Genetic polymorphisms of CYP2C9 significantly influence the pharmacokinetics and pharmacodynamics of some drugs, which might result in adverse drug effects and therapeutic failure. Several studies ...have been performed on CYP2C9 genetic polymorphisms in Han Chinese populations. However, these studies only focused on two commonly investigated alleles, *2 and *3, in relatively small sample sizes. To scale up the gene-scanning region and determine relatively precise data on the genetic distribution pattern in Chinese populations, unrelated healthy Han Chinese volunteers from Zhejiang Province (n=1127) and Hebei (n=1000) Province were recruited as subjects for the direct sequencing of all exons of CYP2C9. As a result, 14 previously reported alleles were detected in this work, and 8 of these alleles (*14, *16, *19, *23, *27, *29, *33 and *34) were described for the first time in Chinese populations. In addition, 37 novel mutations were also detected, of which 22 variants were non-synonymous, and 21 new alleles, *36-*56, were designated by the Human CYP Allele Nomenclature Committee. In vitro functional analysis of these 22 novel CYP2C9 variants revealed that 17 mutations had a significant influence on the protein's catalytic activity. Our study provides the most accurate data on CYP2C9 polymorphisms in Han Chinese populations and detects the largest number of novel allelic variants existing to date. These new alleles will greatly enrich the current knowledge of naturally occurring CYP2C9 variants in Chinese populations.
Summary Background China has experienced a remarkable epidemiological and demographic transition during the past three decades. Far less is known about this transition at the subnational level. ...Timely and accurate assessment of the provincial burden of disease is needed for evidence-based priority setting at the local level in China. Methods Following the methods of the Global Burden of Disease Study 2013 (GBD 2013), we have systematically analysed all available demographic and epidemiological data sources for China at the provincial level. We developed methods to aggregate county-level surveillance data to inform provincial-level analysis, and we used local data to develop specific garbage code redistribution procedures for China. We assessed levels of and trends in all-cause mortality, causes of death, and years of life lost (YLL) in all 33 province-level administrative units in mainland China, all of which we refer to as provinces, for the years between 1990 and 2013. Findings All provinces in mainland China have made substantial strides to improve life expectancy at birth between 1990 and 2013. Increases ranged from 4·0 years in Hebei province to 14·2 years in Tibet. Improvements in female life expectancy exceeded those in male life expectancy in all provinces except Shanghai, Macao, and Hong Kong. We saw significant heterogeneity among provinces in life expectancy at birth and probability of death at ages 0–14, 15–49, and 50–74 years. Such heterogeneity is also present in cause of death structures between sexes and provinces. From 1990 to 2013, leading causes of YLLs changed substantially. In 1990, 16 of 33 provinces had lower respiratory infections or preterm birth complications as the leading causes of YLLs. 15 provinces had cerebrovascular disease and two (Hong Kong and Macao) had ischaemic heart disease. By 2013, 27 provinces had cerebrovascular disease as the leading cause, five had ischaemic heart disease, and one had lung cancer (Hong Kong). Road injuries have become a top ten cause of death in all provinces in mainland China. The most common non-communicable diseases, including ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and cancers (liver, stomach, and lung), contributed much more to YLLs in 2013 compared with 1990. Interpretation Rapid transitions are occurring across China, but the leading health problems and the challenges imposed on the health system by epidemiological and demographic change differ between groups of Chinese provinces. Localised health policies need to be implemented to tackle the diverse challenges faced by local health-care systems. Funding China National Science & Technology Pillar Program 2013 (2013BAI04B02) and Bill & Melinda Gates Foundation.
Formation, adhesion, and accumulation of ice, snow, frost, glaze, rime, or their mixtures can cause severe problems for solar panels, wind turbines, aircrafts, heat pumps, power lines, ...telecommunication equipment, and submarines. These problems can decrease efficiency in power generation, increase energy consumption, result in mechanical and/or electrical failure, and generate safety hazards. To address these issues, the fundamentals of interfaces between liquids and surfaces at low temperatures have been extensively studied. This has lead to development of so called "icephobic" surfaces, which possess a number of overlapping, yet distinctive, characteristics from superhydrophobic surfaces. Less attention has been given to distinguishing differences between formation and adhesion of ice, snow, glaze, rime, and frost or to developing a clear definition for icephobic, or more correctly
pagophobic
, surfaces. In this review, we strive to clarify these differences and distinctions, while providing a comprehensive definition of icephobicity. We classify different canonical families of icephobic (pagophobic) surfaces providing a review of those with potential for scalable and robust development.
Formation, adhesion, and accumulation of ice, snow, frost, glaze, rime, or their mixtures can cause severe problems for solar panels, wind turbines, aircrafts, heat pumps, power lines, telecommunication equipment, and submarines.
A reproducible stationary high-confinement regime with small "edge-localized modes" (ELMs) has been achieved recently in the Experimental Advanced Superconducting Tokamak, which has a metal wall and ...low plasma rotation as projected for a fusion reactor. We have uncovered that this small ELM regime is enabled by a wide edge transport barrier (pedestal) with a low density gradient and a high density ratio between the pedestal foot and top. Nonlinear simulations reveal, for the first time, that the underlying mechanism for the observed small ELM crashes is the upper movement of the peeling boundary induced by an initial radially localized collapse in the pedestal, which stops the growth of instabilities and further collapse of the pedestal, thus providing a physics basis for mitigating ELMs in future steady-state fusion reactors.
Organic Rankine Cycle (ORC) could be used to recover low-grade waste heat. When a vehicle is running, the engine exhaust gas states have a wide range of variance. Defining the operational conditions ...of the ORC that achieve the maximum utilization of waste heat is important. In this paper the performance of different working fluids operating in specific regions was analyzed using a thermodynamic model built in Matlab together with REFPROP. Nine different pure organic working fluids were selected according to their physical and chemical properties. The results were compared in the regions when net power outputs were fixed at 10
kW. Safety levels and environmental impacts were also evaluated. The outcomes indicate that R11, R141b, R113 and R123 manifest slightly higher thermodynamic performances than the others; however, R245fa and R245ca are the most environment-friendly working fluids for engine waste heat-recovery applications. The optimal control principle of ORC under the transient process is discussed based on the analytical results.
► R11, R141b, R113 and R123 manifest the best thermodynamic performances. ► R245fa and R245ca are the most environment-friendly working fluids for the engine waste heat-recovery application. ► The condensing temperature has more important effect than the evaporating pressure to the performance of ORC. ► The optimal control principle of ORC under the transient process was defined according to the calculation results for the vehicle engine waste heat-recovery application. ► ORC thermodynamic model was built in Matlab together with REFPROP.
Summary Objective This study aimed to investigate the role of the Wnt/β-catenin signaling pathway and E-cadherin/β-catenin complex in intermittent cyclic mechanical tension (ICMT)-induced endplate ...cartilage degeneration. Design β-Catenin expression was measured in disc samples obtained from patients with disc degeneration and those with cervical vertebrae fracture or dislocation. Histological staining was performed to examine the disc tissue morphology and extracellular matrix after application of ICMT in vitro and in vivo. Multiple strategies were employed to examine activation of Wnt/β-catenin signaling after ICMT application in vivo and in vitro . Co-immunoprecipitation was performed to examine the interaction between E-cadherin and β-catenin. Pathway-specific inhibitors and an E-cadherin expression plasmid were used to regulate Wnt/β-catenin signaling and E-cadherin expression. Results β-Catenin protein expression was elevated significantly, whereas cartilaginous genes were down-regulated in endplate cartilage samples obtained from patients with disc degeneration. ICMT loading led to Wnt/β-catenin signaling activation and the loss of the chondrogenic phenotype of endplate chondrocytes in both an in vivo rabbit model and in vitro endplate chondrocyte culture system. Inhibition of Wnt/β-catenin signaling suppressed the decrease in ICMT-induced cartilaginous gene expression. Furthermore, E-cadherin expression was inhibited by ICMT stimulation, resulting in a decrease in the interaction between E-cadherin and β-catenin proteins. Over-expression of E-cadherin rescued the cartilaginous gene expression by enhancing the interaction between E-cadherin and β-catenin proteins. Conclusions ICMT promotes endplate cartilage degeneration via activation of Wnt/β-catenin signaling and suppression of physical protein–protein interactions between E-cadherin and β-catenin.
Aims
Ansamycins are a family of macrolactams that are synthesized by type I polyketide synthase (PKS) using 3‐amino‐5‐hydroxybenzoic acid (AHBA) as the starter unit. Most members of the family have ...strong antimicrobial, antifungal, anticancer and/or antiviral activities. We aimed to discover new ansamycins and/or other AHBA‐containing natural products from actinobacteria.
Methods and Results
Through PCR screening of AHBA synthase gene, we identified 26 AHBA synthase gene–positive strains from 206 plant‐associated actinomycetes (five positives) and 688 marine‐derived actinomycetes (21 positives), representing a positive ratio of 2·4–3·1%. Twenty‐five ansamycins, including eight new compounds, were isolated from six AHBA synthase gene–positive strains through TLC‐guided fractionations followed by repeated column chromatography. To gain information about those potential ansamycin gene clusters whose products were unknown, seven strains with phylogenetically divergent AHBA synthase genes were subjected to fosmid library construction. Of the seven gene clusters we obtained, three show characteristics for typical ansamycin gene clusters, and other four, from Micromonospora spp., appear to lack the amide synthase gene, which is unusual for ansamycin biosynthesis. The gene composition of these four gene clusters suggests that they are involved in the biosynthesis of a new family of hybrid PK‐NRP compounds containing AHBA substructure.
Conclusions
PCR screening of AHBA synthase is an efficient approach to discover novel ansamycins and other AHBA‐containing natural products.
Significance and Impact of the Study
This work demonstrates that the AHBA‐based screening method is a useful approach for discovering novel ansamycins and other AHBA‐containing natural products from new microbial resources.
The crystal structure and magnetoresponsive properties of Fe-doped MnCoGe alloys have been investigated using x-ray diffraction (XRD) and magnetic measurements. By alloying the Fe-containing ...isostructure compounds into MnCoGe, a magnetostructural transition from paramagnetic austenite to ferromagnetic martensite with large magnetization difference can be realized in a temperature window between the Curie temperatures of the austenite and martensite, resulting in a magnetic-field-induced martensitic transformation and large magnetic-entropy changes. A structural and magnetic phase diagram of Fe-doped MnCoGe alloys is presented.
► Isostructural alloying can manipulate structural stability of Fe-doped MnCoGe alloys. ► A magnetostructural transition was realized in a temperature window between TCA and TCM. ► The remarkable magnetoresponsive properties in Fe-doped MnCoGe alloys were found. ► A structural and magnetic phase diagram of Fe-doped MnCoGe alloys was proposed.
Abstract
Using the Five-hundred-meter Aperture Spherical radio Telescope (FAST), we have recorded over 1.2 × 10
4
single pulses from PSR B0823+26 (J0826+2637) at 1.25 GHz with 500 MHz bandwidth. ...These high-sensitivity observations detected with FAST are unprecedented. We investigated potentially interesting emission features by analyzing the polarimetric individual pulses during the bright state. The average pulse profile has a weak postcursor component and a wide interpulse along with a narrow main pulse. The pulse energy distribution of the main pulse shows the presence of triple emission modes. When the emission ceases in the main pulse component, low-level emission in the interpulse component is detected, whereas the absence of any emission in the postcursor component is shown. In the postcursor emission region, bright pulses are detected in 422 rotations with the relative pulse energy described by a power-law distribution with index of −2.52 ± 0.09, while the peak flux density ratio appears to follow a logarithmic normal distribution. The intervals between bright pulses can be described with a Poisson process with the occurrence rate estimated to be one bright pulse every 14 s. The fluctuation spectral analysis reveals the existence of a form of periodic amplitude modulation unrelated to subpulse drifting in both the main pulse and interpulse components. Furthermore, the modulation patterns in the main pulse and interpulse are found to be locked in pulse longitude, signifying some information transfer between the two magnetic polar regions.
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