Studies on the inhibitory effect of isavuconazole on flumatinib metabolism in vitro and in vivo

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0−t), AUC(0−∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications

Label-free analysis of protein biomarkers using pattern-optimized graphene-nanopyramid SERS for rapid diagnosis of Alzheimer’s disease

The quantitative and highly sensitive detection of biomarkers such as Tau proteins and Aβ polypeptides is considered one of the most effective methods for the early diagnosis of Alzheimer’s disease (AD). Surface-enhanced Raman spectroscopy (SERS) detection is a promising method that faces, however, challenges like insufficient sensitivity due to the non-optimized nanostructures for specialized analyte sizes and insufficient control of the location of SERS hot spots. Thus, the SERS detection of AD biomarkers is restricted. We reported here an in-depth study of the analytical Raman enhancement factor (EF) of the wafer-scale graphene-Au nanopyramid hybrid SERS substrates using a combination of both theoretical calculation and experimental measurements. Experimental results show that larger nanopyramids and smaller gap spacing lead to a larger SERS EF, with an optimized analytical EF up to 1.1 × 1010. The hybrid SERS substrate exhibited detection limits of 10–15 M for Tau and phospho-Tau (P-Tau) proteins and 10–14 M for Aβ polypeptides, respectively. Principal component analysis correctly categorized the SERS spectra of different biomarkers at ultralow concentrations (10–13 M) using the optimized substrate. Amide III bands at 1200–1300 cm–1 reflect different structural conformations of proteins or polypeptides. Tau and P-Tau proteins are inherently disordered with a few α-helix residuals. The structure of Aβ42 polypeptides transitioned from the α-helix to the β-sheet as the concentration increased. These results demonstrate that the hybrid SERS method could be a simple and effective way for the label-free detection of protein biomarkers to enable the rapid early diagnosis of AD and other diseases

Ore Genesis of the Toudaochuan Gold Deposit in Central Jilin Province, NE China: Constraints from Fluid Inclusions and C–H–O–S–Pb Isotopes

The Toudaochuan gold deposit is a recently discovered lode gold deposit in Central Jilin Province. Gold ore bodies are dominantly controlled by NE-trending fault. The major hydrothermal period can be further divided into the quartz–pyrite stage (stage I), quartz–gold–polymetallic sulfides stage (stage II, major gold mineralization stage), and quartz–carbonate stage (stage III). Primary fluid inclusions (FIs) identified in quartz at different hydrothermal stages include liquid-rich aqueous FIs (L-type), CO2 FIs (C-type, including CO2-bearing C1-type FIs and CO2-rich C2-type FIs), and minor vapor-rich aqueous FIs (V-type). Microthermometry studies on different fluid inclusions indicate that the original ore-forming fluids belonged to the CO2–H2O–NaCl system characterized by a moderate–low temperature and low salinity in stages I and II, and they finally evolved into a H2O–NaCl system characterized by low temperature and low salinity in stage III. Fluid immiscibility is considered to be the key ore-forming mechanism. The initial ore-forming fluid was originated from magmatic water and was mixed with meteoric water in the later stage. The S and Pb isotope data suggest that the ore metal materials were derived from the mixed source of mantle and crust. Based on all the above data, therefore, it can be proposed that the Toudaochuan gold deposit is a mesothermal magmatic–hydrothermal gold deposit

Genesis of Metal Sulfides and Its Significance on Graphite Mineralization in the Huangyangshan Graphite Deposit, East Junggar, Xinjiang Province, China

The Huangyangshan super-large graphite deposit is located in the Qitai area of East Junggar in Xinjiang Province, China. This deposit is well known for its distinguishing properties, including the alkaline granite complex that hosts the graphite ore, the dominantly orbicular structure developed in the graphite ore, and the association of graphite with metal sulfides in the orbicular ore. This study aims to determine the genetic relationship between graphite and metal sulfides in order to better understand the graphite mineralization process of the Huangyangshan deposit. The methods applied in the study include X-ray micro-CT scanning and scanning electron microscopy (SEM) analyses of the orbicular graphite ore and in situ inductive laser ablation-coupled plasma mass spectrometry (LA-ICP-MS) trace element analyses of the pyrrhotite and chalcopyrite associated with the graphite. The analytical results show that the graphite ore is composed of crystalline graphite, K-feldspar, albite, quartz, biotite, amphibole, and metal sulfides. The metal sulfides in the orbicular ore include pyrite, pyrrhotite, pentlandite, and chalcopyrite. According to the color, crystalline shape, texture, and occurrence, pyrrhotite can be classified into four types (I, II, III, and IV), and chalcopyrite into two types (I and II), of which types I, II, and III pyrrhotite and type I chalcopyrite have a close genetic relationship with graphite. The granular types (I, II, and III) of pyrrhotite are enriched in Co, Ni, Se, Ge, and Te and are depleted in As, Sb, Ag, and Au; they also have a high value of Co/Ni, indicating that these types of pyrrhotite have a magmatic origin. Low values of Co/Ni suggest that type IV pyrrhotite has a hydrothermal origin. The similar contents of Co and Ni and the values of Co/Ni compared with the chalcopyrite from the magmatic Co–Ni sulfide deposits imply that type I chalcopyrite has a magmatic origin. In summary, the metal sulfides of the Huangyangshan deposit are genetically related to graphite mineralization and formed predominantly by magmatic processes

Ore Genesis of Shanmen Ag Deposit in Siping Area of Southern Jilin Province, NE China: Constraints from Fluid Inclusions and H-O, S, Pb Isotopes

The Shanmen Ag deposit, located in the southeastern part of the Siping area, Jilin Province, is one of the large-scale Ag deposits in Northeastern (NE) China. Almost all Ag orebodies, Ag-bearing quartz-sulfide veins are strictly controlled by NE-trending faults or brittle fractures and are hosted in the Yanshanian monzonite and quartz diorite. In terms of deposit geology, three mineralization stages are recognized: the pyrite-quartz stage (I), the quartz-Ag-polymetallic sulfide stage (II), and the carbonate-quartz stage (III). The research results of the fluid inclusions in the different stages indicate that the early stage (Stage I) mainly contains three types of fluid inclusions: liquid-rich two-phase (L-type), vapor-rich two-phase (V-type), and CO2 aqueous multi-phase (C-type). The fluid belongs to a medium–high temperature and medium–low salinity H2O-NaCl-CO2 system and has boiling characteristics. The middle stage (Stage II) is mainly characterized by liquid-rich two-phase (L-type) and vapor-rich two-phase (V-type) inclusions, in which the mixing of fluids of different nature leads to the escape of CO2. Only liquid-rich two-phase (L-type) inclusions are distinguished in the late stage (Stage III). The fluids of two later stages belong to the medium-low-temperature and low-salinity H2O-NaCl system. Homogenization temperatures from the early to late stages range from 272.2 to 412.5 °C, 124.1 to 313.3 °C, and 128.6 to 224 °C, respectively. Fluid salinities in the early to late stages range from 1.6 to 12.1, 1.4 to 8.9, and 0.4 to 5.8 wt.% NaCl equivalent, respectively. The gradually decreasing trends of homogenization temperatures and salinities and the reduction in the CO2 content indicate that the release of CO2 and the low-temperature environment are important causes of the precipitation of Ag-bearing minerals. The δ18OH2O values of the ore-bearing quartz veins in the different stages range from −3.7 to +8.1‰, and the δD values of fluid inclusions in the quartz range from −113 to −103‰, indicating that the initial ore-forming fluid was mainly derived from magma and that the input of meteoric water gradually increased during the mineralization process. The δ34S values (ranging from −11.4‰ to +1.8‰) and Pb isotope compositions (206Pb/204Pb = 18.143–18.189, 207Pb/204Pb = 15.543–15.599, 208Pb/204Pb = 38.062–38.251) of sulfides suggest that the ore-forming materials have mixed mantle and crustal sources. Therefore, we propose that the release of CO2 and the low-temperature environment are important conditions for silver minerals precipitation, and the mixing of fluids of different nature is the dominant mechanism causing precipitation. The Shanmen Ag deposit can be classified as an intrusion-related medium–low temperature hydrothermal vein-type deposit

Magma Evolution and Constraints on the Graphite Mineralization Hosted by the Huangyangshan Alkaline Granite Suite in the East Junggar of Xinjiang Province: Evidence from In Situ Analyses of Silicate Minerals

The Huangyangshan super-large graphite deposit, located in the East Junggar area of the Xinjiang Province, is hosted in and has closely temporal, spatial, and genetic relationships with the Huangyangshan alkaline granites. There are such silicate minerals as amphibole, biotite, pyroxene, and plagioclase occurring in the graphite-bearing granites. The integration of the electron microprobe analysis (EMPA) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) enabled us to reveal the physicochemical conditions and evolution process, as well as the relationship of alkaline magmatism with graphite mineralization. The results show that the amphiboles generally have low Al and high Ti, K, Si, and Fe contents, as well as similar rare-earth elements (REEs) patterns and trace element distribution patterns to granites with significantly negative Eu anomalies. In the analyzed samples, primary biotite belongs to Fe-biotite and has characteristics of high Si and Fe and low Al and Mg contents. In the graphite orbicules, the pyroxene phenocrysts develop multiple zonal structures and are characterized by high Si and low Ca and Fe contents. The dominant plagioclase phenocrysts in the graphite orbicules are oligoclase and andesine, with normal and occasionally oscillatory zoning. The calculated crystallization temperature of the pyroxene, amphibole, and primary biotite in graphite orbicules are 840–1012 °C, 681–761 °C, and 658–720 °C, respectively, corresponding with their crystallization order. The pressure and depth calculation results of the amphibole, representing those of the magmatism, are 157–220 Mpa and 5.95–8.32 km, respectively. Both amphibole and biotite crystallized in a reducing environment with extremely low oxygen fugacity. The elemental compositions of these silicates indicate that the Huangyangshan pluton experienced significant mixing of mafic mantle-derived magma and felsic crust-derived magma. The cores of graphite orbicules were formed in a relatively earlier magmatic stage, while the granites and their dioritic enclaves were formed in a later magmatic stage. During magmatism, the mixing of mantle-derived basic magma had an important influence on the evolution and differentiation of the melts. According to the coexisting sulfides with graphite and compositional difference of amphibole and biotite in the granites and graphite ores, the graphite mineralization might be triggered by a magma mixing process

Optimization of control plan for stability of end slope with weak layer in Dongming Open-pit Coal Mine

Aiming at the problems of faults, precipitation, weak layers and other factors inducing the deformation and instability of the end slope of the open-pit mine, taking the north slope of Dongming Open-pit Mine as the engineering practice background, the method of combining numerical simulation theory and limit equilibrium analysis is used. The influence of the weak layer of the north side slope on the deformation and displacement law of the slope rock and soil, and at the same time, combined with the limit equilibrium analysis method to control the stability of the north side slope, two schemes are proposed, namely, slope cutting and load reduction + pressure reduction. Through analysis and research, and based on the calculation results of Geo-slope and engineering geological conditions, the plan of slope cutting and load reduction + presser foot is finally adopted, which provides a reference for safe and efficient production during actual mining

Age, Genesis and Tectonic Setting of the Sayashk Tin Deposit in the East Junggar Region: Constraints from Lu–Hf Isotopes, Zircon U–Pb and Molybdenite Re–Os Dating

The Sayashk tin (Sn) deposit is located within the southern part of the Eastern Junggar orogenic belt in Xinjiang Province and forms part of the Kalamaili alkaline granite belt. There are many Sn polymetallic deposits in the area. To constrain the age, genesis, and tectonic setting of the Sayashk tin deposit in the East Junggar region, we conducted a bulk-rock geochemical analysis of the granite porphyry (SR1) and medium- to fine-grained granite (SR2) hosts of the deposit, LA-ICP-MS zircon U–Pb dating and Lu–Hf isotopic analysis, as well as molybdenite Re–OS dating and combined our results with the metallogenic conditions and other geological characteristics of the deposit. The results show that the Sayashk Sn deposit is indeed spatially, temporally, and genetically closely related to the granite porphyry and medium-fine-grained granite. Both zircon U–Pb ages are 308.2 ± 1.5 Ma and 310.9 ± 1.5 Ma, respectively. The isochron age of molybdenite is 301.4 ± 6.7 Ma, which represents the crystallization age of the granite porphyry and medium-fine-grained granite. Therefore, all of them formed in the late Carboniferous epoch. The medium-fine-grained granites and granite porphyry are characteristically rich in Si and alkali, poor in Ca and Mg, rich in high field-strength elements (HFSE, e.g., Zr, Hf) and Ce, and deficient in Ba, Sr, Eu, P, and Ti. They are typical A-type granites, showing the characteristics of a mixed crustal mantle source. The εHf(t) values of the zircon from the granite porphyry (SR1) range from 10.27 to 16.17 (average 13.71), εHf(t) values of the zircon from the medium-fine-grained granites (SR2) are between 5.72 and 9.21 (average 7.08), and the single model ages (TDM1) and two-stage model ages (TDM2) of the granite porphyry (SR1) fall within the ranges of 319~535 Ma and 339~644 Ma. The single model ages (TDM1) and two-stage model ages (TDM2) of the medium-fine-grained granites (SR2) fall within the ranges of 346~479 Ma and 309~557 Ma. There is little difference between their two-stage model ages and zircon U–Pb ages, indicating that the Sayashk granite may be the product of partial melting of juvenile crustal. Combined with previous research results, the Sayashk Sn deposit formed in a post-collision extensional tectonic setting after the late Carboniferous in the Kalamaili area

Fine-Granularity Urban Microclimate Monitoring Using Wearable Multi-Source Sensors

With the development of urbanization, the environment is the key to the safety of residents’ life and health and the United Nations’ Sustainable Development Goals (SDGs). Urban environmental changes and microclimate problems have attracted widespread attention. For the SDGs, monitoring the urban microclimate more accurately and effectively and ensuring residents’ environmental health and safety is particularly important when designing applications that can replace the traditional fixed-point urban environment or pollution monitoring. Based on the BeiDou Navigation Satellite System platform, this paper proposes a fine-granularity urban microclimate monitoring method using wearable multi-source (PM2.5, PM10, and other air pollutants) sensors innovatively, which includes the satellite position function by adopting the satellite pseudo-range differential positioning technology, environmental data perception through the embedded system and wireless transmission, as well as the GIS data processing and analysis system. The wearable sensor acquires position and service information data through the satellite positioning system and acquires environmental parameters through integrated mobile multi-source sensors. The data are cached and wirelessly transmitted to the cloud server for digital processing. The urban microclimate is evaluated and visualized through algorithm and map API. Mobile monitoring can be flexibly applied to complex and diverse urban spaces, effectively realizing all-weather, all-directional, and accurate microclimate monitoring of urban environmental quality