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The pressure-holding sampling technology for deep-sea sediments has been identified as a prerequisite for studying the sedimentary environment with respect to the mechanical and biological characteristics of sediments. Thus, in this study, we designed a set of abyssal sediment sampling systems based on image recognition technology. First, a system camera was used to obtain the movement trajectory of the sampling cone in the laboratory simulation scene. After collecting the data of the image including the sampler, we preprocessed the data using an underwater image restoration method based on the dark channel prior. An image recognition unit was used to verify that the position of the sampling cone meets the requirement. The main control unit controlled the actuator of the sampling device to accurately control the position of the sampling cone. Furthermore, we used the Mask R-convolutional neural network architecture to build the network framework for controlling the expansion and braking of the sampler. The experimental results showed that the system achieved a very high detection accuracy for the position of the sampling cone.

[Image: see text] The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

Weathered granite has been widely used as an emerging foundation filler for constructing transportation infrastructure. However, various softened rocks weathered due to exposure to water have special properties. Thus, it is necessary to gain a thorough understanding of the various physical and mechanical properties of weathered granite after exposure to water in order to avoid engineering accidents. To this end, this paper conducted a series of undrained triaxial shear tests to compare the mechanical behavior of weathered granite in natural and saturated states. The results demonstrate that the strength of the weathered granite significantly declines when it is exposed to water, and it exhibits noticeable water softening characteristics. Consolidation methods also affect the mechanical properties of weathered granite. The degree of softening of weathered granite decreases with an increase in the deviator stress imposed by the deviator stress consolidation. Subsequently, we established an empirical model for the strain softening of weathered granite suitable for natural and saturated conditions. This model took the elastic modulus of weathered granite before the peak strength as a measure and introduced the strength parameters of the internal friction angle (φ) and the internal cohesion (c). First, the fitted function correlating c and φ with the plastic internal variable was determined, and then the relationship between the strength and the strain-softening parameters was established so as to obtain the complete stress–strain curve of the granite rock. Finally, validation studies were performed to address the capability of the model to predict permanent deformation. It provides a theoretical basis for predicting and calculating the strain softening of weathered granite exposed to water.

Purpose This paper aims to analyse the effect of soft soil grouting on the deformation of the closed shield tunnel with the measured data. Design/methodology/approach Combining the measured data of vertical, horizontal and convergence deformation of the adjacent tunnel during the grouting construction in foundation pit engineering, the influence of grouting on metro tunnel in soft soil area is analyzed. Findings The researches indicate that early grouting has the main effect on the horizontal displacement of the tunnel; Due to the disturbing effect of the uninterrupted grouting construction on the soil and the transfer pressure of the rheological soil to the bottom of the tunnel, the tunnel is obviously lifted; And the convergence deformation of the tunnel increases caused by the overburden pressure in the vertical direction, so that the tunnel appears the phenomenon of staggered seam, large opening of bolted joint, damaged segment even leakage of water. Originality/value The study based on the field monitoring data is rarely reported, especially the topic about inadvertent grouting in soft soil area is likely to cause severe deformation of adjacent metro tunnel.

Imperfect interfaces due to manufacturing errors can affect the dynamic performance of multiferroic composite cylinders, especially in the high frequency range. However, the traditional transfer matrix method will encounter numerical instability when high frequency is involved. In this paper, an alternative approach called the reverberation-ray matrix method is presented for the wave propagation of a fluid-filled multiferroic composite cylinder with imperfect interfaces, which is unconditionally numerically stable for high frequency analysis. Based on the three-dimensional magneto-electro-elastic theory and the Hamiltonian state equation, the reverberation-ray formulations are established to analyze the dispersion relations of laminate composite cylinders. The effects of interfacial imperfection as well as different material and geometric parameters on the dispersion curves of multiferroic composite cylinders are investigated. The present method could be useful for the analysis and damage detection of layered composite cylinders.

A cable-struts structure consists of tension-only cables and compression-only struts. The structural rigidity comes from the pre-stress. To determine the feasible pre-stress for the cable-struts structure efficiently and accurately, the paper first defines the three states for the cable-struts structure based on the loads applied, develops the fuzzy relationship between the internal force and the pre-stress under different states, and studies various essential conditions for the feasible pre-stress. Second, the paper gives a Newton iteration method to update the pre-stress and a simple method for updating the geometry based on the geometrical difference under different states and subsequently develops a process to find the feasible pre-stress, combining the pre-stress updating method with the geometry updating method. Last, the paper selects three types of cable-struts structures as illustrative examples, a traditional Geiger dome, a new form of Geiger dome and a Kiewitt dome with multiple self-stress modes, and successively calculates their feasible pre-stress using the proposed method. The results indicate that the proposed method is able to search for the feasible pre-stress for cable-struts structures efficiently and accurately; it can calculate not only the pre-stress without loads but also the pre-stress considering loads, and it can change the geometry for the feasible pre-stress. Meanwhile, the method is successful in obtaining the feasible pre-stress for the Kiewitt dome with multiple self-stress modes without the optimal process.

Past reconnaissance studies revealed that bridges close to active faults are more susceptible to damage and more than 60% of the bridges in California are skewed. To assess the combined effect of near-fault ground motions and skewness, this paper evaluates the seismic vulnerability of skewed concrete box-girder bridges in California subjected to near-fault and far-field ground motions. The relative risk of skewness and fault-location on the bridges is evaluated by developing fragility curves of bridge components and system accounting for the material, geometric, and structural uncertainties. It is noted that the skewness and bridge site close to active faults make bridges more vulnerable, and the existing modification factor in HAZUS cannot capture the variation in the median value of the fragilities appropriately. A new set of fragility adjustment factors for skewness coupled with the effect of fault location is suggested in this paper., 5 Figure, 8 Table

Structure-borne noise induced by vehicle–bridge coupling vibration is harmful to human health and living environment. Investigating the sound pressure level and the radiation mechanism of structure-borne noise is of great significance for the assessment of environmental noise pollution and noise control. In this paper, the transient noise induced by vehicle–bridge coupling vibration is investigated by employing the hybrid finite element method (FEM) and boundary element method (BEM). The effect of local vibration of the bridge deck is taken into account and the sound responses of the structure-borne noise in time domain is obtained. The precision of the proposed method is validated by comparing numerical results to the on-site measurements of a steel girder-plate bridge in service. It implies that the sound pressure level and its distribution in both time and frequency domains may be predicted by the hybrid approach of FEM–BEM with satisfactory accuracy. Numerical results indicate that the vibrating steel bridge radiates high-level noise because of its extreme flexibility and large surface area for sound radiation. The impact effects of the vehicle on the sound pressure when leaving the bridge are observed. The shape of the contour lines in the area around the bridge deck could be explained by the mode shapes of the bridge. The moving speed of the vehicle only affects the sound pressure components with frequencies lower than 10 Hz.

This paper considers the unusual behavior of functionally graded materials/structures when the surface effect is involved. It is found that on the assumption that the surface energy is not positive semi-definite, the solution can be non-unique. Several examples are given for simple spherically-symmetric and axisymmetric FGM bodies with surface effects characterized by Gurtin-Murdoch surface elasticity. The results show that the conditions for non-uniqueness of solution emerge when the magnitude of negative effective surface modulus is of the order of a characteristic dimension of the problem multiplied by the bulk modulus near the surface, which is quite different from that for homogeneous materials.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure–activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

In calculation of long-term tunnel settlement, non-linear regression method was insufficient to solve parameters of Deng Yinger’s settlement prediction model, so Intelligent Single Particle Optimization (ISPO) was introduced. In the algorithm we used a single particle to search answer in the solution space. In the searching process a new learning strategy was introduced to update the position of the particle, in this way to keep particle near to the global optimum value. Based on the Intelligent Single Particle Optimization (ISPO), long-term settlement of a Singapore tunnel, Shanghai East Yan'an Road Tunnel F19 and Shanghai subway line 1 N12 were predicted. Then the results were compared with the measured data of these tunnels. Results show that the standard deviation by predictive value of ISOP is nearly half of that by nonlinear regression method. This method overcomes the difficulty to determine mathematical model parameters as well as the difficulty to establish objective function. Besides, it provides a new way to predict long-term surface settlement after shield tunneling construction.

Mathematical modeling of the magnetoelectric (ME) effect has been established for some rectangular and disk laminate structures. However, these methods are difficult in other cases, particularly for complex structures. In this work, a new method for the analysis of the ME effect is proposed using a generalized Hamilton's principle, which is conveniently applicable to various laminate structures. As an example, the performance of the rectangular ME laminated composite is analyzed and the equivalent circuit model for the laminate is obtained directly from the analysis. The experimental data is also obtained to compare with the theoretical calculations and to validate the new method. Compared with Dong's method, the new method is more accurate and convenient. In particular, the equivalent circuit for the rectangular laminated composite can be obtained more easily by the proposed method as it does not require the complex treatment used in Dong's method.

[reaction: see text] In an effort to expand the scope of natural product in vitro glycorandomization (IVG), the substrate specificity of NovM was investigated. A test of four aglycon analogues and over 40 nucleotide sugars revealed NovM has a surprisingly stringent substrate specificity and provided only three new "unnatural" natural products. On the basis of the determined substrate specificity, an alternative to the sugar nucleotide biosynthetic dogma and a cautionary note for the general applicability of IVG are introduced.

In vitro “glycorandomization” is a chemoenzymatic approach for generating diverse libraries of glycosylated biomolecules based on natural product scaffolds. This technology makes use of engineered variants of specific enzymes affecting metabolite glycosylation, particularly nucleotidylyltransferases and glycosyltransferases. To expand the repertoire of UDP/dTDP sugars readily available for glycorandomization, we now report a structure-based engineering approach to increase the diversity of α- d -hexopyranosyl phosphates accepted by Salmonella enterica LT2 α- d -glucopyranosyl phosphate thymidylyltransferase (E p ). This article highlights the design rationale, determined substrate specificity, and structural elucidation of three “designed” mutations, illustrating both the success and unexpected outcomes from this type of approach. In addition, a single amino acid substitution in the substrate-binding pocket (L89T) was found to significantly increase the set of α- d -hexopyranosyl phosphates accepted by E p to include α- d - allo -, α- d - altro -, and α- d - talo pyranosyl phosphate. In aggregate, our results provide valuable blueprints for altering nucleotidylyltransferase specificity by design, which is the first step toward in vitro glycorandomization.

Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

Metabolite glycosylation is affected by three classes of enzymes: nucleotidylyltransferases, which activate sugars as nucleotide diphospho-derivatives, intermediate sugar-modifying enzymes and glycosyltransferases, which transfer the final derivatized activated sugars to aglycon substrates. One of the first crystal structures of an enzyme responsible for the first step in this cascade, alpha-D-glucopyranosyl phosphate thymidylyltransferase (Ep) from Salmonella, in complex with product (UDP-Glc) and substrate (dTTP) is reported at 2.0 A and 2.1 A resolution, respectively. These structures, in conjunction with the kinetic characterization of Ep, clarify the catalytic mechanism of this important enzyme class. Structure-based engineering of Ep produced modified enzymes capable of utilizing 'unnatural' sugar phosphates not accepted by wild type Ep. The demonstrated ability to alter nucleotidylyltransferase specificity by design is an integral component of in vitro glycosylation systems developed for the production of diverse glycorandomized libraries.

The exploitation of a unique thymidylyltransferase (Ep ) allows the rapid syntheses of thymidine and uridine 5'-(aminodeoxy-α-D-hexopyranosyl diphosphates), 5'-(acetamidodeoxy-α-D-hexopyranosyl diphosphates), and even 5'-(aminodideoxy-α-D-hexopyranosyl diphosphates), which are amino analogues of the products from the native reaction of Ep .

A new protocol to prepare chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines has been developed. The key steps are Pd/Cu-catalyzed couplings of chiral β-amino esters and aryl bromides, and intramolecular acylation.

N,N-Disubstituted amino esters were prepared by stereoselective conjugate addition of (S)- or (R)-lithium N -benzyl- N -α-methylbenzylamide to α,β-unsaturated esters. The couplings of the formed esters with ethyl glyoxalate followed by hydrogenation afforded 5-alkyl-4-carboethoxy-3-hydroxy-pyrrolidinones stereoselectively.

The synthesis of two isotype-selective antagonists for metabotropic glutamate receptors, (2S,1′ S,2′ S)-2-methyl-2-(carboxycyclopropyl)glycine and (S)-2-amino-2-methyl-4-phosphonobutyric acid from l -alanine is described.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Through scaffold morphing of a known Smoothened antagonist Antag691, a series of novel phenyl imidazole derivatives were developed. Structure-activity-relationship studies and lead optimization led to the discovery of potent, selective and orally bioavailable Smoothened antagonist 19 that is suitable for in vivo studies.

[reaction: see text] The first total synthesis of martinellic acid, a naturally occurring bradykinin receptor antagonist, via a CuI-catalyzed coupling reaction of beta-amino ester 6 with 1,4-diiodobenzene and a guanylation reaction of secondary amine 3 under mild conditions as key steps, is described.

N,N-Disubstituted amino esters were prepared by stereoselective conjugate addition of (S)- or (R)-lithium N -benzyl- N -α-methylbenzylamide to α,β-unsaturated esters. The couplings of the formed esters with ethyl glyoxalate followed by hydrogenation afforded 5-alkyl-4-carboethoxy-3-hydroxy-pyrrolidinones stereoselectively.

A new protocol to prepare chiral 1,2,3,4-tetrahydro-4-oxo-2-alkyl-1-quinolines has been developed. The key steps are Pd/Cu-catalyzed couplings of chiral β-amino esters and aryl bromides, and intramolecular acylation.

The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic high-throughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure−activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.

The overproduction, purification and in vitro characterization of the polyene glycosyltransferases (GTs) AmphDI and NysDI are reported. Enabled by a novel nucleotidyltransferase mutant (RmlA Q83D) for the chemoenzymatic synthesis of unnatural GDP-sugar donors, in conjunction with polyene GT-catalyzed sugar exchange/reverse reactions, the donor and acceptor specificity of these novel enzymes were subsequently probed. The evaluation of polyene GT aglycon and GDP-sugar donor specificity revealed some tolerance to aglycon structural diversity but stringent sugar specificity, culminating in new polyene analogs in which L-gulose or D-mannose replace the native sugar D-mycosamine.

In vitro glycorandomization (IVG) technology is dependent upon the ability to rapidly synthesize sugar phosphates. Compared with chemical synthesis, enzymatic (kinase) routes to sugar phosphates would be attractive for this application. This work focuses upon the development of a high-throughput colorimetric galactokinase (GalK) assay and its application toward probing the substrate specificity and kinetic parameters of Escherichia coli GalK. The demonstrated dinitrosalicylic assay should also be generally applicable to a variety of sugar-processing enzymes. [reaction: see text]

Analogs of the glycopeptide antibiotics vancomycin and teicoplanin with alterations in one or both sugar moieties of the disaccharide have been prepared by tandem action of the vancomycin pathway glycosyltransferases GtfE and GtfD. All four regioisomers (2-, 3-, 4-, 6-) of TDP-deoxyglucoses and UDP/TDP-aminoglucoses were prepared, predominantly by action of D-glucopyranosyl-1-phosphate thymidylyltransferase, E p . GtfE transferred the deoxyglucoses or aminoglucoses onto the 4-OH of 4-hydroxyphenylglycine of both the vancomycin and teicoplanin aglycone scaffolds. Kinetic analysis indicated the 2-, 3-, 4-, and 6-amino-glucoses were transferred by GtfE with only a 4- to 30-fold drop in k cat and no effect on K m compared to the native substrate, UDP/TDP-glucose, suggesting preparative utility. The next enzyme, GtfD, could utilize the variant glucosyl-peptides as substrates for transfer of L-4- epi -vancosamine. The aminosugar moieties in these variant glycopeptides introduce sites for acylation or reductive alkylation.

The exploitation of a unique thymidylyltransferase (E