High shear enhances the adhesion of Escherichia coli bacteria binding to mannose coated surfaces via the adhesin FimH, raising the question as to whether FimH forms catch bonds that are stronger under tensile mechanical force. Here, we study the length of time that E. coli pause on mannosylated surfaces and report a double exponential decay in the duration of the pauses. This double exponential decay is unlike previous single molecule or whole cell data for other catch bonds, and indicates the existence of two distinct conformational states. We present a mathematical model, derived from the common notion of chemical allostery, which describes the lifetime of a catch bond in which mechanical force regulates the transitions between two conformational states that have different unbinding rates. The model explains these characteristics of the data: a double exponential decay, an increase in both the likelihood and lifetime of the high-binding state with shear stress, and a biphasic effect of force on detachment rates. The model parameters estimated from the data are consistent with the force-induced structural changes shown earlier in FimH. This strongly suggests that FimH forms allosteric catch bonds. The model advances our understanding of both catch bonds and the role of allostery in regulating protein activity.
Background-Neovasculature within atherosclerotic plaques is believed to be associated with infiltration of inflammatory cells and plaque destabilization. The aim of the present investigation was to determine whether the amount of neovasculature present in advanced carotid plaques can be noninvasively measured by dynamic, contrast-enhanced MRI. Methods and Results-A total of 20 consecutive patients scheduled for carotid endarterectomy were recruited to participate in an MRI study. Images were obtained at 15-second intervals, and a gadolinium contrast agent was injected coincident with the second of 10 images in the sequence. The resulting image intensity within the plaque was tracked over time, and a kinetic model was used to estimate the fractional blood volume. For validation, matched sections from subsequent endarterectomy were stained with ULEX and CD-31 antibody to highlight microvessels. Finally, all microvessels within the matched sections were identified, and their total area was computed as a fraction of the plaque area. Results were obtained from 16 participants, which showed fractional blood volumes ranging from 2% to 41%. These levels were significantly higher than the histological measurements of fractional vascular area. Nevertheless, the 2 measurements were highly correlated, with a correlation coefficient of 0.80 (PϽ0.001). Conclusions-Dynamic contrast-enhanced MRI provides an indication of the extent of neovasculature within carotid atherosclerotic plaque. MRI therefore provides a means for prospectively studying the link between neovasculature and plaque vulnerability. Key Words: magnetic resonance imaging Ⅲ contrast media Ⅲ carotid arteries Ⅲ atherosclerosis R ecent investigations have targeted neovasculature as an important factor contributing to atherosclerotic plaque vulnerability. Zamir and Silver 1 speculated that the presence of neovasculature within coronary artery walls may play a role in the pathogenesis of vascular disease. Kumamoto et al 2 showed that intimal neovasculature arising from the adventitial vasa vasorum was associated with inflammatory infiltrate. A role for neovasculature in the recruitment of leukocytes to the shoulder regions of lipid-rich plaques was proposed by de Boer et al. 3 Because such inflammatory cells are present at the sites of plaque rupture, 4 neovasculature may be a contributor to or a marker for vulnerable plaque. Support for this claim is provided by Mofidi et al, 5 who found higher microvessel counts in carotid endarterectomy specimens from symptomatic patients than from asymptomatic ones. Similarly, McCarthy et al 6 found microvessels in symptomatic patients were larger and more irregular in shape.These studies suggest that an imaging tool capable of measuring the extent of plaque neovasculature could be invaluable for identifying high-risk plaques or assessing the response to plaque-stabilizing therapies. A strong contender for measuring plaque neovasculature is MRI using an intravenously injected contrast-enhancing agent. Contrastenhanced (CE) MRI h...
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