Since the prevention and mitigation of man-made hazards have been deemed to be the key in developing sustainable infrastructure during rapid urbanisation. Recent four massive water leak incidents ...taken place throughout subway construction in the soft alluvial deposits at Taipei and Kaohsiung, Taiwan, respectively, were reviewed and analysed in this study. The water leak incidents are initiated by the piping either through vertical joints between adjacent wall panels or through the seepage-prone weak zones within soilcrete body. The running leak can be traced using the variation in the piezometric pressure, and similar but smaller variations can also be seen from the soil layers at shallow depths. Lessons learned from this study would be useful in ensuring the highest quality on joints for diaphragm walls and mitigating the effect of ineffective overlapping of jet-grout columns on the watertight effectiveness while digging sump pit or dealing with tunnel-station interface.
The seismic response of an active ground fissure site was simulated by a shaking table test and a FLAC3D numerical simulation model. Coupled dynamic ground motions of earthquake and fissure activity ...were loaded on the model. The characteristics of the fissure site, that is, the movement of the hidden fissure, the uneven subsidence, the acceleration and the lateral and vertical soil pressures, were monitored and analyzed. The following observations were made from this study. The subsidence of the hanging wall was greater than that of the footwall. The stretch caused by the uneven subsidence led to the appearance of the hidden fissure and the gradual widening of the fissure. The peak acceleration in the hanging wall was larger than that of the footwall. The PGA increased with the height of the site. The magnification coefficient of the PGA had the largest value in the fissure, and the magnification coefficient of the PGA decreased with earthquake intensity. The increments of lateral and vertical soil pressure also increased with earthquake intensity. The vertical soil pressure at the location of the fissure was the largest. These dynamic characteristics are vital to the safety design of underground structures in a fissure site.
•The shaking table test and numerical simulation analysis were utilized to study the behavior of ground fissure sites.•The uneven settlement led to the appearance and widening of the hidden fissure.•The acceleration was larger in the hanging wall, and the PGA was largest in the fissure.•The increments of lateral and vertical soil pressure increased with earthquake density.
This paper studies the seismic response of a segmented metro tunnel with flexible joints passing through active ground fissures in Xi’an by shaking table model test. A coupling dynamic ground motion ...was generated in the test model. The tunnel acceleration, earth pressure and tunnel structure strain were monitored and compared. It was observed that each part of the tunnel has an independent movement with flexible joints. The tunnel located in the hanging wall has 3.17 times peak acceleration than that in the foot wall. Higher magnitudes of earth pressures were recorded close to the areas of the ground fissures. The earth pressure in the hanging wall was greater than that in the foot wall. The coupling loads increase the earth pressure. The strain in the middle of the tunnel arch was the largest. The strain at the bottom of the floor was the secondary. The one on the top of the arch was the smallest. The strain increased less in each section because the tunnel is divided into four parts by flexible joints, and no sharp strain increase close to the ground fissure was observed. The results indicate that the flexible joints can decrease the stress concentration. The tunnel with flexible joints can adjust to large deformations in the ground fissure areas.
•The shaking table model test is utilized for the first time to study the behavior of ground fissures sites.•Accelerations are monitored during the loading of the earthquake waves.•Earth pressures are compared in the hanging wall and foot wall.•Flexible joints could effectively reduce the strains of the segmented metro tunnel.
The Litang fault is a left-lateral secondary shear zone in the Sichuan-Yunnan active block that accommodates the tectonic deformation associated with the eastward extrusion of the upper crust of the ...Tibetan Plateau. Based on 1: 50 000 geological mapping of active faults, the Litang fault consists of three geometric segments, the Cuopuhu, Damaoyaba, and Litang segments, in the west of Litang, which are divided by the of Haizi Mountain uplift and the wide-angle bending and branching of the fault near Jinchanggou. This study also identifies the surface rupture of the A.D. 1890 earthquake, which is distributed intermittently along the ∼28 km long Damaoyaba segments and ∼25 km long Litang segments. The maximum horizontal displacement is 4.1 m along Damaoyaba segments, and 4 m along Litang segments. The rupture involves typical left-lateral shear movement. The two ruptures are divided by discontinuous segments or gaps that are ∼18 km long; thus, the total surface rupture is approximately 71 km long. The estimated moment magnitude was
M
w
7.3±0.1. A comprehensive analysis of data obtained from 5 trenches excavated along the Damaoyaba and Litang segments and the trench data by Xu et al. (2005) identifies age constraints of the 4 most recent paleoseimic events occurred B.C. 1468±54–1340±25, B.C. 52±25–A.D. 76±47, A.D. 1115±90, and A.D. 1890, respectively. The recurrence intervals are 1 415±80, 1 104±104, and 775±90 a, which are consistent with quasi-periodic earthquake recurrence behavior. The average recurrence interval is 1 098±112 a.
Lattice beam and prestressed anchor rod are used to enhance stability and prevent failure of soil or rock slopes. In this study, a model of Lattice beam and prestressed anchor rod (LBPAR) system was ...designed with reinforcement mechanisms and a model test was constructed with a circular slip surface of a loess slope. First, interaction between the loess slope and the LBPAR system was investigated by an LBPAR system analysis model. Stability of sliding mass from the sliding bed with an arc-shaped sliding surface was then studied by an experimental model designed. Finally, internal force distribution of lattice beams in the LBPAR system was investigated by using a large-scale physical model test. The results were compared to those calculated using the reverse beam method, indicating that the LBPAR system strengthened the sliding mass in space and improved the overall stability of the loess slope. With vertical loading, the axial tensile stress of the main anchor rod increases continuously. The bending area of the anchor rod was concentrated within 2 m of the sliding surface. And the maximum bending moment reaches 70 N·m. The sliding mass was subject to vertical load pressure, lattice beams’ pressure, and dead weight in the meantime and the maximum earth pressure value is near the node of the lattice beams. It is proved that such a method excels in the engineering design of loess landslides, which has promising applications in the future.
•The seismic response of an active ground fissure site subjected to earthquake is studied by the shaking table test.•The settlement increased with the earthquake acceleration.•The secondary fissures ...and new cracks developed and appeared during the earthquake.•The high frequency component of the wave was reduced from the bottom to the top of the site.
This paper studies the seismic response of an active ground fissure site subjected to earthquake by the shaking table model test. The settlement was induced by the earthquake in the ground fissure site. The settlement increased with the earthquake peak acceleration. The differential settlement has a third-order polynomial relationship with the earthquake intensity. The process of the settlement has three periods, including the rapid deformation stage, the stable deformation stage, and the accelerated development stage. The greatest settlement is in the hanging wall close to the fissure. The secondary fissures and new cracks developed and appeared during the earthquake. The high frequency component of the wave was reduced from the bottom to the top of the site and the low frequency component was amplified. The Fourier amplitude gradual increases correspond to the earthquake acceleration. The results discovery the relationship of subsidence, widen of fissure and the earthquake. It is contribute to the metro design of the fissure area.
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need ...to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC(99)) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 microM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 microM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs.
Docking scoring functions are notoriously weak predictors of binding affinity. They typically assign a common set of weights to the individual energy terms that contribute to the overall energy ...score; however, these weights should be gene family dependent. In addition, they incorrectly assume that individual interactions contribute toward the total binding affinity in an additive manner. In reality, noncovalent interactions often depend on one another in a nonlinear manner. In this paper, we show how the use of support vector machines (SVMs), trained by associating sets of individual energy terms retrieved from molecular docking with the known binding affinity of each compound from high-throughput screening experiments, can be used to improve the correlation between known binding affinities and those predicted by the docking program eHiTS. We construct two prediction models: a regression model trained using IC(50) values from BindingDB, and a classification model trained using active and decoy compounds from the Directory of Useful Decoys (DUD). Moreover, to address the issue of overrepresentation of negative data in high-throughput screening data sets, we have designed a multiple-planar SVM training procedure for the classification model. The increased performance that both SVMs give when compared with the original eHiTS scoring function highlights the potential for using nonlinear methods when deriving overall energy scores from their individual components. We apply the above methodology to train a new scoring function for direct inhibitors of Mycobacterium tuberculosis (M.tb) InhA. By combining ligand binding site comparison with the new scoring function, we propose that phosphodiesterase inhibitors can potentially be repurposed to target M.tb InhA. Our methodology may be applied to other gene families for which target structures and activity data are available, as demonstrated in the work presented here.
Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated ...therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases.
InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each ...year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial catalase-peroxidase KatG are promising candidates for treating infections caused by isoniazid-resistant strains. Previously we reported the synthesis of several diphenyl ethers with nanomolar affinity for InhA. However, these compounds are rapid reversible inhibitors of the enzyme, and based on the knowledge that long drug target residence times are an important factor for in vivo drug activity, we set out to generate a slow onset inhibitor of InhA using structure-based drug design. 2-(o-Tolyloxy)-5-hexylphenol (PT70) is a slow, tight binding inhibitor of InhA with a K1 value of 22 pm. PT70 binds preferentially to the InhA·NAD+ complex and has a residence time of 24 min on the target, which is 14,000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 Å crystal structure of the ternary complex between InhA, NAD+, and PT70 reveals the molecular details of enzyme-inhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket.
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