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Deregulation of redox homeostasis is often associated with an accelerated aging process. Ribose-5-phosphate isomerase A (RPIA) mediates redox homeostasis in the pentose phosphate pathway (PPP). Our previous study demonstrated that Rpi knockdown boosts the healthspan in Drosophila. However, whether the knockdown of rpia-1, the Rpi ortholog in Caenorhabditis elegans, can improve the healthspan in C. elegans remains unknown. Here, we report that spatially and temporally limited knockdown of rpia-1 prolongs lifespan and improves the healthspan in C. elegans, reflecting the evolutionarily conserved phenotypes observed in Drosophila. Ubiquitous and pan-neuronal knockdown of rpia-1 both enhance tolerance to oxidative stress, reduce polyglutamine aggregation, and improve the deteriorated body bending rate caused by polyglutamine aggregation. Additionally, rpia-1 knockdown temporally in the post-developmental stage and spatially in the neuron display enhanced lifespan. Specifically, rpia-1 knockdown in glutamatergic or cholinergic neurons is sufficient to increase lifespan. Importantly, the lifespan extension by rpia-1 knockdown requires the activation of autophagy and AMPK pathways and reduced TOR signaling. Moreover, the RNA-seq data support our experimental findings and reveal potential novel downstream targets. Together, our data disclose the specific spatial and temporal conditions and the molecular mechanisms for rpia-1 knockdown-mediated longevity in C. elegans. These findings may help the understanding and improvement of longevity in humans.

Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.

Objective Decision aids have been developed to help prospective parents make informed, shared decisions about medical tests, but these options are rapidly changing. This study aimed to identify and evaluate publicly available decision aids written in English for prospective parents seeking prenatal test information. Methods A systematic review process was followed using 3 sources: known decision aid repositories, fetal medicine organisations and Google. The search, screening process, quality assessment, and data extraction was performed by two independent researchers. The quality assessment of the decision aids was based on the International Patient Decision Aids Standards (IPDAS v.4.0). Results We identified 13 decision aids, which varied in the screening and diagnostic tests that they discussed. No decision aid met all the IPDAS v.4.0. criteria and no decision aid reported updated risk of miscarriage for amniocentesis and chorionic villus sampling (CVS). There was a lack of decision aids for some common decisions in the prenatal context. Conclusion We identified outdated content in current prenatal decision aids. The findings will inform healthcare professionals of the quality of current prenatal decision aids, which may facilitate their patients’ informed decision-making about prenatal tests. Innovation Considerations for improving future decision aids are outlined.

Purpose The U.S. Department of Veterans Affairs (VA) health care system monitors time from referral to specialist visit. We compared wait times for carpal tunnel release (CTR) at a VA hospital and its academic affiliate. Methods We selected patients who underwent CTR at a VA hospital and its academic affiliate (AA) (2010–2015). We analyzed time from primary care physician (PCP) referral to CTR, which was subdivided into PCP referral to surgical consultation and surgical consultation to CTR. Electrodiagnostic testing (EDS) was categorized in relation to surgical consultation (prereferral vs postreferral). Multivariable Cox proportional hazard models were used to examine associations between clinical variables and surgical location. Results Between 2010 and 2015, VA patients had a shorter median time from PCP referral to CTR (VA: 168 days; AA: 410 days), shorter time from PCP referral to surgical consultation (VA: 43 days; AA: 191 days), but longer time from surgical consultation to CTR (VA: 98 days; AA: 55 days). Using multivariable models, the VA was associated with a 35% shorter time to CTR (AA hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.52–0.82) and 75% shorter time to surgical consultation (AA HR, 0.25; 95% CI, 0.20–0.03). Receiving both prereferral and postreferral EDS was associated with almost a 2-fold prolonged time to CTR (AA HR, 0.49; 95% CI, 0.36–0.67). Conclusions The VA was associated with shorter overall time to CTR compared with its AA. However, the VA policy of prioritizing time from referral to surgical consultation may not optimally incentivize time to surgery. Repeat EDS was associated with longer wait times in both systems. Clinical Relevance Given differences in where delays occur in each health care system, initiatives to improve efficiency will require targeting the appropriate sources of preoperative delay. Judicious use of EDS may be one avenue to decrease wait times in both systems.

Nitrate in plants is preferentially stored in vacuoles; however, how vacuolar nitrate is reallocated and to which biological process(es) it might contribute remain largely elusive. In this study, we functionally characterized three nitrate transporters NPF5.10, NPF5.14, and NPF8.5 that are tonoplast-localized. Ectopic expression in Xenopus laevis oocytes revealed that they mediate low-affinity nitrate transport. Histochemical analysis showed that these transporters were expressed preferentially in pericycle and xylem parenchyma cells. NPF5.10, NPF5.14, and NPF8.5 overexpression significantly decreased vacuolar nitrate contents and nitrate accumulation in Arabidopsis shoots. Further analysis showed that the sextuple mutant (npf5.10 npf5.14 npf8.5 npf5.11 npf5.12 npf5.16) had a higher 15NO3-uptake rate than the wild-type Col-0, but no significant difference was observed for nitrate accumulation between them. The septuple mutant (npf5.11 npf5.12 npf5.16 npf5.10 npf5.14 npf8.5 clca) generated by using CRISPR/Cas9 showed essentially decreased nitrate reallocation compared to wild type when exposed to nitrate starvation, though no further decrease was observed when compared to clca. Notably, NPF5.10, NPF5.14, and NPF8.5 as well as NPF5.11, NPF5.12, and NPF5.16 were consistently induced by mannitol, and more nitrate was detected in the sextuple mutant than in the wild type after mannitol treatment. These observations suggest that vacuolar nitrate efflux is regulated by several functional redundant nitrate transporters, and the reallocation might contribute to osmotic stress response other than mineral nutrition.

Chiang Ching-kuo (1910-1988) is an essential figure to understand the contemporary Chinese world. This article examines the most important chapters of his life, from his experience in the Soviet Union until his presidency in Taiwan during the 1970s and 1980s. Chiang Ching-kuo’s vital trajectory allows us to study the complexities behind the particular Chinese modernization project that materialised in the island as a result of the combination of both exogenous and endogenous elements and a degree of contingency that was not expected by the political elite of the Kuomintang. This work seeks to contribute to the development of the Chinese and Taiwanese studies in Spanish. It advances the concept of “Chinese short century” and opens up new avenues for future research that seek to cast into doubt the dominant discourse around the “Taiwanese miracle”.

Nitrate in plants is preferentially stored in vacuoles; however, how vacuolar nitrate is reallocated and to which biological process(es) it might contribute remain largely elusive. In this study, we functionally characterized three nitrate transporters NPF5.10, NPF5.14, and NPF8.5 that are tonoplast-localized. Ectopic expression in

Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the in vivo exposure of the six key TGT components was performed to screen the anti–NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated in vitro. The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and in vitro verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti–NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti–NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.

In the current study, a predictive model on tool flank wear rate during ultrasonic vibration-assisted milling is proposed. One benefit of ultrasonic vibration is the frequent separation between too...

In laser-assisted milling, higher temperature in shear zone softens the material potentially resulting in a shift of mean residual stress, which significantly affects the damage tolerance and fatigue performance of product. In order to guide the selection of laser and cutting parameters based on the preferred mean residual stress, inverse analysis is conducted by predicting residual stress based on guessed process parameters, which is defined as the forward problem, and applying iterative gradient search to find process parameters for next iteration, which is defined as the inverse problem. An analytical inverse analysis is therefore proposed for the mean residual stress in laser-assisted milling. The forward problem is solved by analytical prediction of mean residual stress after laser-assisted milling. The residual stress profile is predicted through the calculation of thermal stress, by treating laser beam as heat source, and plastic stress by first assuming pure elastic stress in loading process, then obtaining true stress with kinematic hardening followed by the stress relaxation. The variance-based recursive method is applied to solve inverse problem by updating process parameters to match the measured mean residual stress. Three cutting parameters including depth of cut, feed per tooth, and cutting speed, and two laser parameters including laser-tool distance and laser power, are updated with respected to the minimization of resulting residual stress and measurement in each iteration. Experimental measurements are referred on the laser-assisted milling of Ti-6Al-4V grade 5 and ELI. The percentage difference between experiments and predictions is less than 5% for both materials, and the selection is completed within 50 loops.

Gastric cancer(GC), one of the most common malignancies worldwide, seriously threatens human health due to its high morbidity and mortality. Precancerous lesion of gastric cancer(PLGC) is a critical stage for preventing the occurrence of gastric cancer, and PLGC therapy has frequently been investigated in clinical research. Exploring the proper animal modeling methods is necessary since animal experiment acts as the main avenue of the research on GC treatment. At present, N-methyl-N'-nitro-N-nitroso-guanidine(MNNG) serves as a common chemical inducer for the rat model of GC and PLGC. In this study, MNNG-based methods for modeling PLGC rats in related papers were summarized, and the applications and effects of these methods were demonstrated by examples. Additionally, the advantages, disadvantages, and precautions of various modeling methods were briefly reviewed, and the experience of this research group in exploring modeling methods was shared. This study is expected to provide a reference for the establishment of MNNG-induced PLGC animal model, and a model support for the following studies on PLGC.

In the current study, an analytical predictive model on residual stress after ultrasonic vibration–assisted milling is proposed in an effort to provide an accurate and reliable reference. Three types of tool-workpiece separation criteria are checked based on the tool center instantaneous position and velocity. Type I criterion examines the instantaneous velocity of tool tip under combined effects of feed movement and vibration. Type II criterion examines the position of tool center. Type III criterion describes the smaller chip size due to the overlaps between current and previous tool paths as a result of vibration. If none of these criterions is satisfied, the mechanical and thermal stresses are nonzero. The residual stress is then predicted through the calculation of stress distribution in loading process, incremental stress change considering kinematic hardening in plasticity, and the elastic stress release during relaxation process. The proposed predictive residual stress model in ultrasonic vibration–assisted milling is validated through comparison with experimental measurements on AISI 316L alloy. The proposed predictive model is able to match the measured residual stress with high accuracy of 6.4% average error and 23.6% maximum error among all cases. In addition, a sensitivity analysis is conducted. Higher axial depth of milling results in less compressive residual stress. Moreover, both higher ultrasonic vibration amplitude and higher spindle rotation frequency result in more compressive residual stress for AISI 316L alloy.

In current study, an inverse analysis is conducted on tool life based on five process parameters, by predicting tool life based on guessed process parameters, which is defined as the forward problem, and applying iterative gradient search to find process parameters for next iteration, which is defined as the inverse problem. For forward problem, the effect of laser beam is included by treating it as a heat source on top surface. Next, the milling configuration is simplified as orthogonal cutting followed by angular-dependent coordinate transformation at each rotation angle. The effective force due to flank wear is predicted by integrating the stress components along the chip cross section and wear land, and the average stress on tool-workpiece interface is then derived based on the effective force and contact area. The average temperature along the interface is derived by considering secondary and rubbing heat sources. The stress and temperature affects the abrasion, adhesion, and diffusion which determine the flank wear rate. The tool life is then decided as the cutting time when the flank wear limit of the tool is reached. The iterative gradient search or variance-based recursive method is applied to solve inverse problem and update process parameters to match the tool life. Three cutting parameters including depth of cut, feed per tooth, and cutting speed, and two laser parameters including laser-tool distance and laser power are updated in each iteration. The proposed model is validated through experimental measurements on the laser-assisted milling of K24 nickel-based superalloy. The proposed predictive model is able to match the measured tool life with high computation efficiency less than 540 s and high accuracy of less than 7% difference.

An analytical predictive model for residual stress in laser-assisted milling considering material recrystallization caused by laser preheating is proposed. The laser preheating temperature field is predicted by treating the laser beam as a heat source on top surface following Gaussian distribution. Heat convection between top surface and the environment is factored into account. Isothermal boundary conditions are assumed for the area of interest with conduction within the material. Next, the milling configuration is treated as orthogonal cutting at each instance. All process parameters including cutting depth, cutting speed, and tool geometry are therefore transferred. The recrystallization effect and thus the grain growth are considered through calibrated models describing the dependency of strain rate, strain, and temperature on dynamic recrystallization process for specific alloys using exponent functions. The residual stress is then predicted through the calculation of elastic stress distribution in loading process, actual stress with kinematic hardening, and the stress change during relaxation. The proposed model is validated through experimental measurements on the laser-assisted milling of Si3N4 and Ti-6Al-4V. The predictive model matches the trends of experimental measurements with agreement to an average error less than 30% in all cases. The proposed analytical model is valuable for providing a fast, credible, and physics-based method for the prediction of residual stress in laser-assisted milling of various materials.

Iron (Fe) transport and reallocation are essential to Fe homeostasis in plants, but it is unclear how Fe homeostasis is regulated, especially under stress. Here we report that NPF5.9 and its close homolog NPF5.8 redundantly regulate Fe transport and reallocation in Arabidopsis. NPF5.9 is highly upregulated in response to Fe deficiency. NPF5.9 expresses preferentially in vasculature tissues and localizes to the trans-Golgi network, and NPF5.8 showed a similar expression pattern. Long-distance Fe transport and allocation into aerial parts was significantly increased in NPF5.9-overexpressing lines. In the double mutant npf5.8 npf5.9, Fe loading in aerial parts and plant growth were decreased, which were partially rescued by Fe supplementation. Further analysis showed that expression of PYE, the negative regulator for Fe homeostasis, and its downstream target NAS4 were significantly altered in the double mutant. NPF5.9 and NPF5.8 were shown to also mediate nitrate uptake and transport, although nitrate and Fe application did not reciprocally affect each other. Our findings uncovered the novel function of NPF5.9 and NPF5.8 in long-distance Fe transport and homeostasis, and further indicated that they possibly mediate nitrate transport and Fe homeostasis independently in Arabidopsis., Iron (Fe) is essential to plant growth and development, but its transport and homeostasis are very complex. This study reports that two nitrate transporters, NPF5.9 and NPF5.8, act redundantly in long-distance Fe transport and homeostasis independent of their nitrate transport function, revealing a novel mechanism of Fe reallocation mediated by NPF family members.

Flumazenil is an imidazobenzodiazepine derivative that antagonizes the actions of benzodiazepines. The degradation pathway elucidation plays an important role in the drug quality control. In this work, a reliable LC-Q-TOF/MS method was developed to separate and identify the degradation products of flumazenil generated in the stress testing conducted according to the ICH Q1A(R2) guideline. Fifteen degradation products were detected in total including three reported impurities and twelve unknown impurities. Based on the chromatographic and mass spectrometric data acquired, the structures of all the degradation products were identified. Besides, two major degradants were synthetized and further confirmed by NMR. The degradation pathways of flumazenil were elucidated, and the degradation characteristics of benzodiazepines were also discussed. The obtained results are of both great importance for the quality control of flumazenil and good reference for the degradation study of other benzodiazepines.

Milling with minimum quantity lubrication (MQL) is now a commonly used machining technique in industry. The application of the MQL significantly reduces the temperature on the machined surface, while the cost of the lubricants is limited and the pollution caused by the lubricants is better controlled. However, the fast prediction of the milling temperature during the process has not been well developed. This paper proposes an analytical model for milling temperature prediction at the workpiece flank surface with MQL application. Based on the modified orthogonal cutting model and boundary layer lubrication effect, the proposed model takes in the process parameters and can generate the temperature profile at the workpiece surface within 1 min. The model is validated with experimental data in milling AISI D2 steel. With an average absolute error of 10.38%, the proposed model provides a reasonable temperature prediction compared to the experimental results. Based on the proposed model, this paper also investigates the effect of different cutting parameters on the cutting temperature. It is found that the application of the MQL decreases the temperature at the cutting zone, especially at the flank surface of the workpiece, which is due to the heat loss led by air-oil flow.

Key Points Question What are the complications, total payments, and out-of-pocket expenses associated with minor hand surgical procedures performed in different operative settings? Findings In this population-based cohort study of 468 365 minor hand surgical procedures, complications occurred in 3.4% of procedures performed in hospital outpatient departments, 3.3% in ambulatory surgery centers, and 2.9% in office settings. However, ambulatory and hospital-based procedures were significantly more expensive for payers and patients. Meaning The findings of this study suggest that transitioning minor hand procedures to the office may reduce spending for payers and patients without compromising postoperative outcomes., Importance Surgical procedures can be performed in different settings, but the association between the operative setting and patient safety and cost to the patient and payer is unknown. Objective To examine differences in complications, total payments, and out-of-pocket (OOP) spending for minor hand surgical procedures performed in office, ambulatory surgery center (ASC), and hospital outpatient department (HOPD) operative settings. Design, Setting, and Participants A retrospective, population-based cohort study was conducted using deidentified claims data from private employer-sponsored health insurance from January 1, 2009, to December 31, 2017. Patients aged 18 years or older undergoing carpal tunnel release, trigger finger release, excision of wrist ganglion, and excision of small hand masses (N = 468 365) were included. Exposures Operative setting, defined as procedures performed in the clinic setting, ASC, and HOPD. Main Outcomes and Measures Complications during the 90-day postoperative period, total payments (total facility and payer reimbursement), and OOP spending. Results Of the 468 365 patients, 296 378 women (63.3%) and 171 987 men (36.7%) underwent minor hand surgical procedures from 2009 to 2017, with 284 889 procedures (60.8%) performed in HOPDs, 158 659 procedures (33.9%) performed in ASCs, and 24 817 procedures (5.3%) performed in the office setting. Ninety-day complications occurred in 3.4% of procedures performed in HOPDs, 3.3% in ASCs, and 2.9% in office settings (P, This cohort study examines the differences in cost among hospital outpatient departments, ambulatory surgery centers, and office settings for minor hand surgical procedures.

Background Health insurance reimbursement structure has evolved, with patients becoming increasingly responsible for their health care costs through rising out-of-pocket expenses. High levels of cost sharing can lead to delays in access to care, influence treatment decisions, and cause financial distress for patients. Methods Patients undergoing the most common outpatient reconstructive plastic surgery operations were identified using Truven MarketScan databases from 2009 to 2017. Total cost of the surgery paid to the insurer and out-of-pocket expenses, including deductible, copayment, and coinsurance, were calculated. Multivariable generalized linear modeling with log link and gamma distribution was used to predict adjusted total and out-of-pocket expenses. All costs were inflation-adjusted to 2017 dollars. Results The authors evaluated 3,165,913 outpatient plastic and reconstructive surgical procedures between 2009 and 2017. From 2009 to 2017, total costs had a significant increase of 25 percent, and out-of-pocket expenses had a significant increase of 54 percent. Using generalized linear modeling, procedures performed in outpatient hospitals conferred an additional $1999 in total costs (95 percent CI, $1978 to $2020) and $259 in out-of-pocket expenses (95 percent CI, $254 to $264) compared with office procedures. Ambulatory surgical center procedures conferred an additional $1698 in total costs (95 percent CI, $1677 to $1718) and $279 in out-of-pocket expenses (95 percent CI, $273 to $285) compared with office procedures. Conclusions For outpatient plastic surgery procedures, out-of-pocket expenses are increasing at a faster rate than total costs, which may have implications for access to care and timing of surgery. Providers should realize the increasing burden of out-of-pocket expenses and the effect of surgical location on patients' costs when possible.

Background: Patients are increasingly responsible for direct medical expenditures with a growth in out-of-pocket (OOP) expenses, which can impede access to care and affect treatment. This study aims to investigate the impact of capitation on OOP expenses for surgical and presurgical treatment for thumb carpometacarpal (CMC) joint arthritis. Methods: Patients with a diagnosis of thumb CMC arthritis who underwent surgery (2009-2016) comprised our study cohort. Sociodemographic data, total cost, and OOP expenses were collected at the time of surgery and 2 years prior. Patients were stratified by insurance type: fee-for-service (FFS), managed care (MC), Medicare-MC, and Medicare-FFS. Capitated plans were included in the MC and Medicare-MC groups. A generalized linear regression was performed to investigate the association between OOP expenses and insurance type. Results: Our cohort consisted of 7780 patients with FFS insurance, 953 with MC insurance, 2136 with Medicare-FFS, and 265 with Medicare-MC. There was no difference in total costs for FFS and MC (FFS $7281 vs. MC $7306, P = .73; Medicare-FFS $6663 vs. Medicare-MC $6183, P = .19). However, patients with FFS incurred significantly greater OOP costs (FFS $952 vs. MC $434, P < .01; Medicare-FFS $343 vs. Medicare-MC $232, P < .01). In the adjusted regression, MC, Medicare-FFS, and Medicare-MC had approximately 21% to 46% of the predicted OOP expenses of patients with FFS plans ( P < .01). Conclusion: Despite similar total costs, OOP expenses were significantly greater for patients with FFS or Medicare-FFS insurance. With healthcare costs transitioning to patients, providers should consider cost sharing when conferring care to help alleviate the financial burden placed on patients.

Chiang Ching-kuo (1910-1988) is an essential figure to understand the contemporary Chinese world. This article examines the most important chapters of his life, from his experience in the Soviet Union until his presidency in Taiwan during the 1970s and 1980s. Chiang Ching-kuos vital trajectory allows us to study the complexities behind the particular Chinese modernization project that materialised in the island as a result of the combination of both exogenous and endogenous elements and a degree of contingency that was not expected by the political elite of the Kuomintang. This work seeks to contribute to the development of the Chinese and Taiwanese studies in Spanish. It advances the concept of Chinese short century and opens up new avenues for future research that seek to cast into doubt the dominant discourse around the Taiwanese miracle. Chiang Ching-kuo (1910-1988) es una figura imprescindible en la comprensión del Mundo Chino contemporáneo. El presente artículo propone una aproximación a través de los capítulos más importantes de su vida, desde su experiencia en la Unión Soviética hasta su presidencia de Taiwán durante la década de los años setenta y ochenta. La trayectoria vital de Chiang Ching-kuo permite asomarse al complejo nudo de relaciones existentes detrás del especifico proyecto modernizador chino que se cristalizó en la isla debido a una combinación de elementos exógenos y endógenos con un grado de contingencia no prevista por la élite política del Kuomintang. Este trabajo, que busca contribuir al desarrollo de los estudios chinos y taiwaneses en español, propone el concepto de un corto siglo chino y sugiere nuevas líneas de investigación conducentes a cuestionar el discurso dominante sobre el milagro taiwanés.

An analytical predictive model for temperature in laser-assisted milling considering both laser preheating temperature and machining induced temperature rise is proposed. The preheating temperature at top surface is predicted first by considering the heat generation from laser and convection. The heat generation rate is described by Gaussian equation. Within the material, heat conduction is considered with isothermal boundary conditions at side and bottom surfaces. The machining temperature is considered by transferring the milling configuration to orthogonal cutting at each instance. The shearing heat source and secondary rubbing heat source are included for machining temperature prediction. The heat source is calculated from the cutting or plowing forces, and a mirror heat source method is applied to predict temperature rise through integration. The proposed model is validated through experimental measurements on silicon nitride ceramics and Ti-6Al-4V alloy. The proposed predictive model matches the experimental measurements with less than 7.1% difference at laser spot and 5.2% difference in front of the cutting zone with computation time less than 15 s. The model is valuable for providing a fast, credible, and physics-based method for the prediction of temperature in laser-assisted milling of various materials. The overall temperature distribution is accurately calculated by predicting laser preheating temperature and machining induced temperature rise.

A growing number of studies focus on improving the understanding of how the households’ adaptations can be encouraged in the process of coastal hazards and risk management. Particularly, this proce...

Inverse analysis is of value identifying viable solutions of process parameters that can achieve specified process performance. In this study, an inverse analysis method is proposed for the cutting force in laser-assisted milling on Inconel 718. The method uses the analytical model to solve the direct problem and applies a variance-based recursive method to guide the inverse analysis. The half-slot milling is simplified as an orthogonal cutting at each instant, forces in cutting and radial directions are calculated under microstructure evolution, and the axial force is predicted according to tool geometry and coordinates transformation. The inverse analysis identifies five process parameters including feed rate, axial depth of milling, laser preheating temperature, spindle speed, and rake angle, and finds the optimal solution for target performance, the resultant cutting force. Four experiments verified the effectiveness of the proposed method because of a maximum error less than 8% between predicted forces and experimental measurements. The proposed method is valuable in terms of providing a reference for the selection of process parameters under certain cutting force requirements.

Background and purpose Promoting energy metabolism is known to provide therapeutic effects for obesity and associated metabolic disorders. The present study evaluated the therapeutic effects of the newly identified bouchardatine (Bou) on obesity-associated metabolic disorders and the molecular mechanisms of these effects. Experimental approach The molecular mode of action of Bou for its effects on lipid metabolism was first examined in 3T3-L1 adipocytes and HepG2 cells. This was followed by an evaluation of its metabolic effects in mice fed a high-fat diet for 16 weeks with Bou being administered in the last 5 weeks. Further mechanistic investigations were conducted in pertinent organs of the mice and relevant cell models. Key results In 3T3-L1 adipocytes, Bou reduced lipid content and increased sirtuin 1 (SIRT1) activity to facilitate liver kinase B1 (LKB1) activation of AMPK. Chronic administration of Bou (50 mg∙kg−1 every other day) in mice significantly attenuated high-fat diet-induced increases in body weight gain, dyslipidaemia and fatty liver without affecting food intake and no adverse effects were detected. These metabolic effects were associated with activation of the SIRT1–LKB1–AMPK signalling pathway in adipose tissue and liver. Of particular note, UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of Bou-treated mice. Incubation with Bou induced similar changes in primary brown adipocytes isolated from mice. Conclusions and implications Bou may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues and liver through a mechanism involving the SIRT1–LKB1–AMPK axis.

The ongoing development of the digital music ecosystem has fostered a proliferation of products. In this study our aim was to address the digital aspects of physical music products. We analyzed data collected via a survey, using a research model based on an enhanced version of the theory of reasoned action, into which we integrated the following: intangibility attributes of perceived risk, accessibility, and predicted risk; price, range, and trialability as attributes that define the types of digital product; and the entertainment attributes of anticipation of customers' needs and perceived playfulness. Results indicated that consumers' attitude and intention were influenced mainly by product range and, simultaneously, that their decision to buy digital music was influenced by attitude and subjective norms. The results suggest that as trialability had a nonsignificant impact on consumer intention and attitude, consumers' perceived risk may be lowered by reducing the cost of digital music.

Recrystallization effects are considered for the proposed force modeling method of Inconel 718 laser-assisted end milling. Oblique cutting forces are transferred to equivalent orthogonal cutting forces through the chip flow model. According to the classic Oxley’s contact mechanics theory, cutting and axial forces are calculated when shear stress is the same as chip flow stress. The Johnson-Cook model predicts the flow stress as a function of strain, strain rate, and temperature. And one parameter in this model has a physical meaning of initial yield stress, which varies with grain size. The Johnson-Mehl-Avrami-Kolmogorov (JMAK) model describes the dynamic recrystallization process of crystalline material and then predicts grain size through the recrystallized volume fraction. Overall, recrystallization effects are considered by applying a grain size-dependent parameter in the Johnson-Cook model. And the dynamic recrystallization process is considered to predict grain size. Five experiments are conducted through a single-beam coaxial laser-assisted milling spindle. And experimental measurements are compared with analytical predictions. Overall, the proposed model provides accurate results in F x and F z prediction. The maximum error is less than 20%.

It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize c-KIT G-quadruplex with good selectivity against duplex DNA. It was found that 12-N-methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[c]acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway.

Two neutral merocyanine-based near-infrared fluorescent probes were for the first time developed through rational engineering of the classical cationic cyanine scaffold IR-780 for in vivo imaging of amyloid-β plaques. In vivo NIRF imaging revealed that the probe could penetrate the blood-brain barrier and efficiently differentiate the living transgenic and wild-type mice.

A new phloroglucinol derivative, 1-(2,4-dihydroxy-6-methoxyphenyl)-1-tridecanone (1), along with a known analogue, 1-(2,4,6-trihydroxyphenyl)-1-hexadecanone (2), was isolated from the leaves of Syzygium austroyunnanense. Their structures were elucidated on the basis of spectroscopic data and comparison with the literature.

Purpose Our study aimed to evaluate the relationship between electrodiagnostic study (EDS) severity and utilization of treatments for carpal tunnel syndrome (CTS) as well as the duration of time between EDS and carpal tunnel release (CTR). Methods We conducted a retrospective medical chart review at a single tertiary hand center to evaluate CTS-related care that patients received after EDS. We recorded patient age, sex, race/ethnicity, insurance type, CTS-related surgical and nonsurgical healthcare utilization after EDS testing, and number of days between EDS and CTR. Results Among all patients with an eventual diagnosis of CTS who received EDS (n = 210), nearly half had normal or mild severity (23%, n = 48; and 28%, n = 58, respectively) and the other half had moderate or severe EDS findings (26%, n = 55; and 23%, n = 49, respectively). Patients with severe findings had the highest rate of receiving surgery (53%) compared with patients with mild and moderate findings (33% vs 46%, respectively). Among the patients who received CTR (n = 73), patients with severe EDS findings had the shortest time to CTR (59.5 days; interquartile range [IQR], 30–81), compared with mild severity (170 days; IQR, 87–415) and moderate severity (77 day; IQR, 42–292). Moderate and severe EDS findings were associated with significantly higher odds of receiving CTR in adjusted analyses (odds ratio, 2.48, 95% confidence interval, 1.04–5.93 and odds ratio 3.79, 95% confidence interval, 1.51–9.50, respectively) compared with patients with mild EDS findings. However, the odds of receiving steroid injection and hand therapy/orthosis were not significantly different based on severity. Conclusions Electrodiagnostic study severity had a direct relationship to the probability of receiving surgery but did not correlate with use of nonsurgical treatment. The study findings signal a need to evaluate the value of nonsurgical treatments in patients with severe EDS findings. Type of study/level of evidence Prognostic II.

Background and purpose Non-alcoholic hepatic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and non-alcoholic steatohepatitis (NASH) represents its advanced stage. R17 derived from bouchardatine, shows benefits in the metabolic syndrome, but has not been tested in the liver. The present study examined the pharmacological effects of R17 in a model of NAFLD/NASH and its mode of action. Experimental approach The effects of R17 were examined in mice fed a high-fat (HF) diet to induce the pathological characteristics of NAFLD/NASH and in cultures of HuH7 cells. We used histological and immunohistochemical techniques along with western blotting and siRNA. Generation of ROS and apoptosis were measured. Key results Administration of R17 (20 mg·kg-1 , i.p. every other day) for 5 weeks reversed HF-induced hepatic triglyceride content, inflammation (inflammatory cytokines and macrophage numbers), injury (hepatocyte ballooning and apoptosis, plasma levels of alanine aminotransferase and aspartate aminotransferase), and fibrogenesis (collagen deposition and mRNA expression of fibrosis markers). In cultured cells, R17 reduced cell steatosis from both lipogenesis and fatty acid influx. The attenuated inflammation and cell injury were associated with inhibition of both endoplasmic reticulum (ER) stress and oxidative stress. Notably, R17 activated the liver kinase B1-AMP-activated protein kinase (AMPK) pathway by inhibiting activity of ATP synthase, rather than direct stimulation of AMPK. Conclusion and implications R17 has therapeutic potential for NAFLD/NASH. Its mode of action involves the elimination of ER and oxidative stresses, possibly via activating the LKB1-AMPK axis by inhibiting the activity of ATP synthase.

The control of work hardening in laser-assisted milling process while keeping a desirable cutting efficiency is quite challenging. Surface hardness is a good indicator of the work hardening. Therefore, it is valuable to predict surface hardness in laser-assisted milling such that the effects of process parameters can be better quantified to facilitate process planning. In the current study, a general surface hardness predictive model based on theories of metal machining and microstructure evolution in laser-assisted milling process is proposed to describe the grain size variation-induced hardness change. The laser preheating temperature field is first calculated by treating the laser beam as a moving heat source. Then, the oblique milling process is transferred to equivalent orthogonal cutting process at each rotation angle to predict the grain size dependent on dynamic recrystallization process. The inverse relationship between the grain diameter and surface hardness is applied to decide grain size variation-induced hardness change. The model is validated through laser-assisted milling experiments on Ti-6Al-4V and Ti-6Al-4V ELI. The proposed predictive model is able to match the experimental measurements in all cases with an average error of 3% for Ti-6Al-4V and 3.3% for Ti-6Al-4V ELI. In addition, a sensitivity analysis is conducted on Ti-6Al-4V to study the influences of cutting speed, depth of cut, laser power, and laser-tool distance on hardness. The proposed analytical model is valuable for providing a fast, credible, and physics-based method for the prediction of surface hardness in laser-assisted milling of various materials. Through sensitivity analysis, the model is able to guide the selection of cutting and laser parameters when the control of surface hardness is the main target.

Machining temperature is a key factor in ultrasonic vibration-assisted milling as it can significantly influence tool wear rate and residual thermal stresses. In current study, a physics-based analytical predictive model on machining temperature in ultrasonic vibration-assisted milling is proposed, without resorting to iterative numerical simulations. As the tool periodically loses contact with the workpiece under vibration, three types of tool-workpiece separation criteria are first examined based on the tool trajectory under ultrasonic vibration. Type I criterion examines whether the relative velocity between tool and workpiece in cutting direction is opposite to the tool rotation direction. Type II criterion examines whether the instantaneous vibration displacement in radial direction is larger than instantaneous uncut chip thickness. Type III criterion examines whether there is overlap between current and previous tool paths due to vibration. If no contact, the instantaneous temperature rise is zero. Otherwise, the temperature rise is predicted under shearing heat source in shear zone and secondary rubbing heat source along machined surface. A mirror heat source method is applied to predict temperature rise, considering oblique band heat sources moving in a semi-infinite medium. The proposed predictive temperature model in ultrasonic vibration-assisted milling is validated through comparison to experimental measurements on Al 6063 alloy. The proposed predictive model is able to match the measured temperature with high accuracy of 1.85% average error and 5.22% largest error among all cases. Sensitivity analysis is also conducted to study the influences of cutting and vibration parameters on temperature. The proposed model is valuable in terms of providing an accurate and reliable reference for the prediction of temperature in ultrasonic vibration-assisted milling.

BACKGROUND: This study aimed to measure the use of pathology evaluation of breast specimens among patients undergoing reduction mammaplasty and assess rates of new diagnoses of breast disease and associated cost. METHODS: We analyzed the Truven MarketScan Databases from 2009–2015 to identify adult female patients undergoing reduction mammaplasty for macromastia. We recorded patient age, rates of obtaining pathology evaluation, new diagnoses of benign or malignant breast disease after pathology evaluation, and total cost for the surgery encounter. RESULTS: Among 17,738 macromastia patients undergoing reduction mammaplasty, 91.3% (n=16,193) received pathology evaluation. Pathology evaluation rates were clinically similar across age groups

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.

Mycophenolate mofetil is an antiproliferative immunosuppressive agent. Since its clinical efficacy and safety highly depend on the quality, the stability, and impurity profiles of mycophenolate mofetil are paid ever-increasing attention. However, there are few published studies reporting the complete characterization of both the process-related substances and degradation products in mycophenolate mofetil. In the present study, a highly specific and efficient liquid chromatography coupled with quadrupole-time of flight mass spectrometry method was developed for the separation and identification of all the potential impurities in mycophenolate mofetil. According to the ICH Q1A (R2) guideline, the forced degradation studies were conducted to elucidate the stability and degradation pathways of mycophenolate mofetil. A total of 15 related substances, including the process-related substances and stress degradation products were characterized by the established hyphenated method, 11 of them have not been reported before. In view of the synthetic route and degradation pathways of mycophenolate mofetil, the origins and formation mechanisms of these related substances were discussed. Based on the obtained stability and impurity profiles, key points of the manufacturing process were proposed to deliver mycophenolate mofetil with high purity.

The health crisis caused by the new coronavirus (SARS-CoV-2) exposes latent social tensions arising from the process of globalization. The battle for the history of the responsibility for the crisis opens new fronts in which, thanks to social media, the public seems to be actively engaged. The first case of coronavirus in Brazil was confirmed in February, followed by a rapid increase in cases, news, and discourses on social media. Against this background, this article examines the following research question: what themes and sentiments are evoked in tweets posted in Portuguese linking the COVID-19 pandemic to China? We conducted a time series study of tweets posted during the period 19 March to April 3, 2020, retrieving 1.6 million tweets. The data was filtered in three stages and thematic and sentiment analysis was performed across the data set. The findings show that the most frequently occurring themes were the “Chinese virus”, “virus from China”, use of chloroquine, cure, the press and quality of information, dictatorship, China, Bolsonaro, and communism. The content of the tweets on these themes clearly reveals user sentiment, with a predominance of negative sentiments (fear, sadness and anger) and low proportion of sentiments in the category trust. The themes and sentiments evoked in the tweets reveal elements that characterize the current context of political polarization in Brazil and its effects on Twitter users’ understanding of the COVID-19 pandemic.

Laser-assisted machining (LAM) could help to significantly reduce the machining forces and improve machinability of hard to machine materials. The physical ground explanation for machinability improvement of the LAM stay largely unknown. In the current study, a 3D model is developed for the temperature field calculation induced by laser preheating. Taking preheating temperature field as initial input, an analytical milling force model is developed based on Oxley’s contact mechanics. Model validations are conducted by comparing the milling forces between the model predictions and experimental measurements in the LAM of Inconel 718 (IN 718). A good agreement is found. Also, the LAM forces are compared with traditional milling. The reduced specific cutting energy and reduced milling forces in LAM show the improved machinability of IN 718. The proposed analytical model provides a new method for the LAM process optimization.

Carbon monoxide (CO) has captivated great attention in part due to the discovery of the therapeutic and cell-signalling role that CO plays in biological systems. The ever-increasing interest in CO has resulted in the development of rapid and facile approaches for the sensitive and selective detection of CO, which still remains challenging. Herein, the first example of a colorimetric and near-infrared fluorescent dual probe for carbon monoxide (CO) has been developed by assembling an allyl chloroformate moiety with a naphthofluorescein fluorophore, which enables the label-free and visual detection of CO. The living cell imaging results indicate that the probe shows great potential in sensing intracellular CO.

This study disclosed self-assembly of cyclic diguanylate monophosphate (c-di-GMP) and terbium ions (Tb3+) into coordination polymer nanoparticles (CPNPs) at neutral pH based on the electrostatic interaction and coordination-bond formation. The as-synthesized c-di-GMP/Tb3+ CPNPs exhibited weak luminescence due to the coordination of Tb3+ with guanine bases of c-di-GMP that leads to inefficient energy transfer. It was found that the incorporation of Ag+ into the c-di-GMP/Tb3+ CPNPs boosted the luminescence of Tb3+. Since Ag+ can compete with Tb3+ for interacting with guanine bases of c-di-GMP, Tb3+ preferably binds to phosphodioxy groups of c-di-GMP in the presence of Ag+. This electrostatic interaction promotes efficient energy transfer from guanine bases of c-di-GMP to Tb3+. The c-di-GMP/Tb3+/Ag+ CPNPs possessed relatively high quantum yield (30.9 %) and long luminescent lifetime (1.3 ms) as compared to the previously reported nucleotide/Tb3+/Ag+ CPNPs. The CPNP-based sensing system allowed the quantification of c-di-GMP with the linear range of 20–300 nM and the detection limit (signal-to-noise ratio of 3) of 7 nM. The sensing system toward c-di-GMP was created by the combination of the two-step procedure involving the use of polystyrene sulfonic acid-coated magnetite nanoparticles to remove the interfering di- and tri-phosphate nucleotides, followed by the c-di-GMP-mediated formation of the CPNPs in the presence of Tb3+ and Ag+. The CPNP-based sensing system was practically utilized to determine the level of c-di-GMP in bacterial lysates.

This study explores the factors affecting reading time, error rate, visual fatigue, and mental workload of subjects using a monocular optical head-mounted display (OHMD). Forty healthy participants were involved in this study using four factors: gender, reading conditions (walking and sitting), font sizes (12-, 16-, 20-, 24-, 28-, and 32-point), and contrast ratios (3.0:1, 7.5:1, 12.0:1, 16.5:1, and 21.0:1). The reading time, error rate, critical fusion frequency, the National Aeronautics and Space Administration’s raw task load index, and visual fatigue scale were the dependent measures. Gender showed no significant effect on reading time or error rate. Reading conditions, font sizes, and contrast ratios had significant effects on reading time. Large font sizes produced the fastest reading times for both walking and sitting conditions. The walking condition produced significantly more visual fatigue and mental workload than the sitting condition. Font size and contrast ratio had significant effects on reading time and error rate. The fastest reading time was found at the 16.5:1 contrast ratio for both walking and sitting conditions. Combined with the 28-point font size, we found the fastest reading time and lowest error rate performance combination. Considering reading conditions, contrast ratios, and font size combinations, the 16.5:1 contrast ratio with 28-point font size in the sitting condition and the 16.5:1 contrast ratio with 32-point font size in the walking condition showed the best reading times and error rates. The results from this study can provide very useful reference information for OHMDs and related product interface designs.

PURPOSE: We sought to evaluate the use of pre- and post-referral advanced diagnostic testing among patients with three common hand conditions, rates of subsequent tests, and differences in wait time to see a hand surgeon. METHODS: We analyzed a single academic tertiary care center administrative database of encounters from 2006 – 2015 to identify adult patients who were referred to a hand surgeon for three hand conditions (carpal tunnel syndrome [CTS], soft tissue masses [STM], and joint pain [JP]). We recorded patient characteristics, use and timing of diagnostic tests, and wait time for the initial hand surgeon evaluation. RESULTS: Among patients who received advanced diagnostic tests prior to the surgeon evaluation, CTS patients had the highest rate of receiving pre-referral advanced testing (53.4%) compared to 10.6% of JP patients and 5.8% of STM patients. CTS patients had the highest rates of repeat testing (19.5%) compared to patients with JP (1.4%) and STM (0%). Across all three conditions, patients who received pre-referral advanced testing waited an additional 19–94 days to see a surgeon compared to patients who received only post-referral testing or no testing. CONCLUSIONS: The use of pre-referral advanced diagnostic tests is associated with an increased time to see a hand surgeon for common hand conditions. CLINICAL RELEVANCE STATEMENT: Hand surgeons should play a role in identifying patients who do and do not benefit from advanced testing prior to referral to ensure that tests ordered prior to consultation are useful to both patients and treating surgeons.

The overexpression of matrix metalloproteinase (MMP) plays an important role in the context of tumor invasion and metastasis, and MMP-2 has been characterized as the most validated target for cancer. Therefore, it is necessary to design matrix metalloproteinase inhibitors (MMPIs) that would be active and selective against MMP-2 but non-selective toward other MMPs. Areas covered: This article clearly describes the structural character of MMP-2 followed by a review of the recent development of selective MMP-2 inhibitors based on their basic structures. Expert opinion: Over the past 30 years, MMPs have been considered to be attractive cancer targets, and several different types of synthetic inhibitors have been identified as anticancer agents, but only a small number of small MMPIs have been examined in clinical trials, and none of these molecules has been established as anticancer drugs due to their adverse effects. One major possibility is that the MMPIs used in clinical trials were broad-spectrum drugs that also inhibited the anti-tumor effects and influenced the mediation of the normal physiological processes of MMPs. MMP-2 has recently been characterized as the most validated target for cancer. Therefore, the design and synthesis of selective MMP-2 inhibitors would be helpful for the treatment of cancer.

Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC50 = 0.24 μM) compared with Bou (EC50 ≈ 25 μM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins.