Overcoming the challenge of potent endogenous interferences in limaprost quantification: An innovative methodology combining differential mobility spectrometry with LC-MS/MS for ultra-high sensitivity, selectivity and significantly enhanced throughput.

Limaprost, an orally administered analogue of prostaglandin E1, possesses potent vasodilatory, antiplatelet, and cytoprotective properties. Due to its extremely low therapeutic doses and exceedingly low plasma concentrations, the pharmacokinetic and bioequivalence studies of limaprost necessitate a highly sensitive quantitative method with a sub-pg/mL level of lower limit of quantification. Moreover, the intensity of endogenous interferences can even exceed the maximum concentration level of limaprost in human plasma, presenting further challenge to the quantification of limaprost. As a result, existing methods have not yet met the necessary level of sensitivity, selectivity, and throughput needed for the quantitative analysis of limaprost in pharmacokinetic and bioequivalence investigations. This study presents a new methodology that combines differential mobility spectrometry (DMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and utilizes a distinctive strategy to achieve more accurate DMS conditions. This integration yields a method that is currently the most sensitive and features the shortest analytical time, making it the sole technique capable of meeting the requirements for limaprost pharmacokinetic and bioequivalence investigations. This method demonstrates robustness and is successfully employed in a pharmacokinetic investigation of limaprost in human subjects, underscoring that the combination of DMS with LC-MS/MS serves as an efficacious strategy for overcoming the challenges inherent in analyzing biological samples afflicted by multiple interferences.

PROKR1-CREB-NR4A2 axis for oxidative muscle fiber specification and improvement of metabolic function.

Metabolic disorders are characterized by an imbalance in muscle fiber composition, and a potential therapeutic approach involves increasing the proportion of oxidative muscle fibers. Prokineticin receptor 1 (PROKR1) is a G protein-coupled receptor that plays a role in various metabolic functions, but its specific involvement in oxidative fiber specification is not fully understood. Here, we investigated the functions of PROKR1 in muscle development to address metabolic disorders and muscular diseases. A meta-analysis revealed that the activation of PROKR1 upregulated exercise-responsive genes, particularly nuclear receptor subfamily 4 group A member 2 (NR4A2). Further investigations using ChIP-PCR, luciferase assays, and pharmacological interventions demonstrated that PROKR1 signaling enhanced NR4A2 expression by Gs-mediated phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) in both mouse and human myotubes. Genetic and pharmacological interventions showed that the PROKR1-NR4A2 axis promotes the specification of oxidative muscle fibers in both myocytes by promoting mitochondrial biogenesis and metabolic function. Prokr1-deficient mice displayed unfavorable metabolic phenotypes, such as lower lean mass, enlarged muscle fibers, impaired glucose, and insulin tolerance. These mice also exhibited reduced energy expenditure and exercise performance. The deletion of Prokr1 resulted in decreased oxidative muscle fiber composition and reduced activity in the Prokr1-CREB-Nr4a2 pathway, which were restored by AAV-mediated Prokr1 rescue. In summary, our findings highlight the activation of the PROKR1-CREB-NR4A2 axis as a mechanism for increasing the oxidative muscle fiber composition, which positively impacts overall metabolic function. This study lays an important scientific foundation for the development of effective muscular-metabolic therapeutics with unique mechanisms of action.

Regarding reference state to identify priority areas for ecological restoration in a karst region.

Widespread degradation of natural ecosystems around the globe has resulted in several ecological problems. Ecological restoration is considered a global priority as an important means of mitigating ecosystem degradation and enhancing ecosystem services provision. Regarding ecosystem reference state is a prerequisite for ecological restoration. However, there were few studies focusing on how to regard reference state for ecological restoration, especially under a changing climate. Taking Guizhou Province, a typical karst region in China, as a case study area, in this study we firstly assessed ecosystem services under homogeneous climate conditions. Secondly, we defined the optimal ecosystem services as ecosystem reference state, and then evaluated restoration suitability under a comprehensive framework. Finally, ecological restoration priority areas (EPRAs), which included ecological reconstruction areas, assisted regeneration areas and conservation priority areas needing restoration, were identified by integrating restoration suitability and conservation priority areas. The results showed that the services of water conservation and habitat maintenance only increased less than 10% from 2001 to 2018. Identified ecological reconstruction areas and assisted regeneration areas covered 1078 km2 and 1159 km2 respectively. Additionally, 15 conservation priority areas with the total area of 18,507 km2 were identified as conservation priority areas needing restoration. Accounting for 11.78% of the total area, ERPAs were mostly located in the eastern part of Guizhou, including Qiandongnan, Tongren, and Zunyi. The approach proposed here for regarding ecosystem reference state after controlling climate variables and the framework for identifying ERPAs can provide a scientific reference for large-scale ecological restoration planning.

Assessing the Cultural Ecosystem Services Value of Protected Areas Considering Stakeholders' Preferences and Trade-Offs-Taking the Xin'an River Landscape Corridor Scenic Area as an Example.

Improving the accuracy of cultural ecosystem services (CESs) value assessment and paying more attention to the preferences and trade-offs of stakeholders in the administration of CESs are of vital importance for achieving resilient ecosystem management. Combining methodologies from sociology (Q method) and economics (choice experiment), an assessment framework of CESs is introduced to examine stakeholders' preferences and willingness to pay to participate in CESs in protected areas so as to explore how the value of CESs in protected areas can be optimized. The results show that the selection of CESs by stakeholders reflects certain synergies and trade-offs. Visitors can be classified as preferring humanistic-natural recreation, aesthetic-sense of place, or environmental education according to the factor ranking of the Q method. Visitors have a higher willingness to pay for humanistic heritage and a lower willingness to pay for sense of place experience, which can be measured at $6.55 per visit and $0.96 per visit, respectively. This indicates that the local customs and characteristics should be further explored and promoted through traditional festival celebrations and farming activities in further development of protected areas, apart from protecting local cultural heritages such as Huizhou ancient villages and halls. Furthermore, it is also necessary to actively explore the synergistic development of CESs, promote social participation, raise stakeholders' awareness of available services, manage visitors and stakeholders from a demand perspective, and promote the realization of the value of ecological products in protected areas.

Algorithm-based approach to focal liver lesions in contrast-enhanced ultrasound.

Focal liver lesions are commonly encountered. Grey-scale and Doppler sonographic characteristics of focal liver lesions are often non-specific and insufficient to conclusively characterise lesions as benign or malignant. Contrast-enhanced ultrasound is useful for the characterisation of FLLs in patients who are unable to undergo contrast-enhanced computed tomography or magnetic resonance imaging. It is also easily available and relatively cheap. However, interpretation of contrast-enhanced ultrasound can be challenging without a systematic approach. In this pictorial essay, we highlight an algorithm-based approach to FLLs and discuss the characteristic contrast-enhanced ultrasound features of commonly encountered and clinically significant focal liver lesions.

An action recognition method for manual acupuncture techniques using a tactile array finger cot.

The current measurement systems for the physical parameters (rotation frequency, and amplitude) of Traditional Chinese Medicine (TCM) manual acupuncture tend to cause disturbance and inconvenience in clinical application and do not accurately capture the tactile signals from the physician's finger during manual acupuncture operations. In addition, the literature rarely discusses classification of the four basic manual acupuncture techniques (reinforcing by twirling and rotating (RFTR), reducing by twirling and rotating (RDTR), reinforcing by lifting and thrusting (RFLT), and reducing by lifting and thrusting (RDLT)). To address this problem, we developed a multi-PVDF film-based tactile array finger cot to collect piezoelectric signals from the acupuncturist's finger-needle contact during manual acupuncture operations. In order to recognize the four typical TCM manual acupuncture techniques, we developed a method to capture piezoelectric signals in related "windows" and subsequently extract features to model acupuncture techniques. Next, we created an ensemble learning-based action classifier for manual acupuncture technique recognition. Finally, the proposed classifier was employed to recognize the four types of manual acupuncture techniques performed by 15 TCM physicians based on the piezoelectric signals collected using the tactile array finger cot. Among all the approaches, our proposed feature-based CatBoost ensemble learning model achieved the highest validation accuracy of 99.63% and the highest test accuracy of 92.45%. Moreover, we provide the efficiency and limitations of using this action recognition method.

Considering Farmers' Heterogeneity to Payment Ecosystem Services Participation: A Choice Experiment and Agent-Based Model Analysis in Xin'an River Basin, China.

The concept of watershed ecological compensation is one payment for ecosystem services (PES) program that incentivizes stakeholders undertake environmental conservation activities that improve the provision of ecosystem services. Defining the heterogeneity of farmers' willingness to participate in watershed ecological compensation is critically important for fully understanding stakeholders' demands. Accordingly, we designed a choice experiment survey to analyze the heterogeneity of policy preferences and willingness to receive compensation between upstream and midstream farmers in Xin'an River basin, China. Moreover, we simulated the impact of farmers' social capitals' heterogeneity with an agent-based model. The results show that there are significant differences in the preferences of agricultural waste recycling rate and agricultural water quality between farmers in the upstream and midstream. The total willingness of farmers in the upstream and midstream to participate in ecological compensation are RMB 149.88 (USD 22.54)/month and RMB 57.40 yuan (USD 8.63)/month, respectively. Social network size has a negative effect on farmers' willingness to participate the programs. Our findings suggest that the characteristics of farmers' influence their willingness to participate in the PES program. The results of this research can be used to improve PES management policies in the future, as well as to support sustainable environmental development and rural revitalization.

Controlling Non-Grain Production Based on Cultivated Land Multifunction Assessment.

The control of non-grain production (NGP) has become a great challenge for cultivated land protection in China in recent years. A control method for NGP that can coordinate the conflicts between cultivated land protection and farmers' interest is urgently needed. Taking Tongxiang City as an example, this research proposed a solution for the control and management of NGP based on cultivated land multifunctional assessment. The GIS and AHP approach were used to assess production function via a comprehensive evaluation index. The InVEST and FMSPA models were applied to assess ecological function while, the Maxent model was applied to assess recreational function, then multifunctional comprehensive zoning was conducted through natural breakpoint method and spatial overlay analysis. Five development-oriented function zones were considered, including the core area of grain production plus areas for ecological agriculture, leisure agriculture, compound agriculture, and general farmland. Differentiated control measures for NGPs in each functional subarea are proposed considering the current NGP distribution of Tongxiang city. This research can provide a reference for subsequent improvement of land management policies and can aid the achievement of sustainable agricultural development and rural revitalization.

A multilayer affective computing model with evolutionary strategies reflecting decision-makers' preferences in process control.

Many industrial control problems related to multi-objective optimization, such as controller parameters tuning, often require operators to perform multiple-step interactions without considering the changes of decision-makers' affective states and quantitative description of decision-makers' preferences during the interactive decision. Regarding this problem, we developed a multilayer affective computing model (MACM), including three factors: human personality, emotional space, and affective states, to demonstrate the iterative affective computing during the interactions. First, a concise model of affective computing-driven interactive decision-making was built before three submodules involved were described in detail. (1) An affective state recognition method based on facial expressions was presented, providing the basis for obtaining expert affective states during decision-making. (2) An identification method of affective parameters was given, providing an approach to describing personalized affective state-changing rules of different persons. (3) A definition of decision-makers' preferences in interactive decision-making was specified. In addition, a decision-makers' preferences mining method was developed by the MACM and an iterative learning control (ILC) strategy. Thus, we proposed affective computing-driven interactive decision-making method, which provided a simplified approach to converting the interactive decision problems based on decision-makers' preferences to decision issues based on incremental decision vector, along with assisting computers to learn from human experts and perform decision-making automatically in a general sense. Then, two typical process control cases-PI controller tuning for decoupling problem and manipulate vector optimization for batch processes were used to show the correctness and effectiveness of the contributions. Compared with other traditional optimization algorithms without affective state tracking and recognition (fuzzy control, ILC, reinforcement learning, and so on), experimental results indicated that the proposed method could achieve good performance. Finally, this study presented the efficiency and limitations of using this technique for a specific application.

High-throughput and trace analysis of diazepam in plasma using DART-MS/MS and its pharmacokinetic application.

A high-throughput quantitative analytical method based on Direct Analysis in Real Time tandem mass spectrometry (DART-MS/MS) has been developed and validated for the determination of diazepam in rat plasma, whereby analyzing of each sample needs merely 25 µL plasma, simple solid phase extraction sample preparation and 15 s acquisition time. The multiple reaction monitoring (MRM) transitions at m/z 285.2 â†’ 193.1 and 316.0 â†’ 270.0 were selected for the monitoring of diazepam and its internal standard clonazepam respectively. A good linearity within the range of 10-2000 ng/mL, an intra- and inter-day precisions within <7.78% as to an accuracy ranging from 1.04% to 7.92% have been achieved. The method has been successfully applied to the pharmacokinetic study of diazepam in rats' plasma after a single intragastric administration at a dose of 10 mg/kg. The results indicate that this method fulfills the requirements of the bioanalysis in sensitivity and accuracy. It shows considerable promise for application of DART-MS to the quantitative investigation of other drugs.

[Development and application of computer vision-based acupuncture manipulation classification system].

OBJECTIVE: To improve the accuracy of acupuncture manipulation modeling and inheritance, this article explores the feasibility of automatically classifying "twirling" and "lifting and thrusting", two basic acupuncture manipulations in science of acupuncture and moxibustion, with the computer vision technology. METHODS: A hybrid deep learning network model was designed based on 3D convolutional neural network and long-short term memory neural network to extract the spatial-temporal features of video frame sequences, which were then input into the classifier for classification. RESULTS: The model discriminated between "twirling" and "lifting and thrusting" manipulations in 200 videos, with the training and verification accuracy reaching up to 95.4% and 95.3%, respectively. CONCLUSION: This computer vision-based acupuncture manipulation classification system provides an effective way for the data extraction and inheritance of acupuncture manipulations.

[Recognition system of acupuncture manipulations based on an array PVDF tactile sensor and machine learning].

In learning and evaluation of acupuncture manipulations, there are lack of quantitative physical parameters on exertion strength, duration and direction of acupuncture technique at present. Based on the tactile parameters collected during "twirling" and "lifting-thrusting" of needling, a kind of array polyvinylidene fluoride (PVDF) tactile sensor was designed. Followed by, a window segmentation method for tactile signal was proposed and the time domain features of the window were extracted. Finally, an identification method of acupuncture manipulation based on FCM (Fuzzy C-Means) was constructed. Through the experiment, it was proved that this sensor can effectively identify the four kinds of basic acupuncture manipulations, i.e. reinforcing by twirling and rotating, reducing by twirling and rotating, reinforcing by lifting and thrusting and reducing by lifting and thrusting and it was conductive to the quantification and dissemination of acupuncture manipulations.

Clock gene Bmal1 controls diurnal rhythms in expression and activity of intestinal carboxylesterase 1.

OBJECTIVES: We aimed to characterize diurnal rhythms in CES1 expression and activity in mouse intestine, and to investigate a potential role of the core clock gene Bmal1 in generating diurnal rhythms. METHODS: The regulatory effects of intestinal Bmal1 on diurnal CES1 expression were assessed using intestine-specific Bmal1 knockout (Bmal1iKO) mice and colon cancer cells. The relative mRNA and protein levels were determined by qPCR and Western blotting, respectively. Metabolic activity of CES1 in vitro and in vivo were determined by microsomal assays and pharmacokinetic studies, respectively. Transcriptional gene regulation was investigated using luciferase reporter assay. KEY FINDINGS: Total CES1 protein varied significantly according to time of the day in wild-type (Bmal1fl/fl) mice, peaking at ZT6. Of detectable Ces1 genes, Ces1d mRNA displayed a robust diurnal rhythm with a peak level at ZT6, whereas mRNAs of Ces1e, 1f and 1g showed no rhythms in wild-type mice. Loss of intestinal Bmal1 reduced the levels of total CES1 protein and Ces1d mRNA, and blunted their diurnal rhythms in mice. In vitro microsomal assays indicated that intestinal metabolism of mycophenolate mofetil (MMF, a known CES1 substrate) was more extensive at ZT6 than at ZT18. ZT6 dosing of MMF to wild-type mice generated a higher systemic exposure of mycophenolic acid (the active metabolite of MMF) as compared with ZT18 dosing. Intestinal ablation of Bmal1 down-regulated CES1 metabolism at ZT6, and abolished its time-dependency both in vitro and in vivo. Furthermore, Ces1d/CES1 rhythmicity and positive regulation of Ces1d/CES1 by BMAL1 were confirmed in CT26 and Caco-2 cells. Mechanistically, BMAL1 trans-activated Ces1d/CES1 probably via binding to the E-box elements in the gene promoters. CONCLUSIONS: Bmal1 controls diurnal rhythms in expression and activity of intestinal CES1. Our findings have implications for understanding the crosstalk between circadian clock and xenobiotic metabolism in the intestine.

Pharmacokinetics-based chronoefficacy of Fuzi against chronic kidney disease.

OBJECTIVES: Identifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD). METHODS: The Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-ß-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1-/-) mice. KEY FINDINGS: The Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1ß, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy. CONCLUSIONS: The efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.

Upregulation of Tubulointerstitial nephritis antigen like 1 promotes gastric cancer growth and metastasis by regulating multiple matrix metallopeptidase expression.

BACKGROUND AND AIM: Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. METHODS: The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1 in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. RESULTS: TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migration in vitro as well as facilitated GC tumor growth and metastasis in vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. CONCLUSIONS: Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.

Expression level of epithelial cell adhesion molecule (EpCAM) of circulating tumor cells (CTCs) of patients with NSCLC as an early indicator to monitor the effects of postoperative adjuvant chemotherapy.

BACKGROUND: An early indicator for monitoring the effect of adjuvant treatment after lung cancer surgery is urgently needed. The study was to explore the effects of epithelial cell adhesion molecule (EpCAM) of circulating tumor cells (CTCs) in NSCLC patients with postoperative adjuvant chemotherapy. METHODS: Two drugs (platinum-containing chemotherapeutics + platinum-free chemotherapeutics) first-line chemotherapy regimen were given after surgery. MRNA of EpCAM was detected. Chest computed tomography, head computed tomography and abdominal B-ultrasound were reviewed before the first and third chemotherapy. RESULTS: EpCAM in CTCs from peripheral blood between the recurrent group and the non-recurrent group at 1 day before surgery, first, second and third adjuvant chemotherapy were no significant differences (P>0.05). Only one day before the fourth adjuvant chemotherapy treatment, it showed significant difference between the recurrent group and the non-recurrent group (P=0.008). There was a significant difference between the time of imaging diagnosis of recurrence or metastasis and the time of monitoring the expression level of EpCAM in CTCs from peripheral blood (P<0.0001). CONCLUSIONS: EpCAM in CTCs from peripheral blood during postoperative adjuvant chemotherapy was related to recurrence or metastasis of NSCLC patients.

Masquerading Hypervascular Exophytic Liver Nodule.

Patients with liver cirrhosis are at increased risk of developing hepatocellular carcinoma (HCC) and are placed on routine surveillance for HCC. Diagnosis algorithms are in place to guide clinicians in the evaluation of liver lesions detected during surveillance. Radiological assessments are critical with diagnostic criteria based on identification of typical hallmarks of HCCs on multiphasic computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging (MRI). We report a patient with a hypervascular exophytic lesion indeterminate for HCC on CT imaging. While the detection of an exophytic arterially-enhancing lesion in an at-risk patient on CT imaging may prompt clinicians to treat the lesion as HCC without further evaluation, the patient underwent contrast-enhanced MRI with the lesion being eventually diagnosed as an exophytic haemangioma. Thus, no further action was necessary and the patient was continued on routine HCC surveillance. LEARNING POINTS: Radiological surveillance for hepatocellular carcinoma (HCC) is routine in patients at risk of HCC.Diagnosis algorithms that are in place for indeterminate lesions detected during HCC surveillance should be adhered to in order to achieve an accurate diagnosis.Sequential imaging with contrast-enhanced (gadoxetate) MRI should be used to obviate the need for an invasive biopsy when an exophytic lesion indeterminate for HCC is identified during CT imaging in a patient with liver cirrhosis, especially when a hepatic haemangioma remains a differential diagnosis.

Absorption, distribution, metabolism and excretion of the biomaterials used in Nanocarrier drug delivery systems.

Nanocarriers (NCs) are a type of drug delivery system commonly used to regulate the pharmacokinetic and pharmacodynamic properties of drugs. Although a wide variety of NCs has been developed, relatively few have been registered for clinical trials and even fewer are clinically approved. Overt or potential toxicity, indistinct mechanisms of drug release and unsatisfactory pharmacokinetic behavior all contribute to their high failure rate during preclinical and clinical testing. These negative characteristics are not only due to the NCs themselves but also to the materials of the drug nanocarrier system (MDNS) that are released in vivo. In this article, we review the main analytical techniques used for bioassay of NCs and MDNS and their pharmacokinetics after administration by various routes. We anticipate our review will serve to improve the understanding of MDNS pharmacokinetics and facilitate the development of NC drug delivery systems.

A TCM acupoints ranking approach towards post-stroke dysphagia based on an improved MCTS decision method.

Traditional Chinese Medicine (TCM) multiple-acupoints stimulation is widely used to improve dysphagia among post-stroke patients. However, prior research in evidence-based acupuncture mostly focused on the treatment effects of single acupoint's on dysphagia, while the evidence of optimal sequence of multiple-acupoints stimulation remains limited. In this paper, we developed an evaluation method of hybrid knowledge (deterministic knowledge and the experiential group decision knowledge) sequences based on segmentation mechanism of sub-sequence fragments, and then, we proposed a Monte Carlo Tree Search (MCTS) sequential decision-making method under the hybrid knowledge. Thereafter, we applied this proposed sequential decision-making approach to optimizing sequential decision-making schema of multiple-acupoints stimulation, to treat dysphagia among post-stroke patients. Finally, we verified the validity and the feasibility of this method by comparing it to other sequential decision-making search methods.

A Unique Collision-Induced Dissociation Reaction of Cholamine Derivatives of Certain Prostaglandins.

Prostaglandins (PGs) are biologically active metabolites of arachidonic acid containing 20 carbon atoms, a cyclic moiety, and two side chains (A and B) in common. The bioassay of PGs requires high sensitivity because of their low concentration in tissues and blood and has usually been carried out by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative ion mode. Chemical derivatization of PG carboxylic acid groups to introduce positive charge-carrying groups is an established strategy to improve the sensitivity and selectivity of such assays. In this study, we exploited this approach for structural identification of a series of PGs using cholamine derivatization through an amidation reaction. However, we observed that collision-induced dissociation of these derivatives gave rise to unexpected product ions that we postulated were formed by unique long-range intramolecular reactions resulting in dehydration of the B chain accompanied by fragmentation of the A chain through an unusual Hofmann rearrangement. Evidence for the proposed mechanism is presented based on ESI-MS/MS and high resolution mass spectrometry studies of cholamine derivatives of PGE1, PGE2, PGD2, PGI2, and C-17 methyl deuterium-labeled limaprost. Graphical Abstract.