An archeomagnetic study was carried out on potsherds samples from sites in Ontario with ages ranging from A.D. 90 to A.D. 1640 as determined by 14 C dating. Thellier double‐heating paleointensity experiments were performed in air on 65 specimens of 52 samples from seven sample sets. Reliable paleointensity estimates were obtained for 49 specimens. Alternating field and thermal demagnetization, temperature dependence of weak‐field susceptibility, and hysteresis measurements indicate that magnetite of pseudo‐single‐domain grain size is the carrier of natural remanent magnetization. The paleointensity results follow a half‐cycle sine curve, with a steady decrease from 54.0±5.9 μT to 37.6±5.7 μT between A.D. 90 and A.D. 885 and a monotonic increase from 52.0±6.1 μT to 59.4±1.7 μT between A.D. 1200 and A.D. 1900. The paleointensities determined yield virtual axial dipole moments (VADMs) of the Earth's magnetic field that agree well with those from other parts of North America, except between A.D. 900 and A.D. 1400, when they are systematically lower. This discrepancy is probably caused by a substantial non‐dipole field in southwestern North America from the tenth to the fifteenth century, since secular variation studies using potsherds from Arizona and lake sediments from Minnesota show different inclination variations during that period.
The best-characterized Toll-like receptor 4 (TLR4) ligands are lipopolysaccharide (LPS) and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL). Although both molecules are active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants.
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