The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Pharmacologic prophylaxis for atrial fibrillation following cardiac surgery: a systematic review

Atrial Fibrillation (AF) is the most common arrhythmia occurring after cardiac surgery. Its incidence varies depending on type of surgery. Postoperative AF may cause hemodynamic deterioration, predispose to stroke and increase mortality. Effective treatment for prophylaxis of postoperative AF is vital as reduces hospitalization and overall morbidity. Beta - blockers, have been proved to prevent effectively atrial fibrillation following cardiac surgery and should be routinely used if there are no contraindications. Sotalol may be more effective than standard b-blockers for the prevention of AF without causing an excess of side effects. Amiodarone is useful when beta-blocker therapy is not possible or as additional prophylaxis in high risk patients. Other agents such as magnesium, calcium channels blocker or non-antiarrhythmic drugs as glycose-insulin - potassium, non-steroidal anti-inflammatory drugs, corticosteroids, N-acetylcysteine and statins have been studied as alternative treatment for postoperative AF prophylaxis

A comparison of nondeterministic and deterministic switching methods for DC-DC power converters

An analysis and experimental results of the random pulsewidth modulation (RPWM) and random pulse-position modulation (RPPM) methods for dc-dc converters are presented. The characteristics and performance of power converters under two randomized modulations are evaluated. The theoretical relationships of discrete harmonics, continuous noise, and output-voltage ripple of the RPWM and RPPM schemes are established and compared with those of a standard deterministic pulsewidth modulation (PWM) scheme in a buck converter. Limitations in the randomly switched dc-dc converters, which have not been addressed before, are highlighted. Randomized schemes generally have inherent problems in achieving low-output-voltage ripple due to the low-frequency continuous noise within the passband of the converter filter. The inherent low-frequency noise-induced voltage ripple problems of nondeterministic switching methods for dc converters are confirmed experimentally. The performance of the RPPM method is found to be closer to the standard PWM method than that of the RPWM method. For dc-dc power conversion, the RPPM method offers much better output-voltage performance than the RPWM method.link_to_subscribed_fulltex

Effects of continuous noise in randomised switching DC-DC converters

A randomly switched DC-DC converter reduces the magnitude of discrete harmonics but creates continuous noise in the output voltage. Continuous noise within the passband of the output filter is found to induce low-frequency voltage ripple in the converter output. This adverse effect is inherent in all randomised switching schemes and is confirmed by both theory and experiment.link_to_subscribed_fulltex