Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors.

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

High-Performance and Stable Sb2S3 Thin-Film Photodetectors for Potential Application in Visible Light Communication.

Photodetectors (PDs) are critical parts of visible light communication (VLC) systems for achieving efficient photoelectronic conversion and high-fidelity transmission of signals. Antimony sulfide (Sb2S3) as a nontoxic, high optical absorption coefficient, and low-cost semiconductor becomes a promising candidate for applications in VLC systems. Particularly, Sb2S3 PDs were verified to have significantly weak light detection ability in the visible region. However, the response speed of Sb2S3 PDs with existing device structures is still relatively slow. Herein, through optimizing the device structure for the p-i-n type PDs, a p-type Sb2Se3 hole transport layer (HTL) is designed to enhance the built-in electric field and to accelerate the migration of photogenerated carriers for the high responsivity and fast response speed. The optimal thickness of the structure is obtained through the simulation of SCAPS-1D software, and the optimized devices show high-performance parameters, including a responsivity of 0.34 A W-1, a specific detectivity (D*) of 2.20 × 1012 Jones, the -3 dB bandwidth of 440 kHz, high stability, and the value of the Sb2S3 PDs can reach 60% in the range of 360-600 nm, which indicates that the device is very suitable for working in the visible light band. In addition, the resulting Sb2S3 PD is successfully integrated into VLC systems by designing a matched light detection circuit. The results suggest that the Sb2S3 PDs are expected to provide an alternative to future VLC system applications.

Cu-Catalyzed Synthesis of Benzoxazole with Phenol and Cyclic Oxime.

A Cu-catalyzed straightforward synthesis of benzoxazoles from free phenols and cyclic oxime esters is reported. The mild reaction conditions tolerate various electron-withdrawing and electron-donating functional groups on both substrates, affording benzoxazoles in moderate to good yields. With this protocol, large-scale syntheses of Ezutromid and Flunoxaprofe in one or two steps are demonstrated. A catalytic mechanism, which includes Cu-catalyzed amination via inner-sphere electron transfer and consequent annulation, is proposed.

Biogeochemistry of Dominant Plants and Soils in Shewushan Gold Lateritic Deposit, China.

This paper describes the effect of mineral elements on dominant plants in the Shewushan lateritic gold deposit, China. For this purpose, 30 soil profile samples at different depths and 3 kinds of dominant plants including Populus canadensis (Populus X canadensis Moench), Cinnamomun camphora (Cinnamomum camphora (L.) Presl.) and Rhus chinensis (Rhus chinensis Mill.) were collected. The concentration of ore-forming elements including Au, Ag, Pb, Zn, Cu, As, Fe, and S were analyzed. Based on the investigation of two mine profiles, it can be found that Au, Pb, As, and Fe were mainly enriched in laterite layer and the brown clay layer at a depth of 5-11 m. Moreover, the biological accumulate coefficient (BAC) and the contrast coefficient (CM) were calculated to assess the sensitivity and concentrating ability of Populus canadensis and Cinnamomun camphora. To investigate the response of the two species to metal stress, the contents of chlorophyll, malondialdehyde (MDA), and activities of superoxide dismutase (SOD) and peroxidase (POD) were determined. The result showed that Populus canadensis and Cinnamomun camphora have a high tolerance to metal stress and that both of the two species can indicate the content of Au, As, Pb, and Co in topsoil.

Accumulation of uranium and heavy metals in the soil-plant system in Xiazhuang uranium ore field, Guangdong Province, China.

Plants that have grown for many years in the special environmental conditions prevailing in mining areas are naturally screened and show strong capacity to adapt to their environment. The present study investigated the enrichment characteristics of U and other heavy metals (As, Cu, Pb, Mn, Mo, Zn, Cd, Co, and Ni) in the soil-plant system in Xiazhuang uranium mine. Four dominant plants (Castanopsis carlesii, Rhus chinensis, Liriodendron chinense, and Sapium discolor) and soil samples were collected from the mined areas, unmined areas, and background areas away from the ore field. U, As, Cu, Pb, Mn, Mo, Zn, Cd, Co, and Ni concentrations were analyzed by ICP-MS. The results demonstrate that (1) The highest concentrations of U (4.1-206.9 mg/kg) and Pb (43.3-126.0 mg/kg) with the geoaccumulation index (Igeo) greater than 1 show that they are the main soil pollutants in the research area. (2) The biological accumulation coefficient (LBAC) values for Cd, Mn, and Cu are greater than zero in S. discolor, L. chinense, and C. carlesii and these three plants indicate that they can be used for remediation of the soil in the ore field. (3) R. chinensis inhibits the accumulation of heavy metals and shows sensitive pigment responses to the accumulation of U in the leaves. L. chinense has the strongest enrichment effect on heavy metals but exhibits weak biochemical responses under U stress. C. carlesii demonstrates strong adaptation to U and can maintain healthy pigment characteristics in case of high U enrichment. (4) S. discolor, L. chinense, C. carlesii and R. chinensis have strong tolerance to U toxicity and different biochemical responses.

Health risk assessment of heavy metals in the soil-water-rice system around the Xiazhuang uranium mine, China.

Heavy-metal pollutants in the soil and surface water of agricultural areas accumulate in rice and may have adverse effects on the health of consumers. In this study, we determined the levels of heavy-metal contamination in agricultural areas around the Xiazhuang uranium deposits in northern Guangdong Province, China, using equidistant sampling methods along a river near the mine tailings. The pH values of all the water samples were determined. The heavy-metal concentrations in water, bottom sludge, and rice were measured. The extent of contamination was evaluated by calculating Nemerow's pollution index, contamination factor, and hazard quotient. The result shows U transferred from mine to soil and rice with irrigation water. The main pollutants and their pollution indices in soil are U (6.31), Th (4.02), Pb (2.52), Cd (2.36), Zn (1.52), and Mn (1.39). The rice grain can hardly enrich U and Th but were susceptible to Cr and Ni. The contamination factors (CFs) of the pollutants in rice grain are Cr (1.98) and Ni (3.09). The hazard quotient (HQ) shows that Cu (HQ > 1) could pose potential risks for humans upon long-term consumption of the rice.

Robust MST-Based Clustering Algorithm.

Minimax similarity stresses the connectedness of points via mediating elements rather than favoring high mutual similarity. The grouping principle yields superior clustering results when mining arbitrarily-shaped clusters in data. However, it is not robust against noises and outliers in the data. There are two main problems with the grouping principle: first, a single object that is far away from all other objects defines a separate cluster, and second, two connected clusters would be regarded as two parts of one cluster. In order to solve such problems, we propose robust minimum spanning tree (MST)-based clustering algorithm in this letter. First, we separate the connected objects by applying a density-based coarsening phase, resulting in a low-rank matrix in which the element denotes the supernode by combining a set of nodes. Then a greedy method is presented to partition those supernodes through working on the low-rank matrix. Instead of removing the longest edges from MST, our algorithm groups the data set based on the minimax similarity. Finally, the assignment of all data points can be achieved through their corresponding supernodes. Experimental results on many synthetic and real-world data sets show that our algorithm consistently outperforms compared clustering algorithms.

Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.

BACKGROUND: Increasing evidence suggests seizures cause blood-brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. However, the mechanisms underlying BBB damage in seizures remains poorly understood. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures. METHODS: Thirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3-15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood-brain barrier permeability. RESULTS: We found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P < 0.001). CSF MMP-9 levels and QAlb values were higher in RS patients compared with SS and controls. Moreover, CSF MMP-9 concentration showed strong correlation between QAlb values (r = 0.76, P < 0.0001) and between CSF leukocyte counts (r = 0.77, P < 0.0001) in patients after seizures. Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients. CONCLUSIONS: Our results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures.

[XRD, FTIR and XPS analysis of oxidized particles from Dongshengmiao pyrite-polymetallic sulfide deposit, inner Mongolia].

In the present paper, characteristics of material compositions, phase structures, surface element states, and transformation mechanism of oxidized particles from Dongshengmiao pyrite-polymetallic sulfide deposit were studied using modern analytical testing technology including XRD, FTIR and XPS. The results show that the samples consist of gypsum, calcite, quartz, muscovite, goethite, organic matter, etc. Primary ore in deep oxidation zone mainly under went such processes as oxidization, hydrolysis, dehydration and carbonation. Compared to the surface oxidation zone of arid and extremely arid regions in the northwestern China, the oxidation process and oxidizing condition of the deep oxidation zone were less complex. New mineral type was also not found, and extensively developed sulfate minerals were rare to be seen. The research results can not only be applied to mineral identification of oxidized particles from this type of ore deposit but also play an important role in ore exploration, mining, mineral processing, etc.

Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure.

BACKGROUND: Ubiquitin carboxy-terminal hydrolase (UCH-L1) has been established as a reliable and potential biomarker of neuronal damage after acute neurologic insults such as ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. The effects of seizures on UCH-L1 levels in cerebrospinal fluid (CSF) has not been investigated in epileptic patients. The aim of the present study was to evaluate whether CSF UCH-L1 levels are a reliable marker of brain damage from epileptic seizures. METHODS: Thirty-three patients with epilepsy (mean age 45 years) participated. Twenty-five patients had generalized seizures and eight had partial seizures. CSF was sampled by lumbar puncture. The control samples were obtained from 23 adult patients on whom lumbar puncture was performed to exclude neurological disease. CSF UCH-L1 levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Patients with epilepsy had significantly elevated CSF levels of UCH-L1 after seizures compared with controls (p<0.001). CSF UCH-L1 levels were significantly higher in patients with generalized seizures than in patients with partial seizures and controls (p<0.001). Moreover, patients with repetitive generalized tonic-clonic (GTC) seizures had higher CSF UCH-L1 levels than those with a single GTC seizure (p<0.001). CSF UCH-L1 levels in seizure patients showed strong correlation with severity of seizures (r=0.56) and seizure duration (r=0.77). Conversely, CSF UCH-L1 levels in seizure patients did not correlate with the age of patients, duration of epilepsy, age of first seizure, time from last seizure or number of seizures. CONCLUSIONS: Our results suggest that UCH-L1 may serve as a novel biomarker for neuronal damage after epileptic seizure.

Osteochondral autograft transplantation for acute osteochondral fractures associated with an ankle fracture.

BACKGROUND: Osteochondral fractures of the talar dome (OCFT) are frequently associated with ankle fractures. Controversy exists regarding the treatment of acute Grade III and IV OCFT. Osteochondral autograft transplantation (OAT) is a possible operative solution. MATERIALS AND METHODS: We performed OAT in 16 patients with acute Grade III or IV OCFT. There were ten males and six females with the average age of 33.9 (range, 18 to 49) years. The average period of followup was 36.3 (range, 21 to 48) months. OCFT was identified, and clinically determined to be Grade III or IV using radiographs and intraoperative assessment. Seven patients were Grade III, nine patients were Grade IV OCFT. The OAT consisted of two sequential procedures: 1) harvesting of osteochondral autograft cylinder from the nonweightbearing surface of the ipsilateral knee, and 2) implanting the donor graft into the talar defect with press-fit technique. Single cylinder transplantation or a mosaicplasty was used. The outcome was determined by the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, the simplified symptomatology evaluation, plain radiography and MRI. RESULTS: The mean size of the osteochonral fracture defects was 84.1 (range, 50 to 125) mm(2), and the mean depth was 2.5 (range, 1 to 5) mm. The mean AOFAS score was 95.4 (range, 86 to 100) points postoperatively. At the latest followup, there was no radiographic evidence of post-traumatic arthritis. Based on the MRI of all patients, 93.7% of the osteochondral grafts showed bony integration and articular congruity of the talar dome. CONCLUSION: OAT was shown to be an effective treatment with excellent clinical outcome and imaging evidence of graft integration.

[Influence of Cibotium barametz and its processed samples on haemorheology index in mice with adjuvant arthritis].

OBJECTIVE: To discuss the influence of the rhizome of Cibotium barametz on the heamorheology index in mice with adjuvant arthritis and to compare the effect of raw medicinals with that of the processed ones. METHOD: Mice was injected with Freund's complete adjuvant on the rihgt behind foot to make model of adjuvant arthritis (AA). Hydroxyacrbamide tablets were orally administrated by mice with AA to make model of AA due to deficiency in the kidney (DK-AA). And then we determined the heamorheology index of the normal group, positive control group, AA group, DK-AA group and medicinals-treated groups. RESULT: In the groups of AA, and DK-AA, the heamorheology index, such as high shearing, middle shearing, low shearing, plasma viscosity, whole blood reduction viscosity, erythrocyte aggregation exponent, erythrocyte degeneration exponent, sedimentation, sedimentation equation K value, erythrocyte rigidity exponent, erythrocyte electrophoresis time, casson viscosity, casson yield stress, increased significantly. After treated with Cibotium barametz, the heamorheology index except red blood count, packed cell volume, fibrinogen decreased obviously to get normal. CONCLUSION: Rhizome of Cibotium barametz could promote heamorheology in mice with AA and DK-AA to exhibit effect of promoting blood circulation and remove blood stasis. The medicinal rhizomes processed with sand have the effect enhanced.