Based on radon gas properties and its existing projects applications, we firstly attempted to apply geo- physical and chemical properties of radon gas in the field of mining engineering, and imported radioac- tive mea...Based on radon gas properties and its existing projects applications, we firstly attempted to apply geo- physical and chemical properties of radon gas in the field of mining engineering, and imported radioac- tive measurement method to detect the development process of the overlying strata mining-induced fractures and their contained water quality in underground coal mining, which not only innovates a more simple-fast-reliable detection method, but also further expands the applications of radon gas detection technology in mining field. A 3D simulation design of comprehensive testing system for detecting strata mining-induced fractures on surface with radon gas (CTSR) was carried out by using a large-scale 3D solid model design software Pro/Engineer (Pro/E), which overcame three main disadvantages of ''static design thought, 2D planar design and heavy workload for remodification design'' on exiting design for mining engineering test systems. Meanwhile, based on the simulation design results of Pro/E software, the sta- bility of the jack-screw pressure bar for the key component in CTSR was checked with a material mechan- ics theory, which provided a reliable basis for materials selection during the latter machining process.展开更多
The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate...The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.展开更多
基金support for this work provided by the Fundamental Research Funds for the Central Universities(China University of Mining & Technology) (No. 2010ZDP02B02)the State Key Laboratory of Coal Resources and Safe Mining(No. SKLCRSM08X02)
文摘Based on radon gas properties and its existing projects applications, we firstly attempted to apply geo- physical and chemical properties of radon gas in the field of mining engineering, and imported radioac- tive measurement method to detect the development process of the overlying strata mining-induced fractures and their contained water quality in underground coal mining, which not only innovates a more simple-fast-reliable detection method, but also further expands the applications of radon gas detection technology in mining field. A 3D simulation design of comprehensive testing system for detecting strata mining-induced fractures on surface with radon gas (CTSR) was carried out by using a large-scale 3D solid model design software Pro/Engineer (Pro/E), which overcame three main disadvantages of ''static design thought, 2D planar design and heavy workload for remodification design'' on exiting design for mining engineering test systems. Meanwhile, based on the simulation design results of Pro/E software, the sta- bility of the jack-screw pressure bar for the key component in CTSR was checked with a material mechan- ics theory, which provided a reliable basis for materials selection during the latter machining process.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11904036 and 12175081)Fundamental Research Funds for the Central Universities(Grant No.CCNU22QNOO4)。
文摘The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.
