The extracellular matrix polysaccharide hyaluronan (HA) exerts size-dependent effects on leukocyte behavior. Low-molecular weight HA is abundant at sites of active tissue catabolism and promotes inflammation via effects on Toll-like receptor signaling. Conversely, high-molecular weight HA is prevalent in uninjured tissues and is anti-inflammatory. We propose that the ability of high-molecular weight but not low-molecular weight HA to cross-link CD44 functions as a novel form of pattern recognition that recognizes intact tissues and communicates “tissue integrity signals” that promote resolution of local immune responses.

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Traveltime data from the 1993 Southern Sierra Nevada Continental Dynamics seismic refraction experiment reveal low crustal velocities in the southern Sierra Nevada and Basin and Range province of California (6.0 to 6.6 km/s), as well as low upper mantle velocities (7.6 to 7.8 km/s). The crust thickens from southeast to northwest along the axis of the Sierra Nevada from 27 km in the Mojave Desert to 43 km near Fresno, California. A crustal welt is present beneath the Sierra Nevada, but the deepest Moho is found under the western slopes, not beneath the highest topography. A density model directly derived from the crustal velocity model but with constant mantle density satisfies the pronounced negative Bouguer anomaly associated with the Sierra Nevada, but shows large discrepancies of >50 mgal in the Great Valley and in the Basin and Range province. Matching the observed gravity with anomalies in the crust alone is not possible with geologically reasonable densities; we require a contribution from the upper mantle, either by lateral density variations or by a thinning of the lithosphere under the Sierra Nevada and the Basin and Range province. Such a model is consistent with the interpretation that the uplift of the present Sierra Nevada is caused and dynamically supported by asthenospheric upwelling or lithospheric thinning under the Basin and Range province and eastern Sierra Nevada.

1These authors contributed equally to this study. SummaryRecently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1-week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulphated metabolite, 4-methylumbelliferyl sulphate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0Á65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice.