Human cytochrome P450 1A2 (CYP1A2) is one of the major CYPs in the liver ( approximately 13%) and metabolizes about 20% of clinically used drugs. CYP1A2 is a 515-residue protein with a molecular mass ...of 58,294 Dal. The recently published crystal structure of CYP1A2 in complex with alpha-naphthoflavone has showed a rather compact active site with a relatively small volume of the cavity of 375 A(3), which is 44.2% and 49.3% larger than that of CYP2A6 (260 A(3)) and CYP2E1 (190 A(3)), respectively. A series of residues in the substrate recognition regions of CYP1A2 (e.g. Arg108, Thr124, Thr223, Glu225, Phe226, Lys250, Arg251, Lys253, Asn312, Asp313, Glu318, Thr319, Asp320, Thr321, Val322, Leu382, Thr385, and Ile386) have been shown to play important roles in ligand-enzyme binding based on site-directed mutagenesis and homology modeling studies. Typical CYP1A2 substrates generally contain planar ring that can fit the narrow and planar active site of the enzyme, such as propranolol, clozapine, guanabenz, flutamide, imatinib, thalidomide, carbamazepine, lidocaine, theophylline, tacrine, tizanidine, zolpidem, riluzole, zileuton, and leflunomide. CYP1A2 is one of the major enzymes that bioactivate a number of procarcinogens including polycyclic aromatic hydrocarbons (e.g., benzoapyrene), heterocyclic aromatic amines/amides (e.g. 2-amino-1-methyl-6-phenylimidazo4,5-bpyridine), mycotoxins (e.g. aflatoxin B(1)) and some natural compounds such as aristolochic acids present in several Chinese herbal medicines. This enzyme also metabolizes several important endogenous compounds including retinols, melatonin, steroids, uroporphyrinogen and arachidonic acids. Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds. In particular, several therapeutic drugs including antofloxacin, carbamazepine, dihydralazine, furafylline, isoniazid, rofecoxib, clorgyline, thiabendazole, and zileuton are mechanism-based inhibitors of CYP1A2. Reversible and irreversible inhibition of by drugs CYP1A2 may provide an explanation for some clinical drug-drug interactions. Similar to CYP1A1 and 1B1, CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR), a ligand-activated transcription factor and a basic helix-loop-helix protein belonging to the Per-Arnt-Sim family of transcription factors. CYP1A2 is polymorphic and a number of genetic mutations in CYP1A2 have been reported. It has been suggested that approximately 35 to 75% of the interindividual variability in CYP1A2 activity is due to genetic factors. Some of the mutations of CYP1A2 have been found to alter the clearance of drugs that are extensively metabolized by CYP1A2. Collectively, CYP1A2 plays a major role in drug metabolism, procarcinogen activation and some drug-drug interactions; it is important to identify whether a new drug is a substrate, inducer or inhibitor in drug development. This candidate selection might eventually lead to a less prominent role of this enzyme in the future for drug metabolism and minimize the potential for significant polymorphic metabolism in humans and drug-drug interactions when used in combination with CYP1A2 inhibitors.
Although the sun is really far away from us, some solar activities could still influence the performance and reliability of space-borne and ground-based technological systems on Earth. Those ...time-varying conditions in space caused by the sun are also called solar storm or space weather. It is known that aviation activities can be affected during solar storms, but the exact effects of space weather on aviation are still unclear. Especially how the flight delays, the top topic concerned by most people, will be affected by space weather has never been thoroughly researched. By analyzing huge amount of flight data (~ 4 × 10
records), for the first time, we quantitatively investigate the flight delays during space weather events. It is found that compared to the quiet periods, the average arrival delay time and 30-min delay rate during space weather events are significantly increased by 81.34% and 21.45% respectively. The evident negative correlation between the yearly flight regularity rate and the yearly mean total sunspot number during 22 years also confirms such correlation. Further studies show that the flight delay time and delay rate will monotonically increase with the geomagnetic field fluctuations and ionospheric disturbances. These results indicate that the interferences in communication and navigation during space weather events may be the most probable reason accounting for the increased flight delays. The above analyses expand the traditional field of space weather research and could also provide us with brand new views for improving the flight delay predications.
This paper investigates the impacts of competition structures on firms’ incentives for adopting strategic environmental corporate social responsibility (ECSR) certified by a Non-Governmental ...Organization. We show that, to induce firms to adopt certified ECSR, the certifier will set a standard lower than the optimal one, and the standard in Cournot competition is higher than that in Bertrand competition. Finally, we show that firms and consumers benefit from firms’ certified ECSR.
•Effects of competition modes on a NGO certifier’s standard setting are examined.•Effects of certification on firms’ strategic incentives for ECSR are also examined.•The NGO certifier will set a standard lower than the optimal one.•The standard in Cournot competition is higher than that in Bertrand competition.•Firms and consumers both benefit from firms’ certified ECSR.
Solar flares are one of the severest solar activities that have important effects on near-Earth space. Previous studies have shown that flight arrival delays increase as a result of solar flares, but ...the intrinsic mechanism behind this relationship is still unknown. In this study, we conducted a comprehensive analysis of flight departure delays during 57 solar X-ray events by using a huge amount of flight data (~ 5 × 10
records) gathered over a 5-year period. It is found that the average flight departure delay time during solar X-ray events increased by 20.68% (7.67 min) compared to quiet periods. Our analysis also revealed apparent time and latitude dependencies, with flight delays being more serious on the dayside than on the nightside and longer (shorter) delays tending to occur in lower (higher) latitude airports during solar X-ray events. Furthermore, our results suggest that the intensity of solar flares (soft X-ray flux) and the Solar Zenith Angle directly modulate flight departure delay time and delay rate. These results indicate that communication interferences caused by solar flares directly affect flight departure delays. This work expands our conventional understanding of the impacts of solar flares on human society and provides new insights for preventing or coping with flight delays.
Desalination of seawater and brackish water is becoming an increasingly important means to address the scarcity of fresh water resources in the world. Decreasing the energy requirements and ...infrastructure costs of existing desalination technologies remains a challenge. By enabling the manipulation of matter and control of transport at nanometer length scales, the emergence of nanotechnology offers new opportunities to advance water desalination technologies. This review focuses on nanostructured materials that are directly involved in the separation of water from salt as opposed to mitigating issues such as fouling. We discuss separation mechanisms and novel transport phenomena in materials including zeolites, carbon nanotubes, and graphene with potential applications to reverse osmosis, capacitive deionization, and multi-stage flash, among others. Such nanostructured materials can potentially enable the development of next-generation desalination systems with increased efficiency and capacity.
Some studies have found a significant relationship between birth weight (BW) and the risk of coronary heart disease (CHD) in adulthood, but results were inconsistent. The purpose of this study was to ...characterize the association between BW and the risk of CHD in adults. Among 144 papers detected by our search, 27 papers provided data on the relationship between BW and CHD, of which 23 papers considered BW as a continuous variable, and 14 articles considered BW as a categorical variable for this meta-analysis. Based on 23 papers, the mean weighted estimate for the association between BW and the combined outcome of non-fatal and fatal CHD was 0.83 95% confidence interval (CI), 0.80-0.86 per kilogram of BW (P<0.0001). Low birth weight (LBW<2500 g) was associated with increased risk of CHD odds ratio (OR), 1.19; 95% confidence interval (CI), 1.11-1.27 compared with subjects with BW⩾2500 g. LBW, as compared with normal BW (2500-4000 g), was associated with increased risk of CHD (OR, 1.16; 95% CI, 1.08-1.25). High birth weight (HBW⩾4000 g) was associated with decreased risk of CHD (OR, 0.89; 95% CI, 0.81-0.98) compared with subjects with BW<4000 g. In addition, there was an indication (not quite significant) that HBW was associated with a lower risk of CHD (OR, 0.89; 95% CI, 0.79-1.01), as compared with normal BW. No significant evidence of publication bias was present. These results suggest that LBW is significantly associated with increased risk of CHD and a 1 kg higher BW is associated with a 10-20% lower risk of CHD.
In this paper we report the growth of high quality SnS thin films with good crystallinity deposited on two-dimensional (2D) mica substrates. It is believed that the 2D nature of SnS, with strong ...intra-layer covalent bonds and weak inter-layer van der Waals interactions, is responsible for its relative insensitivity to lattice mismatch. We also investigated the reduction of Sn vacancies in the material using Sn-compensation technique during the material growth process. The experimental results clearly demonstrated substantial enhancements in the electrical and structural properties for films deposited using Sn-compensation technique. A mobility of 51 cm
V
s
and an XRD rocking curve full width at half maximum of 0.07° were obtained. Sn-compensated SnS/GaN:Si heterojunctions were fabricated and significant improvement in both the I-V characteristics and the spectral responsivities of the devices were characterized.
A search for exotic dark matter (DM) in the sub-GeV mass range has been conducted using 205 kg day data taken from a p-type point contact germanium detector of the CDEX-10 experiment at China's ...Jinping underground laboratory. New low-mass dark matter searching channels, neutral current fermionic DM absorption (χ+A→ν+A) and DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), have been analyzed with an energy threshold of 160 eVee. No significant signal was found; thus new limits on the DM-nucleon interaction cross section are set for both models at the sub-GeV DM mass region. A cross section limit for the fermionic DM absorption is set to be 2.5×10^{-46} cm^{2} (90% C.L.) at DM mass of 10 MeV/c^{2}. For the DM-nucleus 3→2 scattering scenario, limits are extended to DM mass of 5 and 14 MeV/c^{2} for the massless dark photon and bound DM final state, respectively.
In this paper, the separated solutions of the high-dimensional nonlinear breaking soliton equation are derived by using the multi-linear variable separation and the extended mapping method of Riccati ...equation. And the rich localized excitation structures are investigated. The simulation results verify the proposed scheme. It can get more abundant local excitation structures for high-dimensional nonlinear systems, and it has potential values for certain applications in optical field.
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