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Preparation of human nuclear RNA m6A methyltransferases and demethylases and biochemical characterization of their catalytic activity. Fate by RNA methylation: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell , 27 , Base-resolution maps of 5-formylcytosine and 5-carboxylcytosine reveal genome-wide DNA demethylation dynamics.
Detection of mismatched 5-hydroxymethyluracil in DNA by selective chemical labeling. Methods , 72 , Pseudouridine in a new era of RNA modifications. Visualizing a protein's sugars. TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator.
Unique features of the m 6 A methylome in Arabidopsis thaliana. UO Uptake by Proteins: Dynamic RNA modifications in posttranscriptional regulation. Application of a low cost array-based technique - TAB-Array - for quantifying and mapping both 5mC and 5hmC at single base resolution in human pluripotent stem cells. Genomics , , Small , 10 , Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Synthesis of a FTO inhibitor with anticonvulsant activity.
Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain. Dynamics of spontaneous flipping of a mismatched base in DNA duplex. The dynamics of DNA methylation fidelity during mouse embryonic stem cell self-renewal and differentiation. Reading RNA methylation codes through methyl-specific binding proteins. Programming and inheritance of parental DNA methylomes in mammals. Steady-state hydrogen peroxide induces glycolysis in Staphylococcus aureus and Pseudomonas aeruginosa.
Gene expression regulation mediated through reversible m 6 A RNA methylation. Molecular mechanism and structure of the Saccharomyces cerevisiae iron regulator Aft2. Nucleic acid oxidation in DNA damage repair and epigenetics.
A protein engineered to bind uranyl selectively and with femtomolar affinity. N 6-methyladenosine-dependent regulation of messenger RNA stability. The multiple antibiotic resistance regulator MarR is a copper sensor in Escherichia coli. Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions. Probing subcellular organic hydroperoxide formation via a genetically encoded ratiometric and reversible fluorescent indicator.
Integrative Biology , 5 , A highly sensitive and genetically encoded fluorescent reporter for ratiometric monitoring of quinones in living cells. Global epigenomic reconfiguration during mammalian brain development. Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis. Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency.
ALKBH4-dependent demethylation of actin regulates actomyosin dynamics. Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation.
Sprouts of RNA epigenetics: The discovery of mammalian RNA demethylases. Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR. Tet-mediated covalent labelling of 5-methylcytosine for its genome-wide detection and sequencing. Enhanced 5-methylcytosine detection in single-molecule, real-time sequencing via Tet1 oxidation. Cold Spring Harb Perspect Biol. Reversible RNA adenosine methylation in biological regulation. Trends in Genetics , 29, Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine.
Cancer Cell , 22 , Mapping recently identified nucleotide variants in the genome and transcriptome. Nucleic acid modifications with epigenetic significance. Current Opinion in Chemical Biology , Balance of DNA methylation and demethylation in cancer development.
Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum.
The oxidation-sensing regulator MosR is a new redox dependent transcription factor in Mycobacterium tuberculosis. A selective fluorescent probe for carbon monoxide imaging in living cells. Panorama of DNA hairpin folding observed via diffusion-decelerated fluorescence correlation spectroscopy. Tetrahedron , 68 , Isopeptide bonds of the major pilin protein BcpA influence pilus structure and bundle formation on the surface of Bacillus cereus. Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA.
Staphylococcus aureus CymR is a new thiol-based oxidation-sensing regulator of stress resistance and oxidative response. Pseudomonas aeruginosa global regulator VqsR directly inhibits QscR to control quorum-sensing and virulence gene expression. Heterologous expression and purification of Arabidopsis thaliana VIM1 protein: In vitro evidence for its inability to recognize hydroxymethylcytosine, a rare base in Arabidopsis DNA. Differential function of lip residues in the mechanism and biology of an anthrax hemophore.
Expression of multidrug resistance efflux pump gene norA is iron-responsive in Staphylococcus aureus. Binding of ReO 4 - with an engineered MoO 4 2- -binding protein: Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. The hunt for 5-hydroxymethylcytosine: Selective fluorescent probes for live-cell monitoring of sulphide. Targeting MgrA-mediated virulence regulation in Staphylococcus aureus. Selective recognition of americium by peptide-based reagents.
Science , , Structural and biochemical characterization of N5-carboxyaminoimidazole ribonucleotide synthetase and N5-carboxyaminoimidazole ribonucleotide mutase from Staphylococcus aureus. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell , 20 , Detection of 5-hydroxymethylcytosine in DNA by transferring a keto-glucose by using T4 phage beta-glucosyltransferase.
ChemBioChem , 12 , Detection of 5-hydroxymethylcytosine in a combined glycosylation restriction analysis CGRA using restriction enzyme Taq alpha I. Syntheses of two 5-hydroxymethyl-2'-deoxycytidine phosphoramidites with TBDMS as the 5-hydroxymethyl protecting group and their incorporation into DNA.
Metal-binding properties of Hpn from Helicobacter pylori and implications for the therapeutic activity of bismuth. Redox Signaling in Human Pathogens. Aureusimines in Staphylococcus aureus are not involved in virulence. PLoS One , 5 , e [pdf]. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Structural insight into the oxidation sensing mechanism of the antibiotic resistance regulator MexR.
CcpA mediates proline auxotrophy and is required for the pathogenesis of Staphylococcus aureus infections. In this step, flagella [ 20 , 21 ] and chemotaxis play an important role avoiding the action of the hydrodynamic and repulsive forces as well as selecting the surface [ 22 ], respectively.
In the case of E. In the case of P. It has been observed that P. On the other hand, P. Production of polysaccharides in biofilm forming strains facilitates aggregation, adherence, and surface tolerance, allowing better surface colonization [ 31 ]. Alginate is the main and most studied capsular polysaccharide produced by P.
On the other hand, aggregative polysaccharides confer structural integrity to the biofilm [ 35 ]. Nucleic acids, such as DNA, proteins, surfactants, lipids, glycolipids, membrane vesicles, and ions such as calcium can also be found forming part of the matrix composition and may play an important role in the characteristics that biofilm structure confers to the cells. These three-dimensional structures with macrocolony morphology depend on self-produced extracellular matrix components.
EPS, adhesins, amyloid-forming proteins, and exopolysaccharides all included in biofilm matrix are required to generate these structures in which gradients of nutrients, water, signaling compounds or waste products are present along the different areas of biofilm [ 36 ], conditioning the metabolism of the cells. Detachment allows cells to again take on a planktonic state and can thereby form biofilm in other settings. It has been proposed that bacteria detachment could be caused by active mechanisms initiated by the bacteria themselves such as enzymatic degradation of the biofilm matrix and quorum sensing in response to environmental changes related to nutrition levels and oxygen depletion [ 37 ] and by passive mechanisms mediated by external forces and erosion [ 38 — 41 ].
Biofilm dispersal is an important step in a high number of bacterial species, allowing their transmission from environment to human host, between hosts, and even within a single host spreading the infection [ 39 ]. The role of c-di-GMP levels in the biofilm dispersion has recently been determined, being a second messenger used in signal transduction in a high number of bacteria species [ 42 ].
Thus, it has been proposed that high levels of c-di-GMP increase the sessile behaviour of the bacteria, while low levels increase the motility of the bacteria [ 43 ]. Nowadays, this second messenger is the subject of further research for further review see [ 45 , 46 ]. Biofilms can also be found inside the host cells forming intracellular structures.
The first report of intracellular bacterial communities IBC with biofilm-like properties was described in uropathogenic E. It has been observed that a high number of IBC are associated with the development of chronic cystitis [ 47 , 48 ].
The presence of IBC has also been described in children with recurrent urinary infections by light and confocal laser scanning microscopy. These structures have been associated with an E. As previously commented, bacterial biofilms play an important role in medicine.
Biofilm can be found in the urothelium, prostate stones, and implanted foreign bodies [ 50 ]. Bacteria adhered to the uroepithelium and forming biofilm can invade the renal tissue causing pyelonephritis [ 51 ] and even be responsible for chronic bacterial prostatitis. In the latter case, an additional problem is the difficulties to diagnosis this prostatitis because the colonized bacteria may not be present in the prosthetic secretion or the urine samples [ 52 ]. Biofilms can not only develop into urethral stents but they can also form on catheters causing their blockage.
The environmental conditions created on the catheter surface make it an ideal site for bacterial attachment and formation of biofilm structures [ 55 ]. In this type of medical device, microorganisms producing urease, an enzyme that hydrolyzes urea to ammonium ions, can cause encrustation, formation of infected bladder calculi, and urinary obstruction. The formation of ammonium ions increases the pH of the urine, finally causing the precipitation of magnesium and calcium phosphate crystals [ 56 , 57 ].
The pH value at which precipitation occurs is called nucleation pH [ 58 ]. These crystals can form a layer that protects bacteria from the antimicrobial effects of compounds used for coating or impregnating the catheters [ 59 ].
Proteus mirabilis is the main source of this problem in urinary infections [ 60 ] and presents several virulence factors that allow it to form biofilm such as mannose-resistant fimbriae, capsules, and urease [ 61 ]. Other microorganisms such as Proteus vulgaris and Providencia rettgeri also have the capacity to produce crystalline biofilms [ 56 ].
In addition, biofilm formation may even result in the increased ability of strains causing acute prostatitis to persist in the prostatic secretory system and lead to the recurrent UTIs characteristic of chronic bacterial prostatitis [ 62 ]. In fact, it has been shown that after an episode of acute prostatitis cultures of expressed prostatic secretions are still positive 3 months after the end of a 6-week therapeutic regimen in one-third of men [ 63 ]. Biofilm formation may be the reason why bacterial prostatitis is so difficult to eradicate using conventional treatments.
Recurrent UTIs are common among young, healthy women, despite their urinary tracts generally being anatomically and physiologically normal [ 64 ]. Consequently, the number of studies to elucidate the factors predisposing recurrent UTI in order to develop effective methods of prevention and therapy is encouraged to be increased [ 65 ].
Relapse by uropathogenic E. In these cases, biofilm production may be the key determinant for the persistence of UPEC in the vaginal reservoir, the bladder epithelial cells, or both. Thus, in a study carried out in the Hospital Clinic of Barcelona, 43 ambulatory female patients 18 years of age were included following an index episode of cystitis or pyelonephritis, and they were clinically followed for at least 6 months, collecting urine cultures every month.
One of the most important advantages of biofilm status is the antimicrobial resistance shown by these structures. Biofilm can be up to fold more resistant to antibiotics than planktonic cells due to several mechanisms [ 67 — 71 ]. Some antimicrobial agents are unable to diffuse through the matrix or sometimes the time required for the antibiotic to penetrate into biofilm is longer than the duration of treatment or the antibiotic lifetime. Thus, plasmids, transposons, and other mobile genetic elements can be transmitted between cells forming biofilm by their close relationship, spreading resistance markers.
Antibiotics able to diffuse can be inactivated by the pH inside biofilm. This change in the pH could antagonise the activity of the antibiotic. Persisters are dormant variants of regular cells, not mutants, which may form small colony variants that are high tolerant to extracellular stresses.
They are highly tolerant to antibiotics forming a reservoir of surviving cells [ 74 ] able to rebuild the biofilm population [ 74 — 76 ]. The tolerance to antibiotics could be explained by their reduced metabolism and their ability to switch off the antibiotic targets, such as protein synthesis or DNA replication.
The acquisition of this persister status is mediated by toxin-antitoxin modules [ 77 ]. Taking into account that several antimicrobial agents, such as penicillin, only kill actively growing bacteria, persister cells are a problem for biofilm eradication. Proteins required for maintaining persisters may represent excellent targets for the discovery of compounds capable of effectively treating chronic infections and biofilm-related infections. The level of resistance depends on biofilm stage.
Thus, in the reversible attachment step, antibiotics and antibiofilm are the most effective, because the bacteria have not connected themselves in the matrix and are vulnerable to the action of antibiotics and host immune system [ 19 ]. Once the bacteria begin to secrete EPS and the attachment becomes irreversible, biofilm is more resistant to antibiotics and host immune responses [ 78 ].
The matrix protects the cells within it from exposure to innate immune defences and antimicrobial treatments [ 79 , 80 ] and facilitates communication among them through biochemical signals. Some biofilms have been found to contain water channels that help to distribute nutrients and signalling molecules [ 81 ]. Other studies suggest that resistance of bacteria in biofilm to a high number of antibiotics can be due to the density and physiological state of the culture rather than their residence within biofilm [ 82 ].
In addition, the spread of resistance markers and virulence factors can be promoted through their structure [ 83 ]. It has been demonstrated that the mode of growth of biofilm increases the ability of S. This phenomenon could be facilitated by the close cell-to-cell contact inside biofilms and also by the stabilization of these contacts that may be favored by the biofilm matrix.
Treatment of biofilm-associated infections is a field that requires further study, in part due to the high levels of antibiotic resistance exhibited by biofilm structures conferred in part by the exopolysaccharide matrix.
Several studies recommend combination therapy as the treatment of choice in biofilm-associated infections, with macrolides being one of the first antibiotics chosen [ 85 ]. Macrolides have been shown to be effective against P. The antibiotic combination, clarithromycin plus vancomycin, demonstrated the ability to eradicate both biofilm and planktonic cells [ 87 ] as well as to eradicate biofilm on the titanium washers used in animal experiments [ 88 ]. Roxithromycin plus imipenem favour a higher penetration of neutrophils into biofilm structure destabilizing the biofilm [ 89 ].
Conversely, macrolides have been shown to enhance biofilm formation in Gram-positive bacteria due to an increase in the expression of biofilm-related genes such as ica A, atl E, fru A, pyr R, sar A, and sig B [ 90 ]. This fact has an important clinical implication because the macrolide levels needed for enhancing biofilm formation could be found in clinical niches or settings.
Another approach using antimicrobials consists in coating and impregnating the catheters with these antimicrobial agents. The aim of this procedure is to avoid bacterial attachment to the catheter surface and the posterior development of biofilm [ 91 ]. In this sense, the silver has also been used to coat catheters because it has bactericidal actions.
Silver has broad-spectrum antimicrobial activity. The antimicrobial action of silver compounds is proportional to the bioactive silver ion released and its availability to interact with bacterial or fungal cell membranes. Synthetic cationic peptide variants derived from natural peptides have been used as strategy to target biofilm [ 94 ].
More recently, some substances showing antibacterial properties, such as gendine gentian violet plus chlorhexidine , nitrous oxide, and nitrofurazone nitrofuran , have been used to modify the surface of urinary catheters.
However, the risk of using antibiotics to treat the catheter surface may lead to the development of antimicrobial resistance when the drug levels become subinhibitory [ 60 ]. Biofilms eradication is difficult due to the high level of antimicrobial resistance showed by these structures.
In spite of the previously commented approaches, new therapeutic options are being studied as an alternative to treatments with existing antibiotics in order to avoid not only biofilm formation but also the emergence of resistant bacterial populations in underlying tissues. Here a review of these new approaches is provided. Hydrogels are cross-linked, insoluble, hydrophilic polymers that trap water.
This characteristic provides the catheter with an increase in surface lubrication which consequently decreases the bacterial adhesion to this surface and demonstrates a role in the reduction of encrustation of catheters.
However, the ability of these hydrogels to prevent CAUT remains unclear [ 95 ]. However, this negative effect was suppressed when active agents were added to the hydrogel. In this sense, a high number of antimicrobial agents and other chemical compounds have been used to coat catheters.
Minocycline-rifampicin-coated catheters have been shown to inhibit the biofilm formation of Gram-positive and Gram-negative pathogens, except P. However, one problem with this may be the possible development of resistant phenotypes among the bacteria [ ]. However, no silver-resistant mutants were collected in the aforementioned studies.
Nanoparticle research is currently an area of intense scientific interest due to a wide variety of potential applications in biomedical, optical, and electronic fields.
These particles have the capacity to attach and penetrate into bacterial cells, disrupt the bacterial membrane, and interact with chromosomal DNA [ ]. Nanoparticles of MgF have been used for coating glass surfaces observing an inhibition of biofilm formation by both, E. Catheters have also been coated with these nanoparticles and a significant reduction of bacterial colonization was observed over a period of 1 week in comparison with the catheter uncoated catheter control.
This group also demonstrated the antibacterial and antibiofilm activity of yttrium fluoride YF 3 nanoparticles which showed low solubility and provided extended protection. In addition, another advantage of these nanoparticles was their low cytotoxicity [ ]. Microwave irradiated CaO nanoparticles CaO-NPs have also shown the potential to inhibit biofilm formation against Gram-negative and Gram-positive bacteria [ ].
Silver nanoparticles have also been used for impregnating medical devices due to the silver antimicrobial properties previously commented in this review [ ]. These nanoparticles have been used in medical and pharmaceutical nanoengineering applied to the delivery of therapeutic agents, diagnostic approaches, and as part of biosensors [ ].
However, the mechanism of action of silver nanoparticles remains unknown [ ]. Another aspect related to silver nanoparticles is the toxicity to eukaryotic cells which remains uncharacterized. Iontophoresis is a physical process in which ions flow diffusively in a medium driven by an applied electric field. Thus, it has been observed that low electrical currents enhance the activity of tobramycin and biocides against P. However, this effect has only been observed among those antibiotics that are effective against planktonic cells [ ].