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Conformational states governing the rates of spontaneous transition mutations.

We report the results of a theoretical study, combining the results of sequence analysis and integral equation structural methods for nucleic acids in aqueous solutions, on the effects of nearest neighbors on the (T.G) mispair in solution, for 12 nearest neighbor contexts. Attempts have been made to classify the structural and energetic effects of the 5' and 3' neighbors with respect to the observed spontaneous mutation rates in vertebrates. It is found that 5' nearest neighbor is probably the most critical structural factor in facilitating or discouraging mutations. Local conformational states correlate with discrimination of bases to be excised in mispairs. Our study confirms the role of the flexibility of the DNA molecule in governing the rates of spontaneous mutations.

Base Composition↗

The implementation of workplace violence policy in state government.

Workplace violence has received an increasing amount of attention in the last five years. While it is difficult to conclude that it is actually escalating, the numerous studies do provide numbers that lead one to believe that it is a serious problem. Although agencies and corporations are beginning to develop workplace violence policies, there is no published research that documents the results of the implementation of such policies. The current research examines North Carolina state employees' familiarity with their new workplace violence policy and reporting procedures, how uniformally the policy is being utilized, victims' perceptions of their agencies' responses to their own violent incidents, and their generalized perceptions of the agencies' intent to keep the workplace safe.

Adult↗

Chemically distinct transition states govern rapid dissociation of single L-selectin bonds under force.

Carbohydrate--protein bonds interrupt the rapid flow of leukocytes in the circulation by initiation of rolling and tethering at vessel walls. The cell surface carbohydrate ligands are glycosylated proteins like the mucin P-selectin glycoprotein ligand-1 (PSGL-1), which bind ubiquitously to the family of E-, P-, and L-selectin proteins in membranes of leukocytes and endothelium. The current view is that carbohydrate-selectin bonds dissociate a few times per second, and the unbinding rate increases weakly with force. However, such studies have provided little insight into how numerous hydrogen bonds, a Ca(2+) metal ion bond, and other interactions contribute to the mechanical strength of these attachments. Decorating a force probe with very dilute ligands and controlling touch to achieve rare single-bond events, we have varied the unbinding rates of carbohydrate--selectin bonds by detachment with ramps of force/time from 10 to 100,000 pN/sec. Testing PSGL-1, its outer 19 aa (19FT), and sialyl Lewis(X) (sLe(X)) against L-selectin in vitro on glass microspheres and in situ on neutrophils, we found that the unbinding rates followed the same dependence on force and increased by nearly 1,000-fold as rupture forces rose from a few to approximately 200 pN. Plotted on a logarithmic scale of loading rate, the rupture forces reveal two prominent energy barriers along the unbinding pathway. Strengths above 75 pN arise from rapid detachment (<0.01 sec) impeded by an inner barrier that requires a Ca(2+) bond between a single sLe(X) and the lectin domain. Strengths below 75 pN occur under slow detachment (>0.01 sec) impeded by the outer barrier, which appears to involve an array of weak (putatively hydrogen) bonds.

Calcium↗

Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation.

Quantification of in vivo pituitary hormone secretion requires simultaneous appraisal of implicit 1) secretory-burst waveform, mass, and stochastic pulse timing; 2) basal secretion; 3) biexponential elimination kinetics; and 4) random experimental error (Keenan DM, Licinio J, and Veldhuis JD. Proc Natl Acad Sci USA 98: 4028-4033, 2001). The present study extends this analytic formalism to allow for time of day-dependent waveform adaptation (burst-shape change) at statistically determinable boundary times. Thereby, we test the hypothesis that diurnal mechanisms and glucocorticoid negative feedback jointly govern distinctive facets of the burstlike secretion of ACTH. To this end, we reanalyzed intensively (10 min) sampled 24-h plasma ACTH concentration profiles collected previously under feedback-intact and drug-induced cortisol depletion in nine healthy adults. Akaiki information criterion-based model comparison favored dual (rather than single) secretory-burst representation of 24-h ACTH release in both the intact and low-cortisol setting in eight of nine subjects. Under feedback-intact conditions, analytically predicted waveform changepoints (median clock times 0611 and 1739) flanked an interval of elevated ACTH secretory-burst mass (P < 10-3). Experimental hypocortisolemia did not alter day/night boundaries, but 1) stimulated day ACTH secretory-burst mass (P < 10-3); 2) accelerated day ACTH secretory-burst frequency (P < 10-3); and 3) forced skewness of day ACTH secretory bursts toward more rapid initial release (P < 0.05). In contrast, the basal ACTH secretion rate and regularity of interpulse-interval lengths were invariant of day/night segmentation and cortisol availability. In conclusion, unknown diurnal factors and systemic cortisol concentrations codetermine ACTH secretory-burst waveform, frequency, and mass, whereas neither mechanism regulates basal ACTH release or regularity of the burst-renewal process.

Adaptation, Physiological↗