A Data-Driven Based Response Reconstruction Method of Plate Structure with Conditional Generative Adversarial Network.

Structural-response reconstruction is of great importance to enrich monitoring data for better understanding of the structural operation status. In this paper, a data-driven based structural-response reconstruction approach by generating response data via a convolutional process is proposed. A conditional generative adversarial network (cGAN) is employed to establish the spatial relationship between the global and local response in the form of a response nephogram.

Quasistatic Analysis of Precast Segmental Concrete-Filled Steel-Tube Bridge Pier with External Arched Energy Dissipation Device.

In order to further promote the application of segment-assembled bridge piers in medium- and high-intensity areas, and to reduce the post-earthquake damage and repair cost of bridge piers, in this paper, a precast segmental concrete-filled steel-tube bridge pier (PSCFSTBP) with an external arched energy dissipation device (AEDD) is proposed. Firstly, the effectiveness of the finite-element analysis software ABAQUS 6.14-4 is proved by the test results of the PSCFSTBP and the corresponding finite-element model analysis results.

Numerical Investigation of the Performance of Segmental CFST Piers with External Energy Dissipators under Lateral Cyclic Loadings.

In order to improve the construction efficiency of piers and reduce the local damage of piers, concrete-filled steel tubes (CFST) are used to precast pier segments. Aiming at the problems of the poor integrity and insufficient energy dissipation capacity of dry joint segmental assembled piers, segmental assembled concrete-filled steel tubular piers with external replaceable energy dissipators are being developed. Based on the low cyclic test of a segmental assembled CFST pier, the finite element numerical simulation model of a CFST pier is established based on ABAQUS software, and the validity of the numerical model is verified by the experimental results.

Recent Progress in Sensing Technology Based on Triboelectric Nanogenerators in Dynamic Behaviors.

Under the trend of the rapid development of the internet of things (IoT), sensing for dynamic behaviors is widely needed in many fields such as traffic management, industrial production, medical treatment, building health monitoring, etc. Due to the feature of power supply independence and excellent working performance under a low-frequency environment, triboelectric nanogenerators (TENGs) as sensors are attracting more and more attention. In this paper, a comprehensive review focusing on the recent advance of TENGs as sensors for dynamic behaviors is conducted.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-]pyrimidine RET Inhibitors.

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-]pyrimidine scaffold. The optimization of this pyrrolo[2,3-]pyrimidine core resulted in compound , which demonstrated potent RET kinase inhibition and robust efficacy in RET-driven tumor xenografts upon multiday dosing in mice.

Efficacy and Tolerability of Pyrazolo[1,5-]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

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-]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse studies, compound 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).

Encapsulation Approaches for In-Stent Wireless Magnetoelastic Sensors.

Wireless magnetoelastic sensors offer significant potential for measuring the accumulation of biomass within stents - enabling early detection prior to stent occlusion - but the encapsulation of these sensors remains a critical challenge. The encapsulation must allow the sensors to navigate the curvature and accommodate the contact forces imparted during and after the implantation procedure, while also leaving the sensor open to mechanical interaction with the biomass during the extended period of deployment. This paper is focused on the encapsulation of ribbon-like magnetoelastic sensors (12.

Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy.

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.

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.

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.

Design, synthesis, and structure-activity-relationship of phenyl imidazoles as potent Smoothened antagonists.

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.

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist.

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 in vitro characterization of polyene glycosyltransferases AmphDI and NysDI.

The overproduction, purification, and in vitro characterization of the polyene glycosyltransferases (GTs) AmphDI and NysDI are reported. 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 allowed the donor and acceptor specificities of these novel enzymes to be probed. The evaluation of polyene GT aglycon and GDP-sugar donor specificity revealed some tolerance to aglycon structural diversity, but stringent sugar specificity, and culminated in new polyene analogues in which L-gulose or D-mannose replace the native sugar D-mycosamine.

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest.

Antibiotic optimization via in vitro glycorandomization.

In nature, the attachment of sugars to small molecules is often used to mediate targeting, mechanism of action and/or pharmacology. As an alternative to pathway engineering or total synthesis, we report a useful method, in vitro glycorandomization (IVG), to diversify the glycosylation patterns of complex natural products. We have used flexible glycosyltransferases on nucleotide diphosphosugar (NDP-sugar) libraries to generate glycorandomized natural products and then applied chemoselective ligation to produce monoglycosylated vancomycins that rival vancomycin.

Studies on the substrate specificity of Escherichia coli galactokinase.

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.

Substrate specificity of NovM: implications for novobiocin biosynthesis and glycorandomization.

[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.

Aromatic nucleophilic substitution or CuI-catalyzed coupling route to martinellic acid.

Condensation of beta-amino ester 8b with triflate 7 gives N-aryl amino ester 11, which is converted into 2-substituted 4-oxoquinoline 4 using an intramolecular Dieckmann reaction as the key step. CuI-mediated coupling of beta-amino ester 8a with 1,4-diiodobenzene followed by an intramolecular acylation and Pd-catalyzed carbonylation provide another manner to 4. Alkylation of 4 and subsequent reductive amination deliver the cyclic imine 14, which is transformed into triamine 3 by ordinary operations.

Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides.

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.

Expanding pyrimidine diphosphosugar libraries via structure-based nucleotidylyltransferase engineering.

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 alpha-d-hexopyranosyl phosphates accepted by Salmonella enterica LT2 alpha-d-glucopyranosyl phosphate thymidylyltransferase (E(p)).

Expanding the Pyrimidine Diphosphosugar Repertoire: The Chemoenzymatic Synthesis of Amino- and Acetamidoglucopyranosyl Derivatives.

The exploitation of a unique thymidylyltransferase (E ) 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 E .