The effects of metabolism on the control of hyaluronan synthesis both in healthy and pathologic conditions are critical and still not completely understood. The hyaluronan capacity to bind several receptors triggering specific pathways may represent a valid target for new approach in several therapeutic strategies. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
BackgroundSchool closure is often considered as an option to mitigate influenza epidemics because of its potential to reduce transmission in children and then in the community. The policy is still however highly debated because of controversial evidence. Moreover, the specific mechanisms leading to mitigation are not clearly identified.MethodsWe introduced a stochastic spatial age-specific metapopulation model to assess the role of holiday-associated behavioral changes and how they affect seasonal influenza dynamics. The model is applied to Belgium, parameterized with country-specific data on social mixing and travel, and calibrated to the 2008/2009 influenza season. It includes behavioral changes occurring during weekend vs. weekday, and holiday vs. school-term. Several experimental scenarios are explored to identify the relevant social and behavioral mechanisms.ResultsStochastic numerical simulations show that holidays considerably delay the peak of the season and mitigate its impact. Changes in mixing patterns are responsible for the observed effects, whereas changes in travel behavior do not alter the epidemic. Weekends are important in slowing down the season by periodically dampening transmission. Christmas holidays have the largest impact on the epidemic, however later school breaks may help in reducing the epidemic size, stressing the importance of considering the full calendar. An extension of the Christmas holiday of 1 week may further mitigate the epidemic.ConclusionChanges in the way individuals establish contacts during holidays are the key ingredient explaining the mitigating effect of regular school closure. Our findings highlight the need to quantify these changes in different demographic and epidemic contexts in order to provide accurate and reliable evaluations of closure effectiveness. They also suggest strategic policies in the distribution of holiday periods to minimize the epidemic impact.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-017-2934-3) contains supplementary material, which is available to authorized users.
Hyaluronan (HA) is a glycosaminoglycan composed by repeating units of D-glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) that is ubiquitously present in the extracellular matrix (ECM) where it has a critical role in the physiology and pathology of several mammalian tissues. HA represents a perfect environment in which cells can migrate and proliferate. Moreover, several receptors can interact with HA at cellular level triggering multiple signal transduction responses. The control of the HA synthesis is therefore critical in ECM assembly and cell biology; in this review we address the metabolic regulation of HA synthesis. In contrast with other glycosaminoglycans, which are synthesized in the Golgi apparatus, HA is produced at the plasma membrane by HA synthases (HAS1-3), which use cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates. UDP-GlcUA and UDP-hexosamine availability is critical for the synthesis of GAGs, which is an energy consuming process. AMP activated protein kinase (AMPK), which is considered a sensor of the energy status of the cell and is activated by low ATP:AMP ratio, leads to the inhibition of HA secretion by HAS2 phosphorylation at threonine 110. However, the most general sensor of cellular nutritional status is the hexosamine biosynthetic pathway that brings to the formation of UDP-GlcNAc and intracellular protein glycosylation by O-linked attachment of the monosaccharide β-N-acetylglucosamine (O-GlcNAcylation) to specific aminoacid residues. Such highly dynamic and ubiquitous protein modification affects serine 221 residue of HAS2 that lead to a dramatic stabilization of the enzyme in the membranes.
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