Application of Mine Micro-Seismic Monitoring System on Preventing Against Illegal Mining

AbstractThe establishment and application of the Mine Micro-seismic Monitoring System (MMS), provides a powerful method not only to monitor and predict the mine geological hazard, but also to monitor and prevent against the illegal mining. While there was illegal mining, the system can give you the information including the 3-dimensional spatial coordinates in real time.. The monitoring against the illegal mining was aimed at the blast events, so the blast events should be collected and analyzed specially. On the other hand, the energy of the blast events are larger enough to be easily recognized and be 3-d located and then be analyzed by the MMS, and then the satisfied information can be given by the MMS. This kind of usage of the system has been analyzed and confirmed by a practical example

Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2- d ]pyrimidines

We have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a SNAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and N-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor 9 is identified

Anomalously low ozone of 1997 and 2011 Arctic spring: Monitoring results and analysis

Total ozone observations from the Total Ozone Unit (TOU) aboard the Chinese second generation polar orbiting meteorological satellite, Fengyun-3/A (FY-3/A), revealed that total column ozone over the Arctic declined rapidly from the beginning of March 2011. An extensive region of low column amount formed around mid March; monthly mean total column ozone in March 2011 was about 30% lower than the average observed during 1979—2010. Daily total column density of ozone near the center of low ozone area in mid March was less than 240 Dobson units, about half the total column ozone amount observed during the same period of the prior 10 years. We analyzed total column ozone data from different satellites during 1979—2011. Results show that the Arctic depletion of ozone in spring 2011 was initiated by the cold polar vortex in the lower stratosphere. The March mean total ozone over the Arctic has shown a decreasing trend over the past 32 years, and its variation is strongly correlated with the polar vortex. A similar low ozone process of spring 1997 was compared to that of 2011, but daily variations of total ozone in March over the Northern Hemisphere in 1997 and 2011 have different patterns

Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors

Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogs as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional anti-tumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer

Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis

The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo-ring replacement strategy. The co-crystal structure of Mer with two compounds (7 & 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis

Evolution of vegetation and climate variability on the Tibetan Plateau over the past 1.74 million years

The Tibetan Plateau exerts a major influence on Asian climate, but its long-term environmental history remains largely unknown. We present a detailed record of vegetation and climate changes over the past 1.74 million years in a lake sediment core from the Zoige Basin, eastern Tibetan Plateau. Results show three intervals with different orbital- and millennial-scale features superimposed on a stepwise long-term cooling trend. The interval of 1.74–1.54 million years ago is characterized by an insolation-dominated mode with strong ~20,000-year cyclicity and quasi-absent millennial-scale signal. The interval of 1.54–0.62 million years ago represents a transitional insolation-ice mode marked by ~20,000- and ~40,000-year cycles, with superimposed millennial-scale oscillations. The past 620,000 years are characterized by an ice-driven mode with 100,000-year cyclicity and less frequent millennial-scale variability. A pronounced transition occurred 620,000 years ago, as glacial cycles intensified. These new findings reveal how the interaction of low-latitude insolation and high-latitude ice-volume forcing shaped the evolution of the Tibetan Plateau climate.publishedVersio

UNC2025 , a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

MERTK tyrosine kinase is ectopically expressed in 30–50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia

Application of plastic-damage multidirectional fixed smeared crack model in analysis of RC structures

This paper describes a plasticity-damage multidirectional fixed smeared cracking (PDSC) model to simulate the failure process of concrete and reinforced concrete (RC) structures subjected to different loading paths. The model proposes a unified approach combining a multidirectional fixed smeared crack model to simulate the crack initiation and propagation with a plastic-damage model to account for the inelastic compressive behaviour of concrete between cracks. The smeared crack model considers the possibility of forming several cracks in the same integration point during the cracking process. The plasticity part accounts for the development of irreversible strains and volumetric strain in compression, whereas the strain softening and stiffness degradation of the material under compression are controlled by an isotropic strain base damage model. The theoretical aspects about coupling the fracture, plasticity, and damage components of the model, as well as the model appraisal at both material and structural levels, have been detailed in a former publication. This study briefly summarizes the model formulations, and is mainly dedicated to further explore the potentialities of the proposed constitutive model for the analysis of concrete and RC structures. The model is employed to simulate experimental tests that are governed by nonlinear phenomenon due to simultaneous occurrence of cracking and inelastic deformation in compression. The numerical simulations have predicted with good accuracy the load carrying capacity, ductility, crack pattern, plastic (compressive) zone, and failure modes of all types of structures analysed. The influence of the model parameters that simulate the nonlinear behaviour of concrete under tension and compression is analysed through a parametric study.Portuguese Foundation for Science and Technology in the scope of the SlabSys-HFRC research project, with reference PTDC/ECM/120394/201