Genetic Deletion of Mmp9 Does Not Reduce Airway Inflammation and Structural Lung Damage in Mice with Cystic Fibrosis-like Lung Disease

Elevated levels of matrix metalloprotease 9 (MMP-9) and neutrophil elastase (NE) are associated with bronchiectasis and lung function decline in patients with cystic fibrosis (CF). MMP-9 is a potent extracellular matrix-degrading enzyme which is activated by NE and has been implicated in structural lung damage in CF. However, the role of MMP-9 in the in vivo pathogenesis of CF lung disease is not well understood. Therefore, we used β-epithelial Na⁺ channel-overexpressing transgenic (βENaC-Tg) mice as a model of CF-like lung disease and determined the effect of genetic deletion of Mmp9 (Mmp9^-/-) on key aspects of the pulmonary phenotype. We found that MMP-9 levels were elevated in the lungs of βENaC-Tg mice compared with wild-type littermates. Deletion of Mmp9 had no effect on spontaneous mortality, inflammatory markers in bronchoalveolar lavage, goblet cell metaplasia, mucus hypersecretion and emphysema-like structural lung damage, while it partially reduced mucus obstruction in βENaC-Tg mice. Further, lack of Mmp9 had no effect on increased inspiratory capacity and increased lung compliance in βENaC-Tg mice, whereas both lung function parameters were improved with genetic deletion of NE. We conclude that MMP-9 does not play a major role in the in vivo pathogenesis of CF-like lung disease in mice.     

Effect of Ions and Sequence Variants on the Antagonist Binding Properties of the Histamine H1 Receptor

The histamine H₁ receptor (H₁R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H₁ function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol⁻¹) on doxepin binding affinity. We also examined the effect of four H₁R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol⁻¹, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs.     

Nanorod heterostructures showing photoinduced charge separation

Size- and shape-dependent property modifications of semiconductor nanocrystals have been a subject of intense interest because of their potential for future engineering devices. The bandgap and related optical-property tuning of these materials are mainly governed by the nature of their band edges. In addition, fusing one type of nanocrystal over another enables further control of material properties that are dependent on the relative alignments of their energy levels. On a molecular scale, the synthesis of supramolecular compounds has inspired advances in theories for photoinduced charge transfer. Heterostructured nanocrystals potentially provide a nanoscale analog of such systems. A method for preparing heterostructured nanocrystals of complex morphologies showing photoinduced charge separation is presented. It is shown that the energy and lifetime of the charge-transfer photoluminescence band can be tuned by changing the relative alignment of band edges in CdSe/CdTe heterostructure nanorods. The long-lived charge transfer states in these type II semiconductors may make them attractive for photovoltaic applications.     

An atmospheric pressure glow discharge optical emission source for the direct sampling of liquid media

A glow discharge optical emission spectroscopy (GD-OES) source that operates at atmospheric pressure is described. This device utilizes an electrolytic solution containing the analyte specimen as one of the discharge electrodes. The passage of electrical current (either electrons or positive ions) across the solution/gas phase interface causes local heating and the volatilization of the analyte species. Collisions in the discharge region immediately above the solution surface result in optical emission that is characteristic of the analyte elements. Operation of this device with the analyte solution acting as either the cathode or anode is demonstrated. Current-voltage (i-V) plots reveal abnormal glow discharge characteristics, with operating parameters being dependent on the electrolyte concentration (i.e., solution conductivity) and the gap between the solution surface and the counterelectrode. Typical conditions include discharge currents of 30-60 mA, and potentials of 500-900 V. Electrolyte solutions having pH, pNa, or pLi values of 0.5-2 and interelectrode gaps of 0.5-3 mm produce stable plasmas in which the analyte solutions flow at rates of up to 3.0 mL/min. Preliminary limits of detection are determined for the elements Na, Fe, and Pb to be in the range of 11-14 ppm (approximately 60 ng) for 5-microL sample volumes.     

康复花园

20世纪50年代后,美国日渐泛滥程式化的医疗建筑设计,产生了很多负面影响,一种以病人为本的全新设计理念,在户外辅助治疗的"康复花园"于90年代开始出现.介绍了康复花园的15种设计原则,这些原则有源于经验的,也有基于常识的,是目前所知的最好的康复花园的设计原则,能带来积极的康复效果.现在西方国家的设计师们运用康复花园的经验和理念,在医疗诊断的基础上针对特殊病人对花园的要求设计花园.还有专门为成人和儿童生理复原、精神治疗、老年痴呆、烧伤、艾滋和癌症患者建造的花园等,有很多领域有待深八研究.     

Evaluating rock mass disturbance within open-pit excavations using seismic methods: A case study from the Hinkley Point C nuclear power station

Understanding rock strength is essential when undertaking major excavation projects,as accurate assessments ensure both safe and cost-effective engineered slopes.Balancing the cost-safety trade-off becomes more imperative during the construction of critical infrastructure such as nuclear power stations,where key components are built within relatively deep excavations.Designing these engineered slopes is reliant on rock strength models,which are generally parameterised using estimates of rock properties(e.g.unconfined compressive strength,rock disturbance) measured prior to the commencement of works.However,the physical process of excavation weakens the remaining rock mass.Therefore,the model also requires an adjustment for the anticipated rock disturbance.In practice,this parameter is difficult to quantify and as a result it is often poorly constrained.This can have a significant impact on the final design and cost of excavation.We present results from passive and active seismic surveys,which image the extent and degree of disturbance within recently excavated slopes at the construction site of Hinkley Point C nuclear power station.Results from active seismic surveys indicate that the disturbance is primarily confined to 0.5 m from the excavated face.In conjunction,passive monitoring is used to detected seismic events corresponding to fracturing on the cm-scale and event locations are in agreement with 0.5 m of disturbance into the rock face.This suggests rock disturbance at this site is relatively low and occurred during and immediately after the excavation.A ratio of seismic velocities recorded before and after excavations are used to determine the disturbance parameter required for the Hoek-Brown rock failure criterion,and we assess that rock disturbance is low with the magnitude of the disturbance diminishing more quickly than expected into the excavated slope.Seismic methods provide a low-cost and quick method to assess excavation related rock mass disturbance,which can lead to cost reductions in large excavation projects.     

Degradation of organic matter from black shales and charcoal by the wood-rotting fungus Schizophyllum commune and release of DOC and heavy metals in the aqueous phase

We investigated the degradation of refractory organic matter (OM) by the basidiomycete fungus Schizophyllum commune to understand the release of dissolved organic compounds, heavy metals and sulfur. The investigated OM consisted of: charcoal, the short time end product of high temperature wood alteration in the absence of oxygen and composed mainly of pure OM; and black shales composed of clay minerals, quartz, sulfides and OM formed geogenically in an abiotic long-term process. In both cases, the OM fraction contains mainly polyaromatic hydrocarbons. We investigated the degradation of these fractions by a wood-rotting basidiomycete, which is able to produce exoenzymes like peroxidases and laccases. These enzymes can perform radical reactions to oxidize OM (like lignin) and therefore hypothetically are able to degrade OM from charcoal and/or low grade metamorphic black shales. Release of new components into dissolved organic carbon (DOC) could be detected in both cases. The attack on OM in the case of black shales coincided with the release of the heavy metals Fe, Mn and Ni. By following sulfur concentrations throughout the experiment, it was shown that heavy metal release is not due to pyrite oxidation. Ground black shale and charcoal samples were inoculated with S. commune in a diluted minimal medium containing aspartic acid and glucose. The aqueous and solid phases were sampled after 1, 7, 28 and 84 days. DOC was measured as non purgeable carbon and characterized by size exclusion chromatography and UV detection. Carbon concentrations of the solid phase were determined by element analyses. After initial decrease of the DOC concentrations due to the degradation of the carbon source provided with the medium, DOC increased up to 80 mg/l after 84 days. Carbon decreased in the solid fraction confirming that this carbon was released as DOC by the fungus. The newly generated DOC formed larger agglomerations than the DOC of the growth medium. The investigation proved that the degradation of persistent carbon sources, such as charcoal and black shale, is accelerated by fungal activity. Consequently, the associated release of heavy metals is also accelerated by the fungus. Main products of the biological degradation processes were organic heavy metal complexes which can enter the environment.