Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic ...acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.
Serial focussed ion beam scanning electron microscopy (FIB/SEM) enables imaging and assessment of subcellular structures on the mesoscale (10 nm to 10 µm). When applied to vitrified samples, serial ...FIB/SEM is also a means to target specific structures in cells and tissues while maintaining constituents' hydration shells for in situ structural biology downstream. However, the application of serial FIB/SEM imaging of non-stained cryogenic biological samples is limited due to low contrast, curtaining, and charging artefacts. We address these challenges using a cryogenic plasma FIB/SEM. We evaluated the choice of plasma ion source and imaging regimes to produce high-quality SEM images of a range of different biological samples. Using an automated workflow we produced three-dimensional volumes of bacteria, human cells, and tissue, and calculated estimates for their resolution, typically achieving 20-50 nm. Additionally, a tag-free localisation tool for regions of interest is needed to drive the application of in situ structural biology towards tissue. The combination of serial FIB/SEM with plasma-based ion sources promises a framework for targeting specific features in bulk-frozen samples (>100 µm) to produce lamellae for cryogenic electron tomography.
The goal of this study was to determine whether the Revised NIOSH Lifting Equation (RNLE) CD-ROM training program, when used without an instructor, could adequately train RNLE users to properly ...understand and correctly apply the RNLE. If so, then it can be used to fill a current gap in delivering training to both health and safety professionals, and RNLE end-users that do not have access to instructors or traditional classroom training. Combinations of different training methods (computer-based via CD-ROM versus text-based, and instructor directed versus self-directed/self study) were evaluated as to their effectiveness in enhancing knowledge and skills regarding the proper use of the RNLE. Participants were assigned by classroom units to one of four different instructional groups: instructor led using CD-ROM, self study using CD-ROM training, instructor led using printed text, and self study using printed text. The effectiveness of the training was evaluated using written pre and post-training tests to determine the relative quality and appropriateness of the training materials and their delivery methods. Of particular interest was the performance of the self study using CD-ROM training group compared to both the self study using printed text and the instructor-led using text groups. The CD-ROM self study (without an instructor) was found to be significantly more effective than both the self study using printed text and the instructor-led using text with regards to training in the correct and accurate use of the Revised NIOSH Lifting Equation.
Minocycline, a member of the tetracycline family of antibiotics, is widely used in the treatment of acne. Its use has been associated with intrinsic staining of adult human teeth, bones, and soft ...tissues. It causes blackening of the thyroid glands in both animals and humans. It has been determined that the pigment is the product of an oxidation reaction. Laboratory studies have shown that the pigment formation can be induced by exposure to ultraviolet light in the presence of air, and that an antioxidant, such as ascorbic acid (vitamin C), can block its formation. The present study was undertaken to determine whether the antioxidant vitamin C could prevent the pigmentation of tissues of laboratory rats given minocycline. Based on other studies, one group of rats was given minocycline by stomach tube at a dose of 75 mg/kg/day, 5 days per week, for 6 weeks. A second experimental group was given the same regimen of minocycline plus a supplement of ascorbic acid at a level of 0.1% of the diet. A control group received no treatment at all; all rats were maintained on laboratory rats chow and water ad libitum. The rats were euthanized by carbon dioxide inhalation. Nasomaxillary bones, including central incisors, and thyroid glands were removed and fixed with 10% buffered formalin. Bones and teeth showed no gross signs of staining and, therefore, were not processed further. Thyroid glands were visibly darker in the minocycline group; specimens from all three groups were processed histologically. Microscopic examination revealed extensive deposits of black pigment throughout the follicles of the minocycline group, whereas the group receiving both minocycline and vitamin C showed no sign of pigmentation and were indistinguishable from controls. It is suggested that patients on long-term minocycline medication be monitored for thyroid function.
United in their opposition to the neo-conservatism underpinning America's current political strategies, the contributors offer a grounded critique of the real impact that these policies make, at home ...and abroad. Starting with a close analysis of the Bush administration and the neo-conservative hold on power in Washington, they move on to a broader historical analysis. They set today's topical issues in the context of what they see as a gradual shift towards the right in American politics, and the creeping corporatisation of American society. The contributors show that September 11 was used by the Bush administration to clamp down on civil liberties at home and to step up an aggressive line in foreign policy. The impact on American society, and societies elsewhere, has been deeply damaging. Ranging over this and other topics including the US economy, corporate crime and anti-environmentalism, this book is ideal for anyone who wants a critical introduction to current affairs issues, set within the broader context of America's history of foreign interventions and global capitalism.
Hydrogen peroxide readily penetrates the pulp chamber of freshly extracted teeth. This study was undertaken to determine whether carbamide peroxide also penetrates the pulp chamber. Freshly extracted ...teeth were sectioned 2 to 3 mm apical to the cementoenamel junction and the coronal pulpal tissue was removed. Acetate buffer was placed in the pulp chamber to absorb and stabilize any peroxide that might penetrate. The coronal portion of each tooth was immersed in either carbamide peroxide gel or gelled hydrogen peroxide at various concentrations for 15 min at 37 degrees C. The buffer was removed, leukocrystal violet was added, and the optical density of the resulting blue solution was determined spectrophotometrically. Amounts of peroxide found in the pulp chamber after 15 min ranged from 3.3 +/- 0.38 micrograms for the 10% sample to 40.4 +/- 3.51 micrograms for the 30% sample.
Tobacco products are known to cause oral soft-tissue lesions, but they may also directly affect the teeth. Abrasive particles contained in tobacco products may contribute to dental attrition. We ...studied tobacco samples from 16 brands of cigars, eight brands of snuff, four brands of chewing tobacco and several unprocessed tobacco leaves used as cigar wrappers. Insoluble particulate matter made up about 0.5 percent of the weight of an average tobacco sample.
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