Eicosanoid regulation of debris-stimulated metastasis.

Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.

Strategy for Fault Diagnosis on Train Plug Doors Using Audio Sensors.

As the only entry/exit for passengers getting on and off a train, the train plug door is of great importance to keep train operation safe and reliable. As signal processing technologies develop rapidly, taking the easy acquisition advantages of sound signals, a novel fault diagnosis method for train plug doors using multi-scale normalized permutation entropy (MNPE) and an improved particle swarm optimization based multi-class support vector machine (IPSO-MSVM) is proposed. Firstly, sound samples are collected using high-precision audio sensor. In the features extraction process, a hybrid method blending empirical mode decomposition (EMD), multi-scale permutation entropy (MNPE) with Fisher discrimination criterion is utilized. First, EMD is used to decompose each sound signal into several intrinsic mode functions (IMFs) and a residue for stationary processing. Then, MNPE features are extracted from the IMFs. To obtain the most significant features, the Fisher discrimination criterion is further applied. To address the time-consuming defects of traditional grid based method for selecting the optimal parameters of multi-class SVM, an improved PSO (IPSO) is proposed. The superiority of the IPSO-MSVM model and the hybrid feature extraction method was tested on the collected sound samples by comparing to commonly applied methods. Results indicate the identification accuracy of the proposed method is highest, which reaches 90.54%, demonstrating its feasibility.

Enhancing rail safety through real-time defect detection: A novel lightweight network approach.

The rapid detection of internal rail defects is critical to maintaining railway safety, but this task faces a significant challenge due to the limited computational resources of onboard detection systems. This paper presents YOLOv8n-LiteCBAM, an advanced network designed to enhance the efficiency of rail defect detection. The network designs a lightweight DepthStackNet backbone to replace the existing CSPDarkNet backbone. Further optimization is achieved through model pruning techniques and the incorporation of a novel Bidirectional Convolutional Block Attention Module (BiCBAM). Additionally, inference acceleration is realized via ONNX Runtime. Experimental results on the rail defect dataset demonstrate that our model achieves 92.9% mAP with inference speeds of 136.79 FPS on the GPU and 38.36 FPS on the CPU. The model's inference speed outperforms that of other lightweight models and ensures that it meets the real-time detection requirements of Rail Flaw Detection (RFD) vehicles traveling at 80 km/h. Consequently, the YOLOv8n-LiteCBAM network is with some potential for industrial application in the expedited detection of internal rail defects.

Is the safety index of modern safety integrity level(SIL) truly appropriate for the railway?

Safety is paramount in rail transportation. The International Safety Standard IEC 61508, issued by the International Electrotechnical Commission (IEC) in 2000, describes the modern concept of safety and the specifications for safety evaluation in a systematic manner. On this basis, the EN 50129 railway transportation safety standard and safety integrity level(SIL) are established. Through the above analysis, the relationship between safety-related system reliability, acceptable risk, and safety index is summarized. It is clear that the safety index is based on acceptable risks. Nonetheless, as the economy and society advance, the safety index mandated by the SIL falls behind. Consequently, the principles and methodologies for calculating the safety index are presented. The paper proposes a reference for the Chinese railway safety index based on actual data from the Chinese railways over the past few years.

Fault diagnosis for train plug door using weighted fractional wavelet packet decomposition energy entropy.

As the passage for passengers to get on and off, train plug doors directly affect the operation efficiency of the train and the personal safety of passengers. This paper proposes a non-contact fault diagnosis method for train plug doors based on sound signals. First, empirical mode decomposition (EMD) is utilized to process the raw sound signals. A signal reconstruction method by selecting intrinsic mode functions (IMFs) using hybrid selection criteria is then proposed. Second, novel feature named weighted fractional wavelet packet decomposition energy entropy (WFWPDE) is developed by introducing the idea of fractional calculus and weight to wavelet packet decomposition energy entropy (WDPE). Third, a synchronous optimization strategy is proposed to optimize the weights and hyperparameters of support vector machine (SVM) synchronously. Finally, the superiority and feasibility of the proposed method are verified on field-collected data. By comparing with different fault diagnosis methods, the proposed method performs best on fault diagnosis of train plug doors, with accuracy of 97.87%.

A statistical study of railway safety in China and Japan 1990-2020.

Safety is the precondition and guarantee of railway development. However, due to equipment failure, poor management, misoperation and so on, accidents on the railway occur from time to time. China and Japan, as leading countries in Railway Technology in the world, have done a lot of work in accident prevention and safety. Through the collection and comparison of transport data and typical casualty cases in China and Japan, this paper summarizes the main causes of accidents and the experience of accident prevention in the two countries. And further, puts forward suggestions for preventing accidents and large-scale casualty.

Iridium-monodentate phosphoramidite-catalyzed asymmetric hydrogenation of substituted benzophenone N-H imines.

Homogeneous asymmetric hydrogenation of unprotected benzophenone N-H imines 1a-r using Ir-(S)-N-benzyl-N-methyl-MonoPhos as a catalyst provides chiral amines 2a-r in 80-96% yield with enantioselectivities up to 98% ee (18 examples) for ortho-substituted substrates.

Direct asymmetric reductive amination.

Asymmetric reductive amination of beta-keto amides catalyzed by the chiral catalyst Ru(OAc)(2)((R)-dm-segphos) produces unprotected beta-amino amides with high yields and high enantioselectivities (94.7-99.5% ee). This "one-pot" methodology is general in substrate scope and has been successfully employed to produce sitagliptin with 99.5% ee and 91% assay yield. The excellent reaction efficiency is attributed to the remarkable tolerance to high concentrations of ammonium ion, the high chemoselectivity, and the high enantioselectivity (99.5% ee) of the Ru catalyst system.

Enantioselective hydrogenation of N-H imines.

N-H ketoimines 3a-3v are readily prepared in high yield via organometallic addition to nitriles and isolated as corresponding bench-stable hydrochloride salts. Homogeneous asymmetric hydrogenation of unprotected N-H ketoimines 3a-3v using Ir-(S,S)-f-binaphane as catalyst provides chiral amines 4a-4v in 90-95% yield with enantioselectivities up to 95% ee.

Highly efficient asymmetric synthesis of sitagliptin.

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

A method to remove chattering alarms using median filters.

Chattering alarms are the most found nuisance alarms that will probably reduce the usability and result in a confidence crisis of alarm systems for industrial plants. This paper addresses the chattering alarm reduction using median filters. Two rules are formulated to design the window size of median filters. If the alarm probability is estimated using process data, one rule is based on the probability of alarms to satisfy some requirements on the false alarm rate, or missed alarm rate. If there are only historical alarm data available, the other rule is based on percentage reduction of chattering alarms using alarm duration distribution. Experimental results for industrial cases testify that the proposed method is effective.

An efficient catalyst for Pd-catalyzed carbonylation of aryl arenesulfonates.

Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]

Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: toward the synthesis of an anthrax lethal factor inhibitor.

A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]

A [2 + 2] cycloaddition route to dimethylaminomethylene vinamidinium salts.

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).

Asymmetric hydrogenation of protected allylic amines.

A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.

Catalytic asymmetric synthesis of an HIV integrase inhibitor.

An efficient synthesis of HIV integrase inhibitor (S)-(-)-1 via a unique asymmetric hydrogenation of a mixture of imines/enamine 5a-5b/5c is described. Hydrogenation of the imines/enamine by a Rh(I)-Josiphos complex afforded 6 in 90% yield and 90% ee. Amide formation completed the synthesis of 1 in 58% overall yield from 2, which is readily available from 3,4-dihydro-2H-pyran in a seven-step sequence. A deuterium labeling study suggests the asymmetric hydrogenation proceeds predominantly via the enamine tautomer.

On the mechanism of an asymmetric alpha,beta-unsaturated carboxylic acid hydrogenation: application to the synthesis of a PGD2 receptor antagonist.

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.

The unusual role of CO transfer in molybdenum-catalyzed asymmetric alkylations.

Spectroscopic and crystallographic studies were undertaken to gain insight into the mechanism of the highly regio- and enantioselective allylic aklylation reaction catalyzed by molybdenum. The chiral ligand (L*) consisting of the mixed benzamide/picolinamide of (S,S,)-trans-1,2-diaminocyclohexane reacts with a typical Mo precatalyst, (norbornadiene)Mo(CO)4, to give a neutral complex L*Mo(CO)4 in which the ligand binds to the metal in a bidentate fashion through the pyridine and adjacent amide group. Reaction of this complex with the methyl carbonate of cinnamyl alcohol gives the corresponding pi-allyl complex L*(CO)2Mo(eta3-CH2=CH-CHPh). NMR and X-ray crystallographic characterization of this complex reveal the ligand binds in a facially capping tridentate fashion via the pyridine nitrogen, the nitrogen of the adjacent amide group, which has now been deprotonated, and the carbonyl oxygen of the remote amide. Surprisingly, the face of the allyl group open to attack with nucleophiles is that which would lead to the sense of stereochemistry opposite to that which is observed in catalytic reactions. Furthermore, the allyl complex in its isolated form is unreactive toward sodium dimethyl malonate. However, in the presence of a source of carbon monoxide (either Mo(CO)6 or gaseous CO), the allyl complex reacts with malonate to give the typically observed branched alkylated product in high yield and enantiomeric excess. The metal-containing product of this reaction is the molybdate complex [L*Mo(CO)4]-Na+. Reaction of the molybdate complex with linear or branched allylic carbonates regenerates the allyl complex, thus closing the catalytic cycle. Both the allyl complex and the molybdate complex are the only metal-containing species observed by NMR in typical catalytic reactions and thus appear to be catalyst resting states. Turnover of the catalytic cycle therefore involves shuttling of carbon monoxide between the two catalyst resting states. Coordination of CO appears to be necessary to activate the allyl complex toward nucleophilic attack, in effect stabilizing the molybdenum fragment as a leaving group.

Mechanistic studies of the molybdenum-catalyzed asymmetric alkylation reaction.

Enantiomerically enriched, deuterated branched carbonates (Z)-(S)-PhCH(OCO(2)Me)-CH = CHD (1-D), (Z)-(R)-PhCH(OCO(2)Me)CH = CHD (2-D), and linear carbonate (E)-(S)-PhCH = CHCHD(OCO(2)Me) (3-D) were used as probes in the Mo-catalyzed asymmetric allylic alkylation with sodium dimethyl malonate, catalyzed by ligand-complex 11 derived from the mixed benzamide/picolinamide of (S,S)-transdiaminocyclohexane and (norbornadiene)Mo(CO)(4). The results of these studies, along with x-ray crystallography and solution NMR structural analysis of the pi-allyl intermediate, conclusively established the reaction proceeded by a retention-retention pathway. This mechanism contrasts with that defined for Pd-catalyzed allylic alkylations, which proceed by an inversion-inversion pathway. A proposed rationale for the retention pathway for nucleophilic substitution involves CO-coordination to form a tri-CO intermediate, followed by complexation with the anion of dimethyl malonate to produce a seven-coordinate intermediate, which reductively eliminates to afford product with retention of configuration.