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"Tian, Yang"
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QSAR Study, Molecular Docking and Molecular Dynamic Simulation of Aurora Kinase Inhibitors Derived from Imidazo4,5-bpyridine Derivatives
Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.
Journal Article
إنقاذ العباقرة
تدور أحداث الرواية حول الطالب \"مايكل\" عبقري الفيزياء، الذي أسس جمعية للسفر عبر الزمن لإنقاذ عباقرة التاريخ من المصاعب والأزمات التي تعترض اكتشافاتهم العلمية ومسار حياتهم الطبيعية، وتساعده في ذلك صديقته الوحيدة الطالبة \"تشياو تشياو\" والإنسان الآلي \"ريكي\". والذين تتعدد مغامراتهم ما بين الصين القديمة واليونان القديمة وإنجلترا وسويسرا في العصور الوسطى، ويقابلون كلا من: عالم الرياضيات الإغريقي أرشميدس، والفيزيائي البريطاني إسحاق نيوتن، والبطل الشعبي السويسري ويليام تل.
Book
Ultra-compact fiber tapering: plasmonics and structural bending as new combination of heat and pull
Fabrication of optical fiber tapers is realized with a combination of plasmonic microheaters and specially designed structural bending of optical fibers, which provide the necessary elements of “heat and pull”. The resultant compactness and flame-free condition enable monitoring of the tapering process inside a scanning electron microscope.
Journal Article
إنقاذ العباقرة /
تدور أحداث الرواية حول الطالب \"مايكل\" عبقري الفيزياء، الذي أسس جمعية للسفر عبر الزمن لإنقاذ عباقرة التاريخ من المصاعب والأزمات التي تعترض اكتشافاتهم العلمية ومسار حياتهم الطبيعية، وتساعده في ذلك صديقته الوحيدة الطالبة \"تشياو تشياو\" والإنسان الآلي \"ريكي\". والذين تتعدد مغامراتهم ما بين الصين القديمة واليونان القديمة وإنجلترا وسويسرا في العصور الوسطى، ويقابلون كلا من: عالم الرياضيات الإغريقي أرشميدس، والفيزيائي البريطاني إسحاق نيوتن، والبطل الشعبي السويسري ويليام تل.
Book
A Survey of Recent Indoor Localization Scenarios and Methodologies
Recently, various novel scenarios have been studied for indoor localization. The trilateration is known as a classic theoretical model of geometric-based indoor localization, with uniform RSSI data that can be transferred directly into distance ranges. Then, a trilateration solution can be algebraically acquired from theses ranges, in order to fix user’s actual location. However, the collected RSSI or other measurement data should be further processed and classified to lower the localization error rate, instead of using the raw data influenced by multi-path effect, multiple nonlinear interference and noises. In this survey, a large number of existing techniques are presented for different indoor network structures and channel conditions, divided as LOS (light-of-sight) and NLOS (non light-of-sight). Besides, the input measurement data such as RSSI (received signal strength indication), TDOA (time difference of arrival), DOA (distance of arrival), and RTT (round trip time) are studied towards different application scenarios. The key localization techniques like RSSI-based fingerprinting technique are presented using supervised machine learning methods, namely SVM (support vector machine), KNN (K nearest neighbors) and NN (neural network) methods, especially in an offline training phase. Other unsupervised methods as isolation forest, k-means, and expectation maximization methods are utilized to further improve the localization accuracy in online testing phase. For Bayesian filtering methods, apart from the basic linear Kalman filter (LKF) methods, nonlinear stochastic filters such as extended KF, cubature KF, unscented KF and particle filters are introduced. These nonlinear methods are more suitable for dynamic localization models. In addition to the localization accuracy, the other important performance features and evaluation aspects are presented in our paper: scalability, stability, reliability, and the complexity of proposed algorithms is compared in this survey. Our paper provides a comprehensive perspective to compare the existing techniques and related practical localization models, with the aim of improving localization accuracy and reducing the complexity of the system.
Journal Article
Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing
Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. Here, we report that glycine, serine and threonine catabolic pathway is down-regulated in serum-resistant
Escherichia coli
, whereas exogenous glycine reverts the serum resistance and effectively potentiates serum to eliminate clinically-relevant bacterial pathogens in vitro and in vivo. We find that exogenous glycine increases the formation of membrane attack complex on bacterial membrane through two previously unrecognized regulations: 1) glycine negatively and positively regulates metabolic flux to purine biosynthesis and Krebs cycle, respectively. 2) α-Ketoglutarate inhibits adenosine triphosphate synthase, which in together promote the formation of cAMP/CRP regulon to increase the expression of complement-binding proteins HtrE, NfrA, and YhcD. The results could lead to effective strategies for managing the infection with serum-resistant bacteria, an especially valuable approach for treating individuals with weak acquired immunity but a normal complement system.
Serum-resistant bacteria can escape complement killing in the bloodstream. Here, using metabolomics and metabolite perturbations, the authors describe an altered metabolic state in serum-resistant
Escherichia coli
and show that exogenous glycine potentiates elimination of pathogenic bacteria in vivo.
Journal Article
Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS
Astroglia play active and diverse roles in modulating neuronal/synaptic functions in the CNS. How these astroglial functions are regulated, especially by neuronal signals, remains largely unknown. Exosomes, a major type of extracellular vesicles (EVs) that originate from endosomal intraluminal vesicles (ILVs), have emerged as a new intercellular communication process. By generating cell-type-specific ILVs/exosome reporter (CD63-GFP
f/f
) mice and immuno-EM/confocal image analysis, we found that neuronal CD63-GFP
+
ILVs are primarily localized in soma and dendrites, but not in axonal terminals in vitro and in vivo. Secreted neuronal exosomes contain a subset of microRNAs (miRs) that is distinct from the miR profile of neurons. These miRs, especially the neuron-specific miR-124-3p, are potentially internalized into astrocytes. MiR-124-3p further up-regulates the predominant glutamate transporter GLT1 by suppressing GLT1-inhibiting miRs. Our findings suggest a previously undescribed neuronal exosomal miR-mediated genetic regulation of astrocyte functions, potentially opening a new frontier in understanding CNS intercellular communication.
Our current understanding of exosome signaling among CNS cells is mostly limited to culture models. In this study, authors generated a new cell-type specific exosome reporter mouse line which allows the first in vivo investigation of the localization of neuronal exosomes in the CNS, and also potentially highlights the role of exosomally transferred miR-124-3p in mediating astroglial glutamate uptake function
Journal Article
Engineering Clostridium for improved solvent production: recent progress and perspective
Clostridia are Gram-positive, spore-forming, obligate anaerobic bacteria that can produce solvents such as acetone, ethanol, and butanol, which can be used as biofuels or building block chemicals. Many successful attempts have been made to improve solvent yield and titer from sugars through metabolic engineering of solventogenic and acidogenic clostridia. More recently, cellulolytic and acetogenic clostridia have also attracted high interests for their ability to utilize low-cost renewable substrates such as cellulose and syngas. Process engineering such as in situ butanol recovery and consolidated bioprocessing (CBP) has been developed for improved solvent titer and productivity. This review focuses on metabolic and process engineering strategies for solvent production from sugars, lignocellulosic biomass, and syngas by various clostridia, including conventional solventogenic
Clostridium acetobutylicum
, engineered acidogens such as
C. tyrobutyricum
and
C. cellulovorans
, and carboxydotrophic acetogens such as
C. carboxidivorans
and
C. ljungdahlii
.
Journal Article
Ferroptosis as a target for protection against cardiomyopathy
Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3−/−, Mlkl−/−, or Fadd−/−Mlkl−/− mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated upregulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated inmitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.
Journal Article