Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma.

Overuse of ß2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target ß2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of ß2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E2 signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid ß2-adrenoceptor agonist resistance.

Evaluation of a Modified POSSUM Scoring System for Predicting the Morbidity in Patients Undergoing Lumbar Surgery.

For most spine surgeons, operative intervention is common for the treatment of lumbar disc herniation, lumbar stenosis, lumbar fracture or lumbar spondylolisthesis. However, with the increase in lumbar surgery, the complication rate increases accordingly. Whereas the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) scoring system has been widely used to predict morbidity in various surgical fields, the application of this system in lumbar surgery has not been reported. From January 2008 to January 2010, we recruited 158 patients (85 males and 73 females) with operation for lumbar disc herniation, lumbar stenosis, lumbar fracture, or lumbar spondylolisthesis. All patients were analyzed to compare the morbidity by a modified POSSUM scoring system. According to the modified POSSUM, the expected morbidity was 51 cases (32.3 %), whereas the observed mortality was 42 cases (26.6 %). The overall observed-to-expected ratio was 0.82, and the chi-squared test indicated no statistically significant difference between the expected and observed morbidities (χ (2) = 1.23, P = 0.27), suggesting that the modified POSSUM can accurately estimate the outcome. The modified POSSUM scoring system we developed is a useful tool for predicting and evaluating morbidity in lumbar surgery. Further studies are required to investigate whether this scoring system can predict mortality.

Distinct symmetry and limited peptide refolding activity of the thermosomes from the acidothermophilic archaea Acidianus tengchongensis S5(T).

Recombinant thermosomes from the Acidianus tengchongensis strain S5(T) were purified to homogeneity and assembled in vitro into homo-oligomers (rATcpnalpha or rATcpnbeta) and hetero-oligomers (rATcpnalphabeta). The symmetries of these complexes were determined by electron microscopy and image analysis. The rATcpnalpha homo-oligomer was shown to possess 8-fold symmetry while both rATcpnbeta and rATcpnalphabeta oligomers adopted 9-fold symmetry. rATcpnalphabeta oligomers were shown to contain the alpha and beta subunits in a 1:2 ratio. All of the complexes prevented the irreversible inactivation of yeast alcohol dehydrogenase at 55 degrees C and completely prevented the formation of aggregates during thermal inactivation of citrate synthase at 45 degrees C. All rATcpn complexes showed trace ATP hydrolysis activity. Furthermore, rATcpnbeta sequestered fully chemically denatured substrates (GFP and thermophilic malic dehydrogenase) in vitro without refolding them in an ATP-dependent manner. This property is similar to previously reported properties of chaperonins from Sulfolobus tokodaii and Sulfolobus acidocaldarius. These features are consistent with the slow growth rates of these species of archaea in their native environment.