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PurposeThe inhibition of thrombin has proven to be an efficacious therapeutic approach for managing cardiovascular disease (CVD), with widespread implementation in clinical settings. Oral ingestion of peptides and protein drugs is influenced by gastrointestinal digestive enzymes. We aimed to evaluate the thrombin inhibitory properties of hirudo hydrolysates (HHS) produced by pepsin and propose a comprehensive approach to screen and evaluate thrombin inhibitors.MethodsWe evaluated the in vitro inhibitory properties of the hirudo extract, both before and after hydrolysis with pepsin, toward thrombin. We screened for the most potent thrombin inhibitory peptide (TIP) using nano liquid chromatography-tandem mass spectrometry (Nano LC-MS/MS) coupled with in silico analysis. Next, we employed the thrombin inhibition activity IC50 to investigate the interaction between TIP and thrombin, and conducted in vitro evaluations of its anticoagulant effects (APTT, TT, PT), as well as its ability to inhibit platelet aggregation. Furthermore, we utilized UV-Vis spectroscopy to explore structural changes in thrombin upon binding with TIP and employed molecular dynamics simulations to delve deeper into the potential atomic-level interaction modes between thrombin and TIP.ResultsThe retention rate of thrombin inhibition for HHS was found to be between 60% and 75%. A total of 90 peptides from the HHS were identified using LC-MS/MS combined with de novo sequencing. Asn-Asp-Leu-Trp-Asp-Gln-Gly-Leu-Val-Ser-Gln-Asp-Leu (NDLWDQGLVSQDL, P1) was identified as the most potent thrombin inhibitory peptide after in silico screening (molecular docking and ADMET). Then, the in vitro study revealed that P1 had a high inhibitory effect on thrombin (IC50: 2,425.5 ± 109.7 μM). P1 exhibited a dose-dependent prolongation of the thrombin time (TT) and a reduction in platelet aggregation rate. Both UV-Vis spectroscopy and molecular dynamics simulations demonstrated that P1 binds effectively to thrombin.ConclusionOverall, the results suggested that HHS provides new insights for searching and evaluating potential antithrombotic compounds. The obtained P1 can be structurally optimized for in-depth evaluation in animal and cellular experiments.

BackgroundAging is marked by the gradual deterioration of cells, tissues, and organs and is a major risk factor for many chronic diseases. Considering the complex mechanisms of aging, traditional Chinese medicine (TCM) could offer distinct advantages. However, due to the complexity and variability of metabolites in TCM, the comprehensive screening of metabolites associated with pharmacology remains a significant issue.MethodsA reliable and integrated identification method based on UPLC-Q Exactive-Orbitrap HRMS was established to identify the chemical profiles of Huan Shao Dan (HSD). Then, based on the theory of sequential metabolism, the metabolic sites of HSD in vivo were further investigated. Finally, a deep learning model and a bioactivity assessment assay were applied to screen potential anti-aging metabolites.ResultsThis study identified 366 metabolites in HSD. Based on the results of sequential metabolism, 135 metabolites were then absorbed into plasma. A total of 178 peaks were identified from the sample after incubation with artificial gastric juice. In addition, 102 and 91 peaks were identified from the fecal and urine samples, respectively. Finally, based on the results of the deep learning model and bioactivity assay, ginsenoside Rg1, Rg2, and Rc, pseudoginsenoside F11, and jionoside B1 were selected as potential anti-aging metabolites.ConclusionThis study provides a valuable reference for future research on the material basis of HSD by describing the chemical profiles both in vivo and in vitro. Moreover, the proposed screening approach may serve as a rapid tool for identifying potential anti-aging metabolites in TCM.

The combine harvester equipped with attitude-adjustment functionality significantly enhances its adaptability to complex terrain but often struggles to maintain the reliability of its mechanisms. Therefore, investigating the dynamic load characteristics of the attitude-adjustment mechanism becomes imperative. This article employed the DEM–FMBD (Discrete Element Method–Flexible Multibody Dynamics) bidirectional coupling simulation method to establish a multibody dynamic model of a tracked combine harvester. The study delved into the interaction mechanism and dynamic stress response characteristics between the tracked chassis and the complex terrain under various height adjustments, lateral adjustment angles, longitudinal adjustment angles, and different field-ridge crossing methods. Finally, the accuracy of the coupled simulation model was validated through a constructed stress detection system. The research findings revealed that the displacement and tilt angle deviation of the hydraulic cylinders utilized to execute the chassis adjustment actions in the constructed coupled simulation model was less than 5%, and the deviation between the simulation results and the actual maximum dynamic stress under multiple working conditions ranged from 7% to 15%. This verification confirmed the effectiveness of the DEM–FMBD coupled simulation method. Under different adjustment conditions, the maximum stress position was consistently distributed in the same area of the left-front and left-rear rotating arms. The primary and secondary effects of the various parts of the adjustment mechanism on the overall reliability of the chassis were as follows: left front > right front > left rear > right rear. By implementing the middle height with the adjustment strategy, the dynamic stress extreme value of the adjustment mechanism can be effectively reduced by 21.98%, thereby enhancing the structural stability of the chassis.

During the operation of the longitudinal axis flow threshing device of a combine harvester, the threshed materials form accumulations and blockages on both sides of the screen surface, severely affecting the harvesting process. To evenly distribute the materials on the screen and solve the blockage issue, a multi-wing curved combination centrifugal fan is designed to match the mass distribution of the threshed materials. The movement mechanism of rice threshed materials in the cleaning shoe of a longitudinal axis flow combine harvester is investigated using the coupled CFD-DEM simulation method. The cleaning efficiency and performance of the traditional straight-blade fan screen device and the newly designed cleaning device are compared and analyzed, and field tests are conducted. The results show that the trajectory of the threshed materials cleaned by the device equipped with the multi-wing curved combination centrifugal fan is consistent with the mass distribution of the materials separated by the longitudinal axis flow threshing device. The absolute value of the centroid velocity of the material group in the X/Y direction is greater than that of the traditional fan, indicating that the movement speed of the particle group in the optimized fan is greater than that of the traditional fan. Therefore, in the actual cleaning process, the optimized fan’s air flow distribution more effectively accelerates the movement speed of the threshed materials, increasing the amount of materials cleaned per unit time, thereby improving the cleaning efficiency. Field comparative tests show that the designed cleaning device reduced the cleaning loss rate by up to 25.00% and the impurity content rate by 32.20%, achieving efficient and low-damage cleaning of the combine harvester. The study demonstrates the effectiveness of the proposed method for evenly distributing the materials and provides important reference for the study of other piled particle distribution systems.

Aimed at addressing the problems of the existing straw choppers on combine harvesters, such as a large cutting resistance and poor cutting effect, combined with bionic engineering technology and biological characteristics, a bionic model was used to extract the characteristics of the cutting blades of locusta migratoria manilensis’s upper jaw. A 3D point cloud reconstruction and machine vision methods were used to fit the polynomial curve of the blade edge using Matlab 2016. A straw-cutting process was simulated using the discrete element method, and the cutting effect of the bionic blade was verified. Cutting experiments with rice straws were conducted using a physical property tester, and the cutting resistance of straw to bionic blades and general blades was compared. On the whole, the average cutting force of the bionic blades was lower than that of the general blades. The average cutting force of the bionic blade was 18.74~38.23% lower than that of a smooth blade and 1.63~25.23% lower than that of a serrated blade. Similarly, the maximum instantaneous cutting force of the bionic blade was reduced by 2.30~2.89% compared with the general blade, which had a significant drag reduction effect. By comparing the time–force curves of different blades’ cutting processes, it was determined that the drag-reducing effect of the bionic blade lies in shortening the straw rupture time. The larger the contact area between the blade and the straw, the more uniform the cutting morphology of the straw after cutting. Field experiment results indicate that the average power consumption of a straw chopper partially installed with bionic blades was 5.48% lower than one with smooth blades, measured using a wireless torque analysis module. In this research study, the structure of the straw chopper of an existing combine harvester was improved based on the bionic principle, which reduced resistance when cutting crop straw, thus reducing the power consumption required by the straw chopper and improving the effectiveness and stability of the blades.

Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system’s pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC50 53 ± 0.63 μg/mL) of the iridoid glycosides’ potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE.

Image feature detection serves as the cornerstone for numerous vision applications, and it has found extensive use in agricultural harvesting. Nevertheless, determining the optimal feature extraction technique for a specific situation proves challenging, as the Ground Truth correlation between images is exceedingly elusive in harsh agricultural harvesting environments. In this study, we assemble and make publicly available the inaugural agricultural harvesting dataset, encompassing four crops: rice, corn and soybean, wheat, and rape. We develop an innovative Ground Truth-independent feature detector assessment approach that amalgamates efficiency, repeatability, and feature distribution. We examine eight distinct feature detectors and conduct a thorough evaluation using the amassed dataset. The empirical findings indicate that the FAST detector and ASLFeat yield the most exceptional performance in agricultural harvesting contexts. This evaluation establishes a trustworthy bedrock for the astute identification and application of feature extraction techniques in diverse crop reaping situations.

The shrinkage of the connective tissue and myofiber of lamb meat submitted to heat treatment or air drying at different storage stages (1, 5 and 7 days) was evaluated herein. The longitudinal and transverse shrinkage of heated lamb meat was significantly influenced by storage time and water bath heating temperature (50 °C, 70 °C and 90 °C) (p < 0.001). In contrast, the shrinkage of air-dried lamb meat was not influenced by storage time (p > 0.05). The microstructure of heated lamb meat, namely, the distance between muscle fascicles, the distance between myofibril networks, the area of myofibril networks, and the endomysium circumference, was significantly influenced by storage time (p < 0.05). During storage, the proportion of muscle fibers completely detached from endomysium increased, which could be due to the progressive degradation of proteins linking the endomysium and myofibril, including β-dystroglycan, α-dystroglycan, integrin-β1, and dystrophin. However, degradation of such proteins did not influence the shrinkage of lamb meat stored for five days or longer, since the decreased distance between myofibril networks indicated a higher shrinkage ratio of the endomysium compared to myofibers in samples air-dried at 35 °C or heated at 90 °C. The effect of these proteins on the shrinkage of heated lamb meat (raw meat stored for 1 day or less time) requires further elucidation.

Body tilt is typically unavoidable for agricultural vehicles or platforms when operated over tough terrain in agricultural production, and, therefore, it is not possible to guarantee the operation performance. Current leveling methods mainly focus on wheeled vehicles or adjustment for single working parts rather than the vehicle body, and few of them could be applied to crawler vehicles. The objective of this research was to put forward an adaptive leveling system for combine harvesters based on the development of a new four-point lifting adjustable crawler chassis. The working principle of the proposed adjustable mechanism was studied on the basis of the analysis of adjustment characteristics under multiple posture adjustment conditions in a RecurDyn environment. The design relies on the combination of the attitude detection of the leveling system and adjustment calculation of driving hydraulic cylinders according to the established mathematical models. Within the designed adjustable extent (including adjustment range of vehicle height 0–87.8 mm, lateral inclination ±3.98° and longitudinal inclination −2.9–5.2°), the leveling performance of lateral and longitudinal inclination was then tested separately. The experiment showed that the leveling system could achieve automatic leveling with an accuracy of ±0.4° and could provide technical support for the development of crawler vehicles.

Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown. The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis induced by bleomycin in mice. We found that mPGES-1 deficient (mPGES-1−/−) mice exhibited more severe fibrotic lesions with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type (mPGES-1+/+) mice. The mPGES-1 expression levels and PGE2 content were also decreased in bleomycin-treated mPGES-1+/+ mice compared to saline-treated mPGES-1+/+ mice. Moreover, in both mPGES-1−/− and mPGES-1+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 (EP2) and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells (MRC-5), siRNA-mediated knockdown of mPGES-1 augmented transforming growth factor-β1 (TGF-β1)-induced α-smooth muscle actin (α-SMA) protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase (FAK) inhibitor. In conclusion, these findings revealed mPGES-1 exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of mPGES-1-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of IPF patients.

Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single-center studies. We measured failure-free survival in a prospective observational cohort of patients (n=575) with both newly diagnosed and existing chronic graft-versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0–3 skin score, higher National Institutes of Health 0–3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II–IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio=2.06, 95% confidence interval: 1.29–3.32; P

The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients’ mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.

Background The National Institutes of Health Consensus Conference proposed the term “overlap” graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present.Design and Methods We examined whether the overlap subtype of graft-versus-host disease was associated with a different prognosis, functional limitations, or patient-reported outcomes compared to “classic” chronic graft-versus-host disease without any acute features.Results Prospective data were collected from 427 patients from nine centers. Patients were classified as having overlap (n=352) or classic chronic (n=75) graft-versus-host disease based on reported organ involvement. Overlap cases had a significantly shorter median time from transplantation to cohort enrollment (P=0.01), were more likely to be incident cases (P

Background The 2005 National Institute of Health Chronic Graft-versus-Host Disease Consensus Conference recommended collection of patient-reported outcomes in clinical trials on chronic graft-versus-host disease. We assessed whether changes in chronic graft-versus-host disease severity, determined using National Institute of Health criteria, clinicians’ assessment or patients’ self-evaluation, correlated with patient-reported quality of life as measured by the Short Form-36 and Functional Assessment of Cancer Therapy – Bone Marrow Transplant (FACT-BMT) instruments.Design and Methods Three-hundred and thirty-six adult patients (median age 52 years; range, 19 – 79) with chronic graft-versus-host disease from six transplant centers contributed baseline and follow-up data (from 936 visits overall).Results While the majority of the patients had stable chronic graft-versus-host disease, improvement or worsening was noted in approximately 40% of follow-up visits. Multivariable analysis demonstrated no association between change in chronic graft-versus-host disease severity evaluated by National Institute of Health criteria and change in quality of life, while clinician-reported changes in severity were associated with changes in some quality of life measures. Patient-reported changes in the severity of chronic graft-versus-host disease were associated with changes in all quality of life measures. Comparison of the Short Form-36 and the FACT-BMT suggested that the data collected in the Functional Assessment of Cancer Therapy – General (FACT-G) core survey are sufficient without the need for the Short Form-36 or the FACT–BMT subscale.Conclusions We conclude that serial National Institute of Health and clinician-reported chronic graft-versus-host disease severity assessments cannot substitute for patient-reported outcomes in clinical trials. Collection of just the FACT-G instead of the Short Form-36 and the full FACT-BMT will decrease respondent burden without compromising quality of life assessment.

Due to infectious and bleeding risks, adults with acute myeloid leukemia or high-risk myelodysplastic syndromes typically remain hospitalized after remission induction chemotherapy until blood count recovery. Here, we explored the medical and financial effects of discharge immediately after chemotherapy completion with close outpatient follow up. Within 12 months, 15 patients fulfilling both medical and logistical criteria were discharged early, whereas 5 patients meeting medical criteria only served as inpatient controls. No patient died. Patients discharged early spent a median of 8 days (range 3–36 days), or 54% of their study time, as outpatients. These patients required less time on intravenous antibiotics (6 vs. 16 days; P=0.11), received fewer red blood cell transfusions (0.25 vs. 0.48 units/day; P=0.08), and incurred lower median daily charges ($3,270 vs. $5,467; P=0.01) than controls. Thus, early discharge of selected patients appears, safe and may reduce cost and resource utilization.(ClinicalTrials.gov Identifier: NCT00844441)

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