Recent Advances of Aminopeptidases-Responsive Small-Molecular Probes for Bioimaging.

Aminopeptidases, enzymes with critical roles in human body, are emerging as vital biomarkers for metabolic processes and diseases. Aberrant aminopeptidase levels are often associated with diseases, particularly cancer. Small-molecule probes, such as fluorescent, fluorescent/photoacoustics, bioluminescent, and chemiluminescent probes, are essential tools in the study of aminopeptidases-related diseases. The fluorescent probes provide real-time insights into protein activities, offering high sensitivity in specific locations, and precise spatiotemporal results. Additionally, photoacoustic probes offer signals that are able to penetrate deeper tissues. Bioluminescent and chemiluminescent probes can enhance in vivo imaging abilities by reducing the background. This comprehensive review is focused on small-molecule probes that respond to four key aminopeptidases: aminopeptidase N, leucine aminopeptidase, Pyroglutamate aminopeptidase 1, and Prolyl Aminopeptidase, and their utilization in imaging tumors and afflicted regions. In this review, the design strategy of small-molecule probes, the variety of designs from previous studies, and the opportunities of future bioimaging applications are discussed, serving as a roadmap for future research, sparking innovations in aminopeptidase-responsive probe development, and enhancing our understanding of these enzymes in disease diagnostics and treatment.

Vanin-1-Activated Chemiluminescent Probe: Help to Early Diagnosis of Acute Kidney Injury with High Signal-to-Noise Ratio through Urinalysis.

Acute kidney injury (AKI) is a common medical condition with high morbidity and mortality. Although urinalysis provides a noninvasive and convenient diagnostic method for AKI at the molecular level, the low sensitivity of current chemical probes used in urinalysis hinders the time diagnosis of AKI. Herein, we achieved the sensitive and early diagnosis of AKI by the development of a chemiluminescent probe CL-Pa suitable for detection of urinary Vanin-1. Vanin-1 is considered as an early and sensitive biomarker for AKI, while few chemical probes have been applied to for its efficient detection. By virtue of the low autofluorescence interference during urine imaging in the chemiluminescence model, CL-Pa could realize the monitoring of the up-regulated urinary Vanin-1 with a high signal-to-noise ratio (∼588). Importantly, under the help of CL-Pa, the up-regulation of urinary Vanin-1 of cisplatin-induced AKI mice at 12 h post cisplatin injection was detected, which was much earlier than clinical biomarkers (sCr and BUN) and change of kidney histology (48 h post cisplatin injection). Furthermore, using this probe, the fluctuation of urinary Vanin-1 of mice with different degrees of AKI was monitored. This study demonstrated the ability of CL-Pa in sensitively detecting drug-induced AKI through urinalysis and suggested the great potential of CL-Pa for early diagnosis of AKI and evaluate the efficiency of anti-AKI drugs clinically.

A Novel Real-Time Autonomous Crack Inspection System Based on Unmanned Aerial Vehicles.

Traditional methods on crack inspection for large infrastructures require a number of structural health inspection devices and instruments. They usually use the signal changes caused by physical deformations from cracks to detect the cracks, which is time-consuming and cost-ineffective. In this work, we propose a novel real-time crack inspection system based on unmanned aerial vehicles for real-world applications. The proposed system successfully detects and classifies various types of cracks. It can accurately find the crack positions in the world coordinate system. Our detector is based on an improved YOLOv4 with an attention module, which produces 90.02% mean average precision (mAP) and outperforms the YOLOv4-original by 5.23% in terms of mAP. The proposed system is low-cost and lightweight. Moreover, it is not restricted by navigation trajectories. The experimental results demonstrate the robustness and effectiveness of our system in real-world crack inspection tasks.

Research on Segmentation of Brain Tumor in MRI Image Based on Convolutional Neural Network.

Brain tumors are the brain diseases with the highest mortality and prevalence, and magnetic resonance imaging has high-resolution and multiparameter. As the basis for realizing the quantitative analysis of brain tumors, automatic segmentation plays a vital role in diagnosis and treatment. A new network model is proposed to improve the accuracy of convolutional neural network segmentation of brain tumor regions and control the parameter space scale of the network model. The model first uses a convolutional layer composed of a series of 3D convolution filters to construct a backbone network for feature learning of input 3D MRI image blocks. Then, a pyramid structure constructed by a 3D convolutional layer is designed to extract and fuse features of tumor lesions and context information of different scales and then classify the fused feature at the voxel level to obtain segmentation results. Finally, a conditional random field is used to postprocess segmentation results for structured refinement. By designing massive ablation experiments to analyze the sensitivity of the essential modules of the comparison network, the results confirm that our method can better solve the problems faced by the traditional fully connected convolutional neural network.

Selective detection of ozone in inflamed mice using a novel activatable chemiluminescent probe.

We report here an activatable chemiluminescent probe CL-O3 for the high-contrast imaging of O3in vivo. CL-O3 exhibited a high selectivity toward O3 and was able to evaluate the degree of inflammation in mice by detecting endogenous O3 levels in acute inflamed mice.

Proactive Guidance for Accurate UAV Landing on a Dynamic Platform: A Visual-Inertial Approach.

This work aimed to develop an autonomous system for unmanned aerial vehicles (UAVs) to land on moving platforms such as an automobile or a marine vessel, providing a promising solution for a long-endurance flight operation, a large mission coverage range, and a convenient recharging ground station. Unlike most state-of-the-art UAV landing frameworks that rely on UAV onboard computers and sensors, the proposed system fully depends on the computation unit situated on the ground vehicle/marine vessel to serve as a landing guidance system. Such a novel configuration can therefore lighten the burden of the UAV, and the computation power of the ground vehicle/marine vessel can be enhanced. In particular, we exploit a sensor fusion-based algorithm for the guidance system to perform UAV localization, whilst a control method based upon trajectory optimization is integrated. Indoor and outdoor experiments are conducted, and the results show that precise autonomous landing on a 43 cm × 43 cm platform can be performed.

Effects of Hypothermic Hypoxia/Reoxygenation Fibroblast Culture Medium Containing Sevoflurane on Cardiomyocytes.

We established a model of hypothermic hypoxia/reoxygenation injury of fibroblasts, simulated the process of ischemia/reperfusion injury during cardiopulmonary bypass, and studied the effects of cardiac fibroblasts on cardiomyocyte activity, connexin 43 (Cx43), and calmodulin kinase II (CaMKII) expression. Furthermore, the effects of sevoflurane-treated fibroblast culture medium on cardiac activity, Cx43 protein, and CaMKII expression were observed. The results showed that the fibroblast culture medium damaged by hypothermic hypoxia/reoxygenation could reduce the beating frequency of cardiomyocytes, increase the mortality of cardiomyocytes, decrease the relative expression of Cx43, and increase the relative expression of CaMKII. However, sevoflurane containing hypothermic hypoxia/reoxygenation injury fibroblast culture medium can increase the beating frequency of cardiomyocytes, reduce the mortality of cardiomyocytes, increase the relative expression of Cx43 protein, and decrease the relative expression of CaMKII. The results suggest that the antiarrhythmic effects of sevoflurane on the expression of Cx43 and CaMKII are related to fibroblasts.

Learning-Based Autonomous UAV System for Electrical and Mechanical (E&M) Device Inspection.

The inspection of electrical and mechanical (E&M) devices using unmanned aerial vehicles (UAVs) has become an increasingly popular choice in the last decade due to their flexibility and mobility. UAVs have the potential to reduce human involvement in visual inspection tasks, which could increase efficiency and reduce risks. This paper presents a UAV system for autonomously performing E&M device inspection. The proposed system relies on learning-based detection for perception, multi-sensor fusion for localization, and path planning for fully autonomous inspection. The perception method utilizes semantic and spatial information generated by a 2-D object detector. The information is then fused with depth measurements for object state estimation. No prior knowledge about the location and category of the target device is needed. The system design is validated by flight experiments using a quadrotor platform. The result shows that the proposed UAV system enables the inspection mission autonomously and ensures a stable and collision-free flight.

Prolonged duration of repolarization and decreased conduction velocity in the atrial myocardium after hypothermic ischemia-reperfusion may be related to expressions of inward rectifier potassium channel 2.1 protein and connexin 40.

OBJECTIVES: The study aimed to determine the role of inward rectifier potassium channel 2.1 protein and connexin 40 expressions in regulating the duration of repolarization and conduction velocity of right atrial myocardium in rats following hypothermic ischemia-reperfusion. METHODS: The Langendorff isolated rat cardiac perfusion models were divided into control (C) and hypothermic ischemia-reperfusion groups, with 8 models in group C and 16 models in group ischemia-reperfusion. Depending on the incidence of atrial arrhythmia after reperfusion, the models in group ischemia-reperfusion were further divided into reperfusion non-atrial arrhythmia or reperfusion atrial arrhythmia subgroup. Right atrial monophasic action potential duration at 50% and 90% of repolarization after 30 minutes of continuous perfusion in group C and group ischemia-reperfusion (T0), 105 minutes of continuous perfusion in group C or after 15 minutes of reperfusion in group ischemia-reperfusion (T1) and 120 minutes of continuous perfusion in group C or 30 minutes of reperfusion in group ischemia-reperfusion (T2) were recorded. Right atrial conduction velocity and effective refractory period were recorded at T2. Then, the expressions of inward rectifier potassium channel 2.1 protein and connexin 40 in the right atrial myocardium were detected. RESULTS: Monophasic action potential duration at 50% and 90% were higher at T1 and T2 than those at T0 in subgroup reperfusion atrial arrhythmia (p < 0.05); monophasic action potential duration at 50% in subgroup reperfusion atrial arrhythmia were larger than group C and subgroup reperfusion non-atrial arrhythmia at T1 and T2 (p < 0.05); monophasic action potential duration at 90% in subgroup reperfusion atrial arrhythmia were larger than group C and subgroup reperfusion non-atrial arrhythmia at T1 and T2 (p < 0.05); effective refractory period in subgroup reperfusion atrial arrhythmia was greater than that in group C and subgroup reperfusion non-atrial arrhythmia, and the conduction velocity and the expressions of inward rectifier potassium channel 2.1 protein and connexin 40 were significantly lower than group C and subgroup reperfusion non-atrial arrhythmia (p < 0.05). CONCLUSIONS: The prolonged duration of repolarization and a decrease in conduction velocity of the atrial myocardium occur in rats after hypothermic ischemia-reperfusion. These observed effects may be related to the downregulated expressions of connexin 40 and inward rectifier potassium channel 2.1.

Network construction of aberrantly expressed miRNAs and their target mRNAs in ventricular myocardium with ischemia-reperfusion arrhythmias.

BACKGROUND: Hypothermic ischemia-reperfusion arrhythmia remains the main factor affecting cardiac resuscitation under cardiopulmonary bypass. Existing research shows that certain miRNAs exhibit significantly different expressions and effects in arrhythmias, however, the effect of miRNAs on the progression of hypothermic ischemic-reperfusion arrhythmias (RA) and its potential mechanism remain to be further explored. METHODS: Sprague-Dawley (SD) rats were randomly divided into two groups (n = 8): a normal control group (Group C) and a hypothermic ischemia-reperfusion group (Group IR), which were used to establish a Langendorff isolated cardiac perfusion model. According to the arrhythmia scoring system, rats in group IR were divided into a high-risk group (IR-H) and a low-risk group (IR-L). miRNAs expression profiles of ventricular myocardium with global hypothermic ischemia-reperfusion and those of ventricular myocardium with hypothermic ischemia-RA were established through high-throughput sequencing. Furthermore, the aberrantly expressed miRNAs in myocardium with and without hypothermic ischemia-RA were screened and verified. The target genes of these aberrantly expressed miRNAs were predicted using RNAhybrid and MiRanda software. Based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, we determined the mRNA targets associated with these miRNAs and studied the miRNA-mRNA interaction during the cardiovascular disease progression. The aberrantly expressed miRNAs related to hypothermic ischemia-RA were validated by Real-time Quantitative polymerase chain reaction (RT-qPCR). RESULTS: Eight significantly aberrantly expressed miRNAs (rno-miR-122-5p, rno-miR-429, novel_miR-1, novel_miR-16, novel_miR-17, novel_miR-19, novel_miR-30, and novel_miR-43) were identified, among which six were up-regulated and two were down-regulated. Moreover, target genes and signaling pathways associated with these aberrantly expressed miRNAs were predicted and analyzed. The miRNA-mRNA interaction network graph showed that GJA1 gene was considered as the target of novel_miR-17. CONCLUSIONS: Aberrantly expressed miRNAs were possibly associated with the formation mechanism of hypothermic ischemia-RA. Specific miRNAs, such as novel_miR-17 and rno-miR-429 are probably new potential targets for further functional studies of hypothermic ischemia-RA.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.

BACKGROUND: Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. METHODS: The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. RESULTS: Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. INTERPRETATION: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). FUNDING: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.

INTRODUCTION: Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge. METHODS: Four multicenter trial groups in the world, who have performed prospective controlled studies of hepatoblastoma over the past two decades (COG; SIOPEL; GPOH; and JPLT), joined forces to form the CHIC consortium. With the support of the data management group CINECA, CHIC developed a centralized online platform where data from eight completed hepatoblastoma trials were merged to form a database of 1605 hepatoblastoma cases treated between 1988 and 2008. The resulting dataset is described and the relationships between selected patient and tumor characteristics, and risk for adverse disease outcome (event-free survival; EFS) are examined. RESULTS: Significantly increased risk for EFS-event was noted for advanced PRETEXT group, macrovascular venous or portal involvement, contiguous extrahepatic disease, primary tumor multifocality and tumor rupture at enrollment. Higher age (≥ 8 years), low AFP (<100 ng/ml) and metastatic disease were associated with the worst outcome. CONCLUSION: We have identified novel prognostic factors for hepatoblastoma, as well as confirmed established factors, that will be used to develop a future common global risk stratification system. The mechanics of developing the globally accessible web-based portal, building and refining the database, and performing this first statistical analysis has laid the foundation for future collaborative efforts. This is an important step for refining of the risk based grouping and approach to future treatment stratification, thus we think our collaboration offers a template for others to follow in the study of rare tumors and diseases.

Administration of cathepsin B inhibitor CA-074Me reduces inflammation and apoptosis in polymyositis.

BACKGROUND: Polymyositis (PM) cause pain and weakness of muscle, even threatens patient's lives, but the etiology and pathogenesis of it remains partially understood. Previous studies have proved Cathepsin B (CB) was strongly stained in muscle tissues of PM patients. But no further studies were performed to investigate the role of CB in PM. OBJECTIVE: To investigate the protective effects of CB inhibitor CA-074Me in PM. METHODS: CB expression, inflammation and apoptosis were analyzed in muscle tissues from patients with PM. Guinea pigs were inoculated intraperitoneally with Coxsackie virus B1 (CVB1) and were then immunized with completely emulsified 0.6ml rabbit muscle homogenates in Freund's Complete Adjuvant (FCA) once a week for consecutive three weeks. The effects of CB inhibitor CA-074Me on CB expression, inflammation and apoptosis were then investigated. Inflammation was assessed by histological examination. Both immunohistochemistry and western blot were used to determine the protein expression. The mRNA levels of CB were measured by Real-Time RT-PCR. The apoptosis was determined by TUNEL assay. RESULTS: In patients with PM, the protein levels of CB were significantly up-regulated in muscle tissues compared with healthy controls, which correlated with increases in inflammation score and apoptotic rate in PM patients. Consistently, the expression of CB, inflammation score, CD8(+) T-cell, CD68(+) cell, tumor necrosis factor-alpha (TNF-α) infiltration and apoptotic rate were significantly increased in the guinea-pig model of CVB1-induced polymyositis. Administration of CA-074Me reduced CB expression, decreased inflammation score and attenuated apoptosis in muscle tissues of the guinea-pig model of CVB1-induced polymyositis. The inhibitory effect of CA-074Me on apoptosis was associated with down-regulation of Bax expression and consequent increase in the ratio of Bcl-2/Bax. However, CA-074Me had effect not on CD8(+) T-cells infiltrations but on CD68(+) cells and TNF-α(+) cells infiltrations in the guinea-pig model of CVB1-induced polymyositis. CONCLUSION: This study confirms up-regulation of CB in PM patients and demonstrates that inhibition of CB provides protective effects in a guinea pig model of CVB1-induced PM. Thus, CB will be an important therapeutic target for PM.