To date, two techniques of tooth whitening have been described: 1) Ambulatory (at home) that needs an intraoral device (tray) to apply the gel of peroxide, this one is more cost-effective, the value of the dental color obtained is sustained for long periods; but important changes in this value are not observed before 7th day of the treatment; and 2) in-office (by a professional) that uses photo-activation, this one allows changes in the color of the enamel from the first session, although there is strong evidence that the value of the dental color obtained is not sustained after 6 months [3-5].

Ameri confirmed on a study in Iran that the number of patients who wish to have tooth whitening treatment has increased by over 300% in the last 5 years; however, dentists often encounter the situation that patients prefer the office technique that involves photo-activation. There is evidence that photo-activation with Laser Light Emitting Diodes (LED) used on the in-office technique just turned out to be more advantageous than ambulatory technique, when compared with halogen lamps and lasers, noticing that in the ambulatory technique, the changes in the value of dental color are not observed up to 7 days of treatment. According to Sias and Abdul, the changes obtained in the value of the dental color through a home bleaching technique with 10% carbamide peroxide is held until 2 years after the procedure [4, 5].

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I too recently purchased much the same retail version of MS Office for Mac2019 - at enormous expense I might add, reckoning that, once installed, it'd probably serve me well for around three years minimum. Previous editions of Office for Mac had. Don't know if yours is similar but with mine (the H & S version) you have to sign in to the MS account in order to manage it, and there's a setting for that on the Office menu bar at top of screen. I recall also that you have to look in your e-mail inbox for a confirmation message from Microsoft.

The revelation (if worthy calling it that) from you that my trouble may have been caused by their server being down is interesting, nonetheless. I have, however, embarked now on using LibreOffice instead, the free open-source office software. I've yet to actually install LO. But at least LO is pitched at serious users and not at the frivolous who accumulate short, inconsequential files where it doesn't matter if they get exposed/eventually hacked on a server somewhere.

MS Office was, for some decades, a stalwart applications suite that was IMHO well-designed but I'm afraid that in recent years Microsoft has dumbed down many of its features, seemingly preferrring to appeal to the less-serious office software user using mobile devices.

Before that, when I first opened the document onscreen it was enlarged and beautifully clear, and it was a simple matter of then just setting a suitable default zoom level. Between the original and the Writer version of the document there was a slight change in layout, affecting the breaking of paragraphs across the page boundaries, but again that was ultra-simple to put right. Possibly, I'll need to refine some of the page layout settings to get the headers and footers more like they were for me in MS Word. But, thus far, I'm as pleased as punch. I've not tried using any of the other apps in the suite yet, though. These days, where office work's concerned, it's word-processing that I'm engaged in most of the time.

SIRT1, the founding member of the mammalian family of seven NAD+-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.

Sirtuins are a family of highly conserved NAD+-dependent deacylases that have been linked to a number of important biological processes across a broad span of diverse organisms such as Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophilla melanogaster and Mus musculus, among others1,2. Sirtuins generally catalyze the deacylation of modified lysine residues in protein substrates coupled with the breakdown of NAD+ into nicotinamide (NAM) and 2'-O-acyl-ADP-ribose. Of the seven sirtuins (SIRT1-7) that have been identified in mammals3, human SIRT1 (hSIRT1) is the most studied isoform, and has been shown to be regulated by calorie restriction and to be involved in multiple biological processes4,5,6,7. The validated, protective role of increased mammalian SIRT1 activity in metabolic disorders8, neurodegeneration9 and inflammation10,11 makes this enzyme an attractive therapeutic target. To this end, the development of pharmacological approaches to increase the enzymatic activity of hSIRT1 might lead to a new generation of therapeutic agents for a wide spectrum of diseases associated with aging. Small molecule sirtuin-activating compounds (STAC) have been developed which increase the catalytic deacetylation of specific Lys residues by hSIRT1 in multiple substrates, resulting in a variety of biological responses12,13,14. However, the molecular mechanism of hSIRT1 activation by STACs remains controversial. Questions as to whether STACs directly activate hSIRT1 persist15 despite evidence of allosteric activation13. Recently, a single point mutation of the Glu230 residue of hSIRT1 has been shown to attenuate kinetic activation by STACs16, further demonstrating a direct effect on hSIRT1. Structural characterizations of hSIRT1 fragments have shed light on the inhibitor binding and key regulatory element17,18. Similar to other sirtuins, hSIRT1 catalytic domain contains a Rossmann-fold large lobe and a zinc-binding small lobe and undergoes a significant conformational change of domain closure upon substrate/ligand occupying the active site19,20,21. However, the molecular details governing the binding of STACs to SIRT1 remain elusive, due to the difficulty in obtaining a detailed X-ray crystallographic structure of the full-length enzyme. To address this, we developed an engineered hSIRT1 (mini-hSIRT1) that is biochemically equivalent to the full-length enzyme with respect to basal catalytic activity and activation by STACs. X-ray crystallographic analysis of mini-hSIRT1 resulted in the first detailed structural determination of a fully functional human SIRT1 with a bound small molecule activator. The details of STAC binding to mini-hSIRT1 were translated to the full-length enzyme using structure-guided mutagenesis which corroborated the importance of key amino acids in the binding of STACs. These data are important in elucidating the molecular basis for STAC-mediated activation of hSIRT1 which will be critical for the development of future therapeutic agents.

Interestingly, a STAC-mediated dimer of mini-hSIRT1 related by crystallographic symmetry was observed in the crystal lattices (Fig. 2d). Size exclusion chromatography (SEC) indicates that the apparent size of mini-hSIRT1 increases in the presence of STAC 1, which is likely correspondent to the mini-hSIRT1 dimer species (Supplementary Fig. 4). We are currently attempting to determine if the observed crystallographic dimer has any relevance in the observed biology of STAC-mediated SIRT1 activation.

We used site-directed mutagenesis on the full-length hSIRT1 to confirm the key residues of the SBD that were identified by the mini-hSIRT1 structures. The following point mutants of full-length hSIRT1 were generated probing three classes of residues: (a) residues which appear to directly interact with STACs (T219A, I223A, N226A and I227A); (b) SBD residues with no apparent role in activator binding (Q222A and V224A); and (c) Glu230, previously demonstrated to be important for SIRT1 activation16 (E230K, E230A and E230Q) (Fig. 2b). None of the mutants significantly impaired the basal catalytic activity using the Ac-p53(W5) substrate or affected inhibition by EX-527, a Trifluoroacetic acid (TFA)-p53 peptide (Ac-RHK-KTFA-L-Nle-F-NH2), or NAM (Supplementary Tables 4 and 5). 589ccfa754

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