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Rail fastener status recognition and detection are key steps in the inspection of the rail area status and function of real engineering projects. With the development of and widespread interest in image processing techniques and deep learning theory, detection methods that combine the two have yielded promising results in practical detection applications. In this paper, a semantic-segmentation-based algorithm for the state recognition of rail fasteners is proposed. On the one hand, we propose a functional area location and annotation method based on a salient detection model and construct a novel slab-fastclip-type rail fastener dataset. On the other hand, we propose a semantic-segmentation-framework-based model for rail fastener detection, where we detect and classify rail fastener states by combining the pyramid scene analysis network (PSPNet) and vector geometry measurements. Experimental results prove the validity and superiority of the proposed method, which can be introduced into practical engineering projects.

This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plant-sterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compound was the development of a four-reaction telescope process and a selective O-alkylation of a triol intermediate. These improvements enabled the successful delivery of kilogram-scale batches of API for preclinical development studies.

The process development and production of two cycloartenol triterpenoid glycosides on a multikilogram scale are described. The two compounds were used as key intermediates for the synthesis of a γ-secretase modulator and a novel potential therapeutic agent for Alzheimer’s disease (SPI-1865). This practical and efficient process includes extraction of precursor triterpenoid glycosides from Actaea racemosa (black cohosh) and a ZrCl4-catalyzed rearrangement reaction.

A novel class of 5-amino-2,5-dideoxy-2,2-difluorocytidine derivatives has been synthesized in order to identify anticancer nucleoside analogs. Several synthetic routes were devised and implemented which relied upon either SN2 displacement or reductive amination to provide the desired derivatives.

A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aβ42 levels.

Non-alcoholic steatohepatitis (NASH), characterized by hepatocyte injury, inflammation, and fibrosis, is the main cause of chronic liver disease in the Western world. There are currently no approved pharmacological therapies for NASH, underscoring the urgent need for effective treatments. The farnesoid X receptor (FXR) has emerged as an attractive target for the treatment of metabolic and chronic liver diseases. EDP-305 is an FXR agonist currently in phase 2 clinical trials for Primary Biliary Cholangitis (PBC) and NASH. Here, we demonstrate that EDP-305 is a selective and potent FXR agonist that regulates multiple pathways relevant to NASH progression. EDP-305 exhibits anti-fibrotic and anti-inflammatory gene signatures in human macrophage and stellate cell lines, as well as favorable effects on lipid metabolism in hepatocytes, including enhanced low density lipoprotein (LDL)-cholesterol uptake and decreased triglyceride accumulation. The therapeutic potential of EDP-305 was further evaluated in two murine models of NASH: a streptozotocin-high fat diet STAMTM model and a dietary induced NASH (DIN) model driven by high fat, cholesterol, and fructose feeding. In both NASH models, EDP-305 significantly decreased hepatocyte ballooning and lowered the non-alcoholic fatty liver disease (NAFLD) activity score. EDP-305 also significantly attenuated hepatic steatosis and dyslipidemia observed in the DIN mouse model. Conclusion: EDP-305 is a potent FXR agonist with a favorable gene expression profile for NASH treatment as evidenced by the hepato-protective and anti-steatotic effects observed in vivo. The preclinical characterization of EDP-305 presented here suggests that it holds promise for the treatment of NASH.

[structure: see text] Simplified analogues of the lobatamides have been synthesized and evaluated for inhibition of bovine V-ATPase. The salicylate phenol, enamide NH, and the ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug–drug-interactions (DDIs). Using structure–activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.

A series of 5′-amino derivatives of gemcitabine are synthesized in order to identify anticancer nucleoside analogues (no biological activity reported).

[formula: see text] A new approach to the assembly of enamides is described using copper(I) carboxylate-catalyzed substitution of vinyl iodides and amides. Modified reaction conditions have been developed to synthesize the O-methyloxime enamide side chains related to the natural products lobatamides A-F, oximidine I and II, and CJ-12,950.

Introduction Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. Methods Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. Results In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. Conclusions Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβpeptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Sinceγ-secretase is critical for Aβproduction, many in the biopharmaceutical community focused onγ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to controlγ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβpeptides without affecting otherγ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators ofγ-secretase activity have been discovered that spare theεcleavage of APP and other substrates while decreasing the production of Aβ42. Multiple chemical classes ofγ-secretase modulators have been identified which differ in the pattern of Aβpeptides produced. Ideally, modulators will allow theεcleavage of all substrates while shifting APP cleavage from Aβ42and other highly amyloidogenic Aβpeptides to shorter and less neurotoxic forms of the peptides without altering the total Aβpool. Here, we compare chemically distinct modulators for effects on APP processing andin vivoactivity.

A new approach to the assembly of enamides is described using copper(I) carboxylate-catalyzed substitution of vinyl iodides and amides. Modified reaction conditions have been developed to synthesize the O-methyloxime enamide side chains related to the natural products lobatamides A−F, oximidine I and II, and CJ-12 950.

Stereochemical studies of the photocycloaddition of a chiral alpha,beta-enone and isobutylene lead to a working hypothesis for the geometry of the 3(pi-pi*) excited state of the enone. [reaction: see text]

[structure: see text] The lobatamides and related salicylate enamide natural products are potent mammalian V-ATPase inhibitors. To probe details of binding of the lobatamides to mammalian V-ATPase, three photoactivatable analogues bearing benzophenone photoaffinity labels have been prepared. The analogues were designed on the basis of a simplified acyclic analogue 2. Late-stage installation of the enamide side chain and tandem deallylation/amidation were employed in synthetic routes to these derivatives. Simplified analogue 2 showed strong inhibition against bovine clathrin-coated vesicle V-ATPase (10 nM). Analogues 3-5 were also evaluated for inhibition of bovine V-ATPase in order to select a suitable candidate for future photoaffinity labeling studies.

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C is reported. The synthesis involves Cu(I)-mediated enamide formation and Na(2)CO(3)-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Macrolactonization was accomplished using a Mitsunobu protocol. The stereochemical assignment of lobatamide C was achieved by Mosher ester analysis and comparison with prepared stereoisomers.

[reaction: see text] Copper(I)-mediated C-N bond formation has been employed to prepare both N-acyl vinylogous carbamic acids and ureas. The novel N-acyl vinylogous carbamic acid antibiotic, CJ-15,801, was synthesized using this methodology.

Uncoupling protein 2 (UCP2) negatively regulates insulin secretion. UCP2 deficiency (by means of gene knockout) improves obesity- and high glucose-induced beta cell dysfunction and consequently improves type 2 diabetes in mice. In the present study, we have discovered that the small molecule, genipin, rapidly inhibits UCP2-mediated proton leak. In isolated mitochondria, genipin inhibits UCP2-mediated proton leak. In pancreatic islet cells, genipin increases mitochondrial membrane potential, increases ATP levels, closes K(ATP) channels, and stimulates insulin secretion. These actions of genipin occur in a UCP2-dependent manner. Importantly, acute addition of genipin to isolated islets reverses high glucose- and obesity-induced beta cell dysfunction. Thus, genipin and/or chemically modified variants of genipin are useful research tools for studying biological processes thought to be controlled by UCP2. In addition, these agents represent lead compounds that comprise a starting point for the development of therapies aimed at treating beta cell dysfunction.