Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design

A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 µM respectively for PDE9 and PDE5, and about three orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors

Extracorporeal Circulation for Great Vessels Surgery: A Review of 131 Cases

A retrospective analysis of 131 cases of major vascular surgery, mainly aneurysms of the ascending and descending aorta, was undertaken to determine whether use of different bypass methods chosen according to location of the individual lesions resulted in improved results. For the 93 cases of ascending aortic aneurysm, the method for cardiac protection was improved by the use of continuous retrograde coronary sinus perfusion with cardioplegic blood. In sixteen cases with dissection involving the aortic arch, deep hypothermic circulatory arrest and continuous retrograde cerebral perfusion through the superior vena cava was employed for brain protection. The safe brain circulation arrest time was thus prolonged to the longest record of 81 minutes. Among the group of 93 cases, there were four operative and four hospital deaths, giving a mortality rate of 8.6% (8/93). For the 34 cases of descending aortic aneurysms, left heart bypass was employed to avoid ischemia of the heart, lungs, brain, and the abdominal organs; the operative mortality rate was 8.8% (3/34). In three cases of interrupted aortic arch, separate upper and lower body perfusion under deep hypothermia with low flow rate perfusion for the upper body provided the necessary conditions for radical surgery. In one patient with Budd-Chiari syndrome, a total corrective surgery was achieved under right heart bypass

Clinical Study of the Protective Effect of Exogenous Creatine Phosphate on Ischemic Myocardium during Open Heart Surgery

This study was designed to evaluate the myocardial protective effect of exogenous creatine phosphate (CP) added to cardioplegic solution for use in open heart surgery. Ninety-eight patients were divided into a control group (n = 44) and a CP group (n =54). The spontaneous recovery rate of heart beat after aortic declamping was recorded and changes of serum enzymes including CPK, LDH, CPK-MB, HBDH, and AST were evaluated. The ultrastructural alterations of the myocardial tissue were observed in 4 patients (2 cases from each group) who had cardiac valve replacement. The spontaneous recovery rate of heart beat in the CP group was significantly higher than the control group (39/54 versus 22/44 ), and the peak values of leakage of serum enzymes of the control group appeared earlier and receded later than those of the CP group. Electron microscope examination revealed better preservation of the ultrastructures of the myocardial tissue in the CP group than that of the control group. This data indicates that exogenous creatine phosphate added to the cardioplegic solution offers a better protective effect on the ischemic myocardium during open heart surgery

The Assessment of Brain Injury with Measurement of Calcium Fluorescent Intensity of a Vital Brain Slice

Retrograde cerebral perfusion (RCP) is one of cerebral protection methods during deep hypothermic circulatory arrest (DHCA). However, the mechanism is unclear. In this study with laser confocal scanning microscope (LCSM), calcium fluorescent intensity of vital brain slice was compared between RCP and DHCA group. Sixteen swine, weighing from 19 – 20 kg and supplied by Beijing College of Agriculture, were used for the experiment. After 90 min of DHCA or RCP through the superior vena cava, the animals were rewarmed for 120 min. Through tentorium of the cerebellum and enucleation of the eyeball, vital brain slices (cerebellula and retina) were obtained and fluorescein labeled in artificial cerebrospinal fluid containing 5 μmol/L Fluo-3/AM (fluoresence probe). The calcium fluorescent intensity was examined by LCSM. The results indicated that calcium fluorescent intensity of vital brain slice was lower in the RCP group (cerebellula, 9.16 ± 3.98; retina, 21.48 ± 14.27) than that in the DHCA group (cerebellula, 31.97 ± 20.59; retina, 44.07 ± 21.01) (p < .05). More moderate and severe eosinophilic degeneration was found in the DHCA group than in the RCP group (p < .05) through morphological examination. The statistical analysis also indicated the calcium fluorescent intensity of the vital brain slice was correlated with the level of moderate and severe eosinophilic degeneration of thee neuron (r = 0.86, p < .05). So “calcium overload” contributes to the injury of neuron after DHCA. RCP is able to attenuate “calcium overload,” which has the effect of cerebral protection

The non-significant correlation between landscape ecological risk and ecosystem services in Xi'an Metropolitan Area, China

As critical prerequisite for sustainable development research of social ecosystem (SDSE), the relationship between landscape security pattern and ecosystem services should be explicitly evaluated to support SDSE research. However, the existing evaluation system lacking of integrating analysts of the factors led to vague knowledge of the SDSE mechanism. To tackle this issue, this study, therefore, explored the relationship between landscape ecological risk and ecosystem services (e.g. carbon sequestration, soil conservation, water yield, crop production and residential support) at Xi’an Metropolitan Area using remote sensing data in 2010 and 2020. The results show that the overall landscape ecological risk decreased from 0.2618 to 0.2479. Although the rapid development of urban leading improvement for landscape ecological security and residential support, the total ecosystem services has declined due to the decline in water yield and crop production. Preventing the landscape ecological risk on landscape fragmentation cannot improve the level of ecosystem services. Notably, the stronger interference of human activities overwhelmingly caused a single advantageous ecosystem services with extreme risk, while the less caused multiple advantageous ecosystem services of ecological regulation with medium–low level ecological risk. Additionally, the competitive relationship between the crop production and residential support would not produce higher risk led by the intervention of human activity. The integrating of crop production and carbon sequestration (or soil conservation) resulted in high risk. Using these results, a potential spatial plan of Xi'an Metropolitan Area is then made based on multiple advantageous areas of ecosystem services. This study benefits decision-making for regional comprehensive risk prevention, future spatial pattern planning and development orientation, and sustainable development research of social ecosystem

Cardiopulmonary Bypass for Thoracic Aortic Aneurysm: A Report on 488 Cases

Our objective was to investigate different cardiopulmonary bypass (CPB) techniques for thoracic aortic aneurysm retrospectively. Four hundred and eighty-eight patients with thoracic aortic aneurysm received surgical treatment. Total CPB was used routinely in 331 cases with ascending aortic aneurysm. When the aneurysm expanded to the aortic arch, brain protection was executed by adopting deep hypothermia circulatory arrest (DHCA) or DHCA combined with retrograde cerebral perfusion (RCP). Selected cerebral perfusion via carotid artery was used in three cases and separated upper and lower body perfusion in five cases. Left heart bypass was adopted for the surgeries of 157 cases with descending aortic aneurysm. In two of the cases, ventricular defibrillation could not be achieved, and then bypass was altered to separated upper and lower body perfusion to acquire satisfactory outcome. In the ascending aortic aneurysm group, DHCA time in the 17 patients was 10–63 minutes (mean 35.58 ± 18.81 min), and DHCA ± RCP time in 61 patients was 16–81 minutes (mean 43.43 ± 17.91 min). Total mortality of aortic aneurysm surgery requiring full CPB was 5.4% (18/331), in which eight patients died in emergency operations. The total mortality of emergency operation was 11.9% (8/67). In the descending aortic aneurysm group, time of left heart bypass was 125.56 ± 57.28 min, and the total mortality was 7% (11 of 157 patients). Three patients developed postoperative paraplegia. Techniques for extracorporeal circulation for surgery of the aorta are dependent on the nature of the disease and require a flexible approach to meet the specific anatomical challenge. The ability to alter the perfusion circuit to meet unexpected situations should be anticipated and planned for. In this series, we have varied our approach to perfusion techniques as required with acceptable outcome data as compared to the international literature

Integration of a Gold-Specific Whole <i>E. coli</i> Cell Sensing and Adsorption Based on BioBrick

Detection and recovery of heavy metals from environmental sources is a major task in environmental protection and governance. Based on previous research into cell-based visual detection and biological adsorption, we have developed a novel system combining these two functions by the BioBrick technique. The gold-specific sensory gol regulon was assembled on the gold-chaperone GolB (Gold-specific binding protein), which is responsible for selectively absorbing gold ions, and this led to an integration system with increased probe tolerance for gold. After being incorporated into E. coli, this system featured high-selective detection and recycling of gold ions among multi-metal ions from the environment. It serves as an efficient method for biological detection and recovery of various heavy metals. We have developed modular methods for cell-based detection and adsorption of heavy metals, and these offer a quick and convenient tool for development in this area