053230x19003546.
Анотація:
Proton-dependent oligopeptide transporters (POTs) belong to the major facilitator superfamily (MFS) and transport dipeptides and tripeptides from the extracellular environment into the target cell. The human POTs PepT1 and PepT2 are also involved in the absorption of various orally ingested drugs. Previously reported structures revealed that the bacterial POTs possess 14 helices, of which H1–H6 and H7–H12 constitute the typical MFS fold and the residual two helices are involved in the cytoplasmic linker. PepTSo2 from Shewanella oneidensis is a unique POT which reportedly assembles as a 200 kDa tetramer. Although the previously reported structures suggested the importance of H12 for tetramer formation, the structural basis for the PepTSo2-specific oligomerization remains unclear owing to the lack of a high-resolution tetrameric structure. In this study, the expression and purification conditions for tetrameric PepTSo2 were optimized. A single-particle cryo-EM analysis revealed the tetrameric structure of PepTSo2 incorporated into Salipro nanoparticles at 4.1 Å resolution. Furthermore, a combination of lipidic cubic phase (LCP) crystallization and an automated data-processing system for multiple microcrystals enabled crystal structures of PepTSo2 to be determined at resolutions of 3.5 and 3.9 Å. The present structures in a lipid bilayer revealed the detailed mechanism for the tetrameric assembly of PepTSo2, in which a characteristic extracellular loop (ECL) interacts with two asparagine residues on H12 which were reported to be important for tetramerization and plays an essential role in oligomeric assembly. This study provides valuable insights into the oligomerization mechanism of this MFS-type transporter, which will further pave the way for understanding other oligomeric membrane proteins.
40
Mandal, Ajeet, Antresh Kumar, Ashutosh Singh, Andrew M. Lynn, Khyati Kapoor, and Rajendra Prasad. "A key structural domain of the Candida albicans Mdr1 protein." Biochemical Journal 445, no. 3 (July 13, 2012): 313–22. http://dx.doi.org/10.1042/bj20120190.
Анотація:
A major multidrug transporter, MDR1 (multidrug resistance 1), a member of the MFS (major facilitator superfamily), invariably contributes to an increased efflux of commonly used azoles and thus corroborates their direct involvement in MDR in Candida albicans. The Mdr1 protein has two transmembrane domains, each comprising six transmembrane helices, interconnected with extracellular loops and ICLs (intracellular loops). The introduction of deletions and insertions through mutagenesis was used to address the role of the largest interdomain ICL3 of the MDR1 protein. Most of the progressive deletants, when overexpressed, eliminated the drug resistance. Notably, restoration of the length of the ICL3 by insertional mutagenesis did not restore the functionality of the protein. Interestingly, most of the insertion and deletion variants of ICL3 became amenable to trypsinization, yielding peptide fragments. The homology model of the Mdr1 protein showed that the molecular surface-charge distribution was perturbed in most of the ICL3 mutant variants. Taken together, these results provide the first evidence that the CCL (central cytoplasmic loop) of the fungal MFS transporter of the DHA1 (drug/proton antiporter) family is critical for the function of MDR. Unlike other homologous proteins, ICL3 has no apparent role in imparting substrate specificity or in the recruitment of the transporter protein.
41
TSIGELNY, IGOR F., JERRY GREENBERG, VALENTINA KOUZNETSOVA, and SANJAY K. NIGAM. "MODELING OF GLYCEROL-3-PHOSPHATE TRANSPORTER SUGGESTS A POTENTIAL 'TILT' MECHANISM INVOLVED IN ITS FUNCTION." Journal of Bioinformatics and Computational Biology 06, no. 05 (October 2008): 885–904. http://dx.doi.org/10.1142/s0219720008003801.
Анотація:
Many major facilitator superfamily (MFS) transporters have similar 12-transmembrane α-helical topologies with two six-helix halves connected by a long loop. In humans, these transporters participate in key physiological processes and are also, as in the case of members of the organic anion transporter (OAT) family, of pharmaceutical interest. Recently, crystal structures of two bacterial representatives of the MFS family — the glycerol-3-phosphate transporter (GlpT) and lac-permease (LacY) — have been solved and, because of assumptions regarding the high structural conservation of this family, there is hope that the results can be applied to mammalian transporters as well. Based on crystallography, it has been suggested that a major conformational "switching" mechanism accounts for ligand transport by MFS proteins. This conformational switch would then allow periodic changes in the overall transporter configuration, resulting in its cyclic opening to the periplasm or cytoplasm. Following this lead, we have modeled a possible "switch" mechanism in GlpT, using the concept of rotation of protein domains as in the DynDom program17and membranephilic constraints predicted by the MAPAS program.23We found that the minima of energies of intersubunit interactions support two alternate positions consistent with their transport properties. Thus, for GlpT, a "tilt" of 9°–10° rotation had the most favorable energetics of electrostatic interaction between the two halves of the transporter; moreover, this confirmation was sufficient to suggest transport of the ligand across the membrane. We conducted steered molecular dynamics simulations of the GlpT-ligand system to explore how glycerol-3-phosphate would be handled by the "tilted" structure, and obtained results generally consistent with experimental mutagenesis data. While biochemical data remain most consistent with a single-site alternating access model, our results raise the possibility that, while the "rocker switch" may apply to certain MFS transporters, intermediate "tilted" states may exist under certain circumstances or as transitional structures. Although wet lab experimental confirmation is required, our results suggest that transport mechanisms in this transporter family should probably not be assumed to be conserved simply based on standard structural homology considerations. Furthermore, steered molecular dynamics elucidating energetic interactions of ligands with amino acid residues in an appropriately modeled transporter may have predictive value in understanding the impact of mutations and/or polymorphisms on transporter function.
42
Gayraud, Barbara, Douglas R. Keene, Lynn Y. Sakai, and Francesco Ramirez. "New Insights into the Assembly of Extracellular Microfibrils from the Analysis of the Fibrillin 1 Mutation in the Tight skin Mouse." Journal of Cell Biology 150, no. 3 (August 7, 2000): 667–80. http://dx.doi.org/10.1083/jcb.150.3.667.
Анотація:
The Tight skin (Tsk) mutation is a duplication of the mouse fibrillin 1 (Fbn1) gene that results in a larger (418 kD) than normal (350 kD) protein; Tsk/+ mice display increased connective tissue, bone overgrowth, and lung emphysema. Lung emphysema, bone overgrowth, and vascular complications are the distinctive traits of mice with reduced Fbn1 gene expression and of Marfan syndrome (MFS) patients with heterozygous fibrillin 1 mutations. Although Tsk/+ mice produce equal amounts of the 418- and 350-kD proteins, they exhibit a relatively mild phenotype without the vascular complications that are associated with MFS patients and fibrillin 1–deficient mice. We have used genetic crosses, cell culture assays and Tsk-specific antibodies to reconcile this discrepancy and gain new insights into microfibril assembly. Mice compound heterozygous for the Tsk mutation and hypomorphic Fbn1 alleles displayed both Tsk and MFS traits. Analyses of immunoreactive fibrillin 1 microfibrils using Tsk- and species-specific antibodies revealed that the mutant cell cultures elaborate a less abundant and morphologically different meshwork than control cells. Cocultures of Tsk/Tsk fibroblasts and human WISH cells that do not assemble fibrillin 1 microfibrils, demonstrated that Tsk fibrillin 1 copolymerizes with wild-type fibrillin 1. Additionally, copolymerization of Tsk fibrillin 1 with wild-type fibrillin 1 rescues the abnormal morphology of the Tsk/Tsk aggregates. Therefore, the studies suggest that bone and lung abnormalities of Tsk/+ mice are due to copolymerization of mutant and wild-type molecules into functionally deficient microfibrils. However, vascular complications are not present in these animals because the level of functional microfibrils does not drop below the critical threshold. Indirect in vitro evidence suggests that a potential mechanism for the dominant negative effects of incorporating Tsk fibrillin 1 into microfibrils is increased proteolytic susceptibility conferred by the duplicated Tsk region.
43
Nourani, A., M. Wesolowski-Louvel, T. Delaveau, C. Jacq, and A. Delahodde. "Multiple-drug-resistance phenomenon in the yeast Saccharomyces cerevisiae: involvement of two hexose transporters." Molecular and Cellular Biology 17, no. 9 (September 1997): 5453–60. http://dx.doi.org/10.1128/mcb.17.9.5453.
Анотація:
In the yeast Saccharomyces cerevisiae, multidrug resistance to unrelated chemicals can result from overexpression of ATP-binding cassette (ABC) transporters such as Pdr5p, Snq2p, and Yor1p. Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p. Here, we describe the isolation, by an in vivo screen, of two new Pdr1p-Pdr3p target genes: HXT11 and HXT9. HXT11 and HXT9, encoding nearly identical proteins, have a high degree of identity to monosaccharide transporters of the major facilitator superfamily (MFS). In this study, we show that the HXT11 product, which allows glucose uptake in a glucose permease mutant (rag1) strain of Kluyveromyces lactis, is also involved in the pleiotropic drug resistance process. Loss of HXT11 and/or HXT9 confers cycloheximide, sulfomethuron methyl, and 4-NQO (4-nitroquinoline-N-oxide) resistance. Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted. These data show that the two putative hexose transporters Hxt11p and Hxt9p are transcriptionally regulated by the transcription factors Pdr1p and Pdr3p, which are known to regulate the production of ABC transporters required for drug resistance in yeast. We thus demonstrate the existence of genetic interactions between genes coding for two classes of transporters (ABC and MFS) to control the multidrug resistance process.
44
Väisänen, Enni, Junko Takahashi, Ogonna Obudulu, Joakim Bygdell, Pirkko Karhunen, Olga Blokhina, Teresa Laitinen, et al. "Hunting monolignol transporters: membrane proteomics and biochemical transport assays with membrane vesicles of Norway spruce." Journal of Experimental Botany 71, no. 20 (August 10, 2020): 6379–95. http://dx.doi.org/10.1093/jxb/eraa368.
Анотація:
Abstract Both the mechanisms of monolignol transport and the transported form of monolignols in developing xylem of trees are unknown. We tested the hypothesis of an active, plasma membrane-localized transport of monolignol monomers, dimers, and/or glucosidic forms with membrane vesicles prepared from developing xylem and lignin-forming tissue-cultured cells of Norway spruce (Picea abies L. Karst.), as well as from control materials, comprising non-lignifying Norway spruce phloem and tobacco (Nicotiana tabacum L.) BY-2 cells. Xylem and BY-2 vesicles transported both coniferin and p-coumaryl alcohol glucoside, but inhibitor assays suggested that this transport was through the tonoplast. Membrane vesicles prepared from lignin-forming spruce cells showed coniferin transport, but the Km value for coniferin was much higher than those of xylem and BY-2 cells. Liquid chromatography-mass spectrometry analysis of membrane proteins isolated from spruce developing xylem, phloem, and lignin-forming cultured cells revealed multiple transporters. These were compared with a transporter gene set obtained by a correlation analysis with a selected set of spruce monolignol biosynthesis genes. Biochemical membrane vesicle assays showed no support for ABC-transporter-mediated monolignol transport but point to a role for secondary active transporters (such as MFS or MATE transporters). In contrast, proteomic and co-expression analyses suggested a role for ABC transporters and MFS transporters.
45
Dorsey, Caleb W., Marcelo E. Tolmasky, Jorge H. Crosa, and Luis A. Actis. "Genetic organization of an Acinetobacter baumannii chromosomal region harbouring genes related to siderophore biosynthesis and transport." Microbiology 149, no. 5 (May 1, 2003): 1227–38. http://dx.doi.org/10.1099/mic.0.26204-0.
Анотація:
The Acinetobacter baumannii 8399 clinical isolate secretes dihydroxybenzoic acid (DHBA) and a high-affinity catechol siderophore, which is different from other bacterial iron chelators already characterized. Complementation assays with enterobactin-deficient Escherichia coli strains led to the isolation of a cosmid clone containing A. baumannii 8399 genes required for the biosynthesis and activation of DHBA. Accordingly, the cloned fragment harbours a dhbACEB polycistronic operon encoding predicted proteins highly similar to several bacterial proteins required for DHBA biosynthesis from chorismic acid. Genes encoding deduced proteins related to the E. coli Fes and the Bacillus subtilis DhbF proteins, and a putative Yersinia pestis phosphopantetheinyl transferase, all of them involved in the assembly and utilization of catechol siderophores in other bacteria, were found next to the dhbACEB locus. This A. baumannii 8399 gene cluster also contained the om73, p45 and p114 predicted genes encoding proteins potentially involved in transport of ferric siderophore complexes. The deduced products of the p114 and p45 genes are putative membrane proteins that belong to the RND and MFS efflux pump proteins, respectively. Interestingly, P45 is highly related to the E. coli P43 (EntS) protein that participates in the secretion of enterobactin. Although P114 is similar to other bacterial efflux pump proteins involved in antibiotic resistance, its genetic arrangement within this A. baumannii 8399 locus is different from that described in other bacteria. The product of om73 is a Fur- and iron-regulated surface-exposed outer-membrane protein. These characteristics together with the presence of a predicted TonB box and its high similarity to other siderophore receptors indicate that OM73 plays such a role in A. baumannii 8399. The 184 nt om73–p114 intergenic region contains promoter elements that could drive the expression of these divergently transcribed genes, all of which are in close proximity to almost perfect Fur boxes. This arrangement explains the iron- and Fur-regulated expression of om73, and provides strong evidence for a similar regulation for the expression of p114.
46
Domínguez, Gonzalo, Eladio Cardiel, Elsa Sánchez, and Pablo-Rogelio Hernández. "Assessment of the effects of exposure to extremely low-frequency magnetic fields on MDCK epithelial cell lines under a controlled environment." Journal of Radiation Research 62, no. 2 (February 17, 2021): 259–68. http://dx.doi.org/10.1093/jrr/rrab001.
Анотація:
Abstract To assess the effects of exposure to extremely low-frequency magnetic fields (ELF-MFs) on MDCK cell lines, experiments were performed in a chamber under controlled conditions (temperature, humidity and CO2). Therefore, the measured physicochemical and electrical changes in the cells are due solely to the magnetic field exposure and not to external factors. A developed sinusoidal magnetic field generator produced the ELF-MFs with a uniform magnetic field and adjustable intensity and frequency. Three experimental indicators were used: (i) transepithelial electrical impedance (TEEI); (ii) cell migration and proliferation; and (iii) expression of the proteins of the tight junctions, and changes in the area and shape of the cell nuclei. No significant effects on TEEI values were observed when 10 and 50 G 60 Hz magnetic fields were applied to confluent cell monolayers. There were no significant differences in migration and proliferation of the cell monolayer exposed to 60 Hz magnetic fields10 and 50 G , but a contact inhibition factor was observed. The expression of the CLDN-1 protein decreased by 90% compared with the control, while ZO-1 protein expression increased by 120%. No significant effects were observed in the area and shape of the cell nuclei. Experimentation in a controlled environment, under physiological conditions, ensures that the observed effects were strictly due to exposure to magnetic fields. Different exposure conditions are necessary to determine the impact on TEEI and cell migration–proliferation indicators.
47
Leus, Inga V., Marcela Olvera, Justyna W. Adamiak, Lauren L. Nguyen, and Helen I. Zgurskaya. "Acinetobacter baumannii Survival under Infection-Associated Stresses Depends on the Expression of Resistance–Nodulation–Division and Major Facilitator Superfamily Efflux Pumps." Antibiotics 13, no. 1 (December 20, 2023): 7. http://dx.doi.org/10.3390/antibiotics13010007.
Анотація:
Multidrug efflux transporters are major contributors to the antibiotic resistance of Acinetobacter baumannii in clinical settings. Previous studies showed that these transporters are tightly integrated into the physiology of A. baumannii and have diverse functions. However, for many of the efflux pumps, such functions remain poorly defined. In this study, we characterized two putative drug efflux pumps, AmfAB and AmfCD (Acinetobacter Major Facilitator), that are homologous to EmrAB-like transporters from Escherichia coli and other Gram-negative bacteria. These pumps comprise the Major Facilitator Superfamily (MFS) transporters AmfB and AmfD and the periplasmic membrane fusion proteins AmfA and AmfC, respectively. We inactivated and overproduced these pumps in the wild-type ATCC 17978 strain and its derivative strains lacking the major efflux pumps from the Resistance–Nodulation–Division (RND) superfamily and characterized antibiotic susceptibilities and growth of the strains under stresses typical during human infections. We found that neither AmfAB nor AmfCD contribute to the antibiotic non-susceptibility phenotypes of A. baumannii. The two pumps, however, are critical for the adaptation and growth of the bacterium under acidic stress, whereas AmfCD also contributes to growth under conditions of low iron, high temperature, and in the presence of bile salts. These functions are dependent on the presence of the RND pumps, the inactivation of which further diminishes A. baumannii survival and growth. Our results suggest that MFS transporters contribute to stress survival by affecting the permeability properties of the A. baumannii cell envelope.
48
Hadjivassiliou, Marios, Mario Manto, and Hiroshi Mitoma. "Rare Etiologies in Immune-Mediated Cerebellar Ataxias: Diagnostic Challenges." Brain Sciences 12, no. 9 (August 30, 2022): 1165. http://dx.doi.org/10.3390/brainsci12091165.
Анотація:
The cerebellum is particularly enriched in antigens and represents a vulnerable target to immune attacks. Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies, such as gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Apart from these well-established entities, cerebellar ataxia (CA) occurs also in association with autoimmunity against ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells, as well as the brainstem antigens. Most of these conditions manifest diverse neurological clinical features, with CAs being one of the main clinical phenotypes. The term primary autoimmune cerebellar ataxia (PACA) refers to ataxic conditions suspected to be autoimmune even in the absence of specific well-characterized pathogenic antibody markers. We review advances in the field of IMCAs and propose a clinical approach for the understanding and diagnosis of IMCAs, focusing on rare etiologies which are likely underdiagnosed. The frontiers of PACA are discussed. The identification of rare immune ataxias is of importance since they are potentially treatable and may lead to a severe clinical syndrome in absence of early therapy.
49
Prasad, Rajendra, Atanu Banerjee, Nitesh Kumar Khandelwal, and Sanjiveeni Dhamgaye. "The ABCs of Candida albicans Multidrug Transporter Cdr1." Eukaryotic Cell 14, no. 12 (September 25, 2015): 1154–64. http://dx.doi.org/10.1128/ec.00137-15.
Анотація:
ABSTRACTIn the light of multidrug resistance (MDR) among pathogenic microbes and cancer cells, membrane transporters have gained profound clinical significance. Chemotherapeutic failure, by far, has been attributed mainly to the robust and diverse array of these proteins, which are omnipresent in every stratum of the living world.Candida albicans, one of the major fungal pathogens affecting immunocompromised patients, also develops MDR during the course of chemotherapy. The pivotal membrane transporters thatC. albicanshas exploited as one of the strategies to develop MDR belongs to either the ATP binding cassette (ABC) or the major facilitator superfamily (MFS) class of proteins. The ABC transporterCandidadrug resistance 1 protein (Cdr1p) is a major player among these transporters that enables the pathogen to outplay the battery of antifungals encountered by it. The promiscuous Cdr1 protein fulfills the quintessential need of a model to study molecular mechanisms of multidrug transporter regulation and structure-function analyses of asymmetric ABC transporters. In this review, we cover the highlights of two decades of research on Cdr1p that has provided a platform to study its structure-function relationships and regulatory circuitry for a better understanding of MDR not only in yeast but also in other organisms.
50
Callahan, Terrence M., Mark S. Rose, Maura J. Meade, Marilyn Ehrenshaft, and Robert G. Upchurch. "CFP, the Putative Cercosporin Transporter of Cercospora kikuchii, Is Required for Wild Type Cercosporin Production, Resistance, and Virulence on Soybean." Molecular Plant-Microbe Interactions® 12, no. 10 (October 1999): 901–10. http://dx.doi.org/10.1094/mpmi.1999.12.10.901.
Анотація:
Many species of the fungal genus Cercospora, including the soybean pathogen C. kikuchii, produce the phytotoxic polyketide cercosporin. Cercosporin production is induced by light. Previously, we identified several cDNA clones of mRNA transcripts that exhibited light-enhanced accumulation in C. kikuchii. Targeted disruption of the genomic copy of one of these, now designated CFP (cercosporin facilitator protein), results in a drastic reduction in cercosporin production, greatly reduced virulence of the fungus to soybean, and increased sensitivity to exogenous cercosporin. Sequence analysis of CFP reveals an 1,821-bp open reading frame encoding a 65.4-kDa protein similar to several members of the major facilitator superfamily (MFS) of integral membrane transporter proteins known to confer resistance to various antibiotics and toxins in fungi and bacteria. We propose that CFP encodes a cercosporin transporter that contributes resistance to cercosporin by actively exporting cercosporin, thus maintaining low cellular concentrations of the toxin.