197 research outputs found

    The dental plaque biofilm matrix

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    The extracellular matrix is a critical component of microbial biofilms, such as dental plaque, maintaining the spatial arrangement of cells and coordinating cellular functions throughout the structure. The extracellular polymeric substances that comprise the matrix include carbohydrates, nucleic acids, proteins, and lipids, which are frequently organized into macromolecular complexes and/or are associated with the surfaces of microbial cells within the biofilm. Cariogenic dental plaque is rich in glucan and fructan polysaccharides derived from extracellular microbial metabolism of dietary sucrose. By contrast, the matrix of subgingival dental plaque is a complex mixture of macromolecules that is still not well understood. Components of the matrix escape from microbial cells during lysis by active secretion or through the shedding of vesicles and serve to anchor microbial cells to the tooth surface. By maintaining the biofilm in close association with host tissues, the matrix facilitates interactions between microorganisms and the host. The outcome of these interactions may be the maintenance of health or the development of dental disease, such as caries or periodontitis. The matrix affords microbial cells protection against chemical and physical insults and hinders the eradication of pathogenic dental plaque. Therefore, strategies to control the matrix are critical to maintain oral health. This review discusses recent advances in our understanding of the composition, origins, and function of the dental plaque matrix, with a focus on subgingival dental plaque. New strategies to control subgingival dental plaque based on targeting the biofilm matrix are also considered

    Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment

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    The rising number of multi-drug resistant tuberculosis (MDR-TB) cases worldwide prompted the World Health Organisation (WHO) to release an emergency update on the guidelines for the management of drug-resistant TB. These guidelines recommended that treatment of MDR-TB should include at least 4 effective drugs and that standardised treatment regimens should be based on resistance patterns for each country/region. Most importantly, treatment regimens should not be dependant on results of drug susceptibility testing (DST) for ethambutol (EMB) or pyrazinamide (PZA). In response, the South African Department of Health has prepared a draft drug-resistant TB treatment policy in which PZA remains one of the 4 effective drugs, while EMB should be replaced with terizidone or cycloserine, if resistant to EMB (disregarding inaccurate DST). Analyses of recent drug-resistance patterns in South Africa indicate a high frequency of undetected EMB and PZA resistance and their association with MDR-TB. Accordingly, we recommend that the WHO guidelines be followed more closely in which 4 other effective drugs are used to treat MDR-TB. EMB and PZA can be included provided they are not counted as one of the four effective drugs. However these guidelines do not address the root cause of the amplification of resistance in undiagnosed MDR-TB patients in South Africa. This can only be achieved by the implementation of rapid DST methods in all TB cases prior to initiation of therapy. Ultimately this would curb the amplification of resistance and the evolution of XDR -TB

    The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma

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    Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed

    Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe

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    Human serum transferrin (hTF) binds Fe(III) tightly but reversibly, and delivers it to cells via a receptor-mediated endocytosis process. The metal-binding and release result in significant conformational changes of the protein. Here, we report the crystal structures of diferric-hTF (Fe N Fe C-hTF) and bismuth-bound hTF (Bi N Fe C-hTF) at 2.8 and 2.4 Å resolutions respectively. Notably, the N-lobes of both structures exhibit unique 'partially-opened' conformations between those of the apo-hTF and holo-hTF. Fe(III) and Bi(III) in the N-lobe coordinate to, besides anions, only two (Tyr95 and Tyr188) and one (Tyr188) tyrosine residues, respectively, in contrast to four residues in the holo-hTF. The C-lobe of both structures are fully closed with iron coordinating to four residues and a carbonate. The structures of hTF observed here represent key conformers captured in the dynamic nature of the transferrin family proteins and provide a structural basis for understanding the mechanism of metal uptake and release in transferrin families. © 2012 Macmillan Publishers Limited. All rights reserved.published_or_final_versio

    Updated Nucleosynthesis Constraints on Unstable Relic Particles

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    We revisit the upper limits on the abundance of unstable massive relic particles provided by the success of Big-Bang Nucleosynthesis calculations. We use the cosmic microwave background data to constrain the baryon-to-photon ratio, and incorporate an extensively updated compilation of cross sections into a new calculation of the network of reactions induced by electromagnetic showers that create and destroy the light elements deuterium, he3, he4, li6 and li7. We derive analytic approximations that complement and check the full numerical calculations. Considerations of the abundances of he4 and li6 exclude exceptional regions of parameter space that would otherwise have been permitted by deuterium alone. We illustrate our results by applying them to massive gravitinos. If they weigh ~100 GeV, their primordial abundance should have been below about 10^{-13} of the total entropy. This would imply an upper limit on the reheating temperature of a few times 10^7 GeV, which could be a potential difficulty for some models of inflation. We discuss possible ways of evading this problem.Comment: 40 pages LaTeX, 18 eps figure

    On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

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    A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

    New insights into the genetic etiology of Alzheimer's disease and related dementias

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    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele
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