New N-acylated aminoalkanoic acids from tea roots derived biocontrol agent Clonostachys rosea 15020.

Four new N-acylated aminoalkanoic acids, namely clonoroseins E-H (1-4), together with three previously identified analogs, clonoroseins A, B, and D (5-7), were identified from the endophytic fungus Clonostachys rosea strain 15020 (CR15020), using Feature-based Molecular Networking (FBMN). The elucidation of their chemical structures, including their absolute configurations, was achieved through spectroscopic analysis combined with quantum chemical calculations. Bioinformatics analyses suggested that an iterative type I HR-PKS (CrsE) generates the polyketide side chain of these clonoroseins. Furthermore, a downstream adenylate-forming enzyme of the PKS (CrsD) was suspected to function as an amide synthetase. CrsD potentially facilitates the transformation of the polyketide moiety into an acyl-AMP intermediate, followed by nucleophilic substitution with either ß-alanine or γ-aminobutyric acid to produce amide derivatives. These findings significantly expand our understanding of PKS-related products originating from C. rosea and also underscore the powerful application of FBMN analytical methods in characterization of new compounds.

Global trends and prospects in health economics of robotic surgery: a bibliometric analysis.

BACKGROUND: Over 10 million robotic surgeries have been performed. However, the cost and benefit of robotic surgery need to be evaluated to help hospitals, surgeons, patients, and payers make proper choices, making a health economic analysis necessary. The authors revealed the bibliometric profile in the field of health economics of robotic surgery to prompt research development and guide future studies. MATERIALS AND METHODS: The Web of Science Core Collection scientific database was searched for documents indexed from 2003 to 31 December 2022. Document types, years, authors, countries, institutions, journal sources, references, and keywords were analyzed and visualized using the Bibliometrix package, WPS Office software, Microsoft PowerPoint 2019, VOSviewer software (version 1.6.18), ggplot2, and Scimago Graphica. RESULTS: The development of the health economics of robotic surgery can be divided into three phases: slow-growing (2003-2009), developing (2010-2018), and fast-developing (2019-2022). J.C.H. and S.L.C. were the most active and influential authors, respectively. The USA produced the most documents, followed by China, and Italy. Korea had the highest number of citations per document. Surgical Endoscopy and Other Interventional Techniques accepted most documents, whereas Annals of Surgery, European Urology, and Journal of Minimally Invasive Gynecology had the highest number of citations per document. The Journal of Robotic Surgery is promising. The most-cited document in this field is New Technology and Health Care Costs - The Case of Robot-Assisted Surgery in 2010. The proportion of documents on urology is decreasing, while documents in the field of arthrology are emerging and flourishing. CONCLUSION: Research on the health economics of robotic surgery has been unbalanced. Areas awaiting exploration have been identified. Collaboration between scholars and coverage with provisions for evidence development by the government is needed to learn more comprehensively about the health economics of robotic surgery.

Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology.

Transparent microelectrode arrays (MEAs) that allow multimodal investigation of the spatiotemporal cardiac characteristics are important in studying and treating heart disease. Existing implantable devices, however, are designed to support chronic operational lifetimes and require surgical extraction when they malfunction or are no longer needed. Meanwhile, bioresorbable systems that can self-eliminate after performing temporary functions are increasingly attractive because they avoid the costs/risks of surgical extraction. We report the design, fabrication, characterization, and validation of a soft, fully bioresorbable, and transparent MEA platform for bidirectional cardiac interfacing over a clinically relevant period. The MEA provides multiparametric electrical/optical mapping of cardiac dynamics and on-demand site-specific pacing to investigate and treat cardiac dysfunctions in rat and human heart models. The bioresorption dynamics and biocompatibility are investigated. The device designs serve as the basis for bioresorbable cardiac technologies for potential postsurgical monitoring and treating temporary patient pathological conditions in certain clinical scenarios, such as myocardial infarction, ischemia, and transcatheter aortic valve replacement.

Graphene Biointerface for Cardiac Arrhythmia Diagnosis and Treatment.

Heart rhythm disorders, known as arrhythmias, cause significant morbidity and are one of the leading causes of mortality. Cardiac arrhythmias are frequently treated by implantable devices, such as pacemakers and defibrillators, or by ablation therapy guided by electroanatomical mapping. Both implantable and ablation therapies require sophisticated biointerfaces for electrophysiological measurements of electrograms and delivery of therapeutic stimulation or ablation energy. In this work, a graphene biointerface for in vivo cardiac electrophysiology is reported for the first time. Leveraging sub-micrometer-thick tissue-conformable graphene arrays, sensing and stimulation of the open mammalian heart are demonstrated both in vitro and in vivo. Furthermore, the graphene biointerface treatment of atrioventricular block (the kind of arrhythmia where the electrical conduction from the atria to the ventricles is interrupted) is demonstrated. The graphene arrays show effective electrochemical properties, namely interface impedance down to 40 Ω cm2 at 1 kHz, charge storage capacity up to 63.7 mC cm-2 , and charge injection capacity up to 704 µC cm-2 . Transparency of the graphene structures allows for simultaneous optical mapping of cardiac action potentials, calcium transients, and optogenetic stimulation while performing electrical measurements and stimulation. The report presents evidence of the significant potential of graphene biointerfaces for advanced cardiac electrophysiology and arrhythmia therapy.

Melanoma molecular subtyping and scoring model construction based on ligand-receptor pairs.

Melanoma is a malignancy of melanocytes, responsible for a high percentage of skin cancer mortality. Ligand-Receptor pairs, a type of cellular communication, are essential for tumor genesis, growth, metastasis, and prognosis. Yet, the role of Ligand-Receptor pairs in melanoma has not been fully elucidated. Our research focused on the function of Ligand-Receptor pairs in melanoma prognosis. We screened 131 melanoma prognosis corresponded ligand-receptor pairs by analyzing the TCGA data of melanoma and the 2293 LR pairs retrieved from the connectomeDB2020 database. And further developed subtypes of melanoma according to the expression of these ligand-receptor pairs by Consensus Clustering. Then we using lasso cox regression and stepwise multivariate regression analysis established a ligand-receptor pairs-based scoring model for the evaluation of melanoma prognosis. Our study demonstrated that the ligand-receptor pairs are vital to the molecular heterogeneity of melanoma, and characterized three different melanoma ligand-receptor pairs subtypes. Among them, the C3 subtype showed a better prognosis, while the C1 subtype exhibited a low prognosis state. And our analysis then found out that this could be related to the differed activation and inhabitation of the cell cycle and immune-related pathways. Using lasso cox regression and stepwise multivariate regression analysis, we further identified 9 key ligand-receptor pairs and established a scoring model that effectively correlated with the prognosis, immune pathways, and therapy of melanoma, showing that the LR.score model was a trustworthy and independent biomarker for melanoma prognosis evaluation. In sum, we found that ligand-receptor pairs are significantly associated with the prognosis and therapy of melanoma. And our ligand-receptor-based scoring model showed potential for the evaluation of melanoma prognosis and immune therapy outcome prediction, which is crucial to the survival for the patients.

Simultaneous triple-parametric optical mapping of transmembrane potential, intracellular calcium and NADH for cardiac physiology assessment.

Investigation of the complex relationships and dependencies of multiple cellular processes that govern cardiac physiology and pathophysiology requires simultaneous dynamic assessment of multiple parameters. In this study, we introduce triple-parametric optical mapping to simultaneously image metabolism, electrical excitation, and calcium signaling from the same field of view and demonstrate its application in the field of drug testing and cardiovascular research. We applied this metabolism-excitation-contraction coupling (MECC) methodology to test the effects of blebbistatin, 4-aminopyridine and verapamil on cardiac physiology. While blebbistatin and 4-aminopyridine alter multiple aspects of cardiac function suggesting off-target effects, the effects of verapamil were on-target and it altered only one of ten tested parameters. Triple-parametric optical mapping was also applied during ischemia and reperfusion; and we identified that metabolic changes precede the effects of ischemia on cardiac electrophysiology.

Open-source low-cost cardiac optical mapping system.

Fluorescent imaging with voltage- or calcium-sensitive dyes, known as optical mapping, is one of the indispensable modern techniques to study cardiac or neural electrophysiology, unsurpassed by temporal and spatial resolution. High-speed CMOS cameras capable of optical registration of action potential propagation are in general very costly. We present a complete solution priced below US$1,000 (including camera and lens) at the moment of publication with an open-source image acquisition and processing software. We demonstrate that the iDS UI-3130CP rev.2 camera we used in this study is capable of 200x200 977 frames per second (FPS) action potential recordings from rodent hearts, with the signal-to-noise-ratio of a conditioned signal of 16 ± 10. A comparison with a specialized MiCAM Ultimate-L camera has shown that signal-to-noise ratio (SNR) while lower is sufficient for accurate measurements of AP waveform, conduction velocity (± 0.04 m/s) and action potential duration (± 7ms) in mouse and rat hearts. We used 4-aminopyridine to prolong the action potential duration in mouse heart, thus demonstrating that the proposed system is adequate for pharmacological studies.

Acetylcholine Reduces IKr and Prolongs Action Potentials in Human Ventricular Cardiomyocytes.

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) on repolarization in human ventricular cardiomyocytes, as well as the effect of ACh on the rapid component of the delayed rectifier K+ current (IKr). Here, we investigated the effect of ACh on the action potential parameters in human ventricular preparations and on IKr in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Using standard microelectrode technique, we demonstrated that ACh (5 µM) significantly increased the action potential duration in human left ventricular myocardial slices. ACh (5 µM) also prolonged repolarization in a human Purkinje fiber and a papillary muscle. Optical mapping revealed that ACh increased the action potential duration in human left ventricular myocardial slices and that the effect was dose-dependent. Perforated patch clamp experiments demonstrated action potential prolongation and a significant decrease in IKr by ACh (5 µM) in hiPSC-CMs. Computer simulations of the electrical activity of a human ventricular cardiomyocyte showed an increase in action potential duration upon implementation of the experimentally observed ACh-induced changes in the fully activated conductance and steady-state activation of IKr. Our findings support the hypothesis that ACh can influence the repolarization in human ventricular cardiomyocytes by at least changes in IKr.

Multiparametric slice culture platform for the investigation of human cardiac tissue physiology.

Human cardiac slices have emerged as a promising model of the human heart for scientific research and drug testing. Retaining the normal tissue architecture, a multi-cell type environment, and the native extracellular matrix, human cardiac slices faithfully replicate organ-level adult cardiac physiology. Previously, we demonstrated that human cardiac tissue slices cultured for 24 h maintained normal electrophysiology. In this project, we further optimized the organotypic culture condition to maintain normal electrophysiology of the human cardiac slices for 4 days. The prolonged culture of human cardiac tissue slices demonstrated here enables the study of chronic drug effects, gene therapies, and gene editing. To achieve greater control of the culture environment, we have also developed an automated, self-contained heart-on-a-chip system. The culture system supports media circulation, oxygenation, temperature control, electrical stimulation, and static mechanical loading. The culture parameters can be individually adjusted to establish the optimal culture condition to achieve long-term culture and to minimize tissue dedifferentiation. The development of the heart-on-a-chip technology presented here further encourages the use of organotypic human cardiac slices as a platform for pre-clinical drug testing and research in human cardiac physiology.