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Background: The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). Objective: The aim of this study was to investigate CB1 receptors in PD with [18F]FMPEP‐d2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18F]FMPEP‐d2 binding. Methods: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18F]FMPEP‐d2 high‐resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [18F]FMPEP‐d2 binding, 15 subjects with PD underwent [18F]FMPEP‐d2 PET twice, both on and off antiparkinsonian medication. Results: [18F]FMPEP‐d2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region. Conclusions: Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Present-day Software Engineering working environment is highly international. Teams are commonly formed of people from different nationalities and cultural backgrounds. The team’s productivity and efficiency depend significantly on its members’ international communication and collaboration competences. Therefore, understanding the required competences is essential. The software organizations hiring new software engineers need to be able to define and describe the competences, and the junior software engineers applying for their first jobs should know what competences they need to possess and demonstrate. In this study, to increase understanding of necessary communication and collaboration competences in the international Software Engineering working environment, competences were, first, analyzed from the job advertisements applicable to junior software engineers and, second, identified by a literature review. The results were compared to identify what competences junior software engineers should learn and demonstrate, to be competent in the international software engineer job markets. The job advertisement findings show that the international operational environment expects extensive competence in collaboration, high competence in English, and considerable competence in local language and communication. Intercultural competence and other languages are hardly expected. The literature review emphasizes inter-related communication, collaboration, intercultural, and language competences at various levels. Eventually, junior software engineers should demonstrate a tolerant and adaptable attitude, cooperativeness, independence, openness, courage to influence, oral and written social interaction skills, fluent professional English and local language communication skills as well as field-specific and general collaboration methods. The findings benefit juniors and Software Engineering education through which also employers obtain more competent jobseekers.

Background Unhealthy behaviours increase cancer risk. However, lifestyle habits co-occur and their joint association with cancer is not known. Methods A survey among midlife employees included data on lifestyle habits and covariates (N = 8960, response rate 67%, 80% women). The joint variables of lifestyle habits were prospectively linked with register data on cancer diagnosis (mean follow-up time 12.1 years). Cox proportional hazard model was used to calculate hazard ratios (HR), and their 95% confidence intervals. Results Smoking was associated with subsequent cancer risk and the association was strengthened by inactivity (HR 1.94, 1.46–2.59) and unhealthy diet (HR 1.92, 1.43–2.57). Smoking combined with both low (HR 1.70, 1.19–2.41) and moderate (HR 1.68, 1.27–2.23) alcohol consumption was also associated with increased cancer risk, as was unhealthy diet combined with moderate alcohol consumption (HR 1.55, 1.17–2.06) and inactivity (HR 1.44, 1.10–1.88). Inactivity combined with either low (HR 1.44, 1.06–1.96) or moderate (HR 1.47, 1.11–1.95) alcohol use was associated with subsequent cancer risk. Conclusions Key unhealthy behaviours have additive effects. Preventive measures should be targeted to especially smokers and those having several adverse lifestyle habits. [ABSTRACT FROM AUTHOR]

This paper investigates the global convergence problem of SLAM algorithms, a problem that has been subject to topological obstacles. This is due to the fact that state-space of attitude kinematics, $SO(3)$ , is a non-contractible manifold. Hence, $SO(3)$ is not diffeomorphic to Euclidean space. Therefore, existing SLAM algorithms can only guarantee almost global convergence. In order to overcome topological obstructions, this paper introduces a gradient-based hybrid observer that ensures global asymptotic convergence of estimation errors to zero. Moreover, integral action is augmented into the proposed observer to estimate unknown constant bias. Accordingly, a projection scheme is designed to cope with the integral action. Lyapunov stability theorem is used to prove the global asymptotic convergence of the proposed algorithm. Experimental and simulation results are provided to evaluate the performance and demonstrate the effectiveness and robustness of the proposed observer.

When a mobile manipulator’s wheel loses contact with the ground, the manipulator may overturn, causing material damage, and in the worst case, putting human lives in danger. The overturning stability of wheeled mobile manipulators must not be overlooked at any stage of the mobile manipulator’s life, starting from the design phase, continuing through the commissioning period and extending to the operational phase. The various overturning stability criteria formulated throughout the years do not explicitly consider normal wheel loads, with most of them relying on the prescribed stability margins in terms of overturning moments. These formulations commonly consider the overturning moments regarding axes connecting the adjacent manipulator’s contact points with the ground and could be notably restrictive. Explicit expressions for the supporting forces of the manipulator provide the best insights into the relevant affecting terms that contribute to the overturning (in)stability. They also reduce the necessity for considering about which axis the manipulator could overturn and simultaneously enable the formulation of more intuitive stability margins and on- line overturning prevention techniques. The present study presents a general dynamics modelling approach in the Newton–Euler framework using 6D vectors and provides normal wheel load equations for a typical 4-wheeled rigid-chassis mobile manipulator traversing uneven terrain. The given expressions are expected to become the standard guidelines in considered wheeled mobile manipulators and to provide a basis for effective overturning stability criteria and overturning avoidance techniques. Based on the presented results, specific improvements of the state-of-the-art criteria are discussed.

Abstract The hydraulic exoskeleton is one research hotspot in the field of robotics, which can take heavy load due to the high power density of the hydraulic system. However, the traditional hydraulic system is normally centralized, inefficient, and bulky during application, which limits its development in the exoskeleton. For improving the robot’s performance, its hydraulic actuating system should be optimized further. In this paper a novel hydraulic actuating system (HAS) based on electric-hydrostatic actuator is proposed, which is applied to hip and knee joints. Each HAS integrates an electric servo motor, a high-speed micro pump, a specific tank, and other components into a module. The specific parameters are obtained through relevant simulation according to human motion data and load requirements. The dynamic models of the HAS are built, and validated by the system identification. Experiments of trajectory tracking and human-exoskeleton interaction are carried out, which demonstrate the proposed HAS has the ability to be applied to the exoskeleton. Compared with the previous prototype, the total weight of the HAS in the robot is reduced by about 40%, and the power density is increased by almost 1.6 times.

The bulldozer is a mobile earthmoving machine with a differentially steered mobile base and an onboard manipulator used for soil cutting and transportation. Grading the ground to match a desired contour is an end-effector path-following task, with required joint rates dependent on mobile base motion. The offline planning of travel velocity profiles that respect the available hydraulic flowrate limits is difficult due to uncertainties in the machine–soil interactions. Hence, we propose a flow-bounded velocity controller enabling accurate automatic grading with online velocity scaling. The capacity of hydrostatic transmission and manipulator actuators, as well as the desired velocity, are considered when deciding the commanded velocity reference for the mobile base. Our dynamic simulation results show that, with the proposed controller, a desired ground profile is cut accurately when the machine operates at its performance limits. Comparison to constant velocity driving shows that errors in blade positioning are reduced dramatically. Constant velocity selected to keep the flow within limits results in longer completion times compared to our solution, making it more time optimal. Furthermore, the rpm of the diesel engine can be reduced to save fuel without compromising control performance.

Series elastic actuators (SEAs) have become a common actuation method in torque-controlled electric lightweight arm applications that physically interact with the environment in assembly tasks. Compared to traditional actuators, SEAs can provide high force fidelity, shock tolerance, and force sensing for interaction control. Considering inherent system dynamics and the variable stiffness of the fluid, the control design for hydraulic SEAs (HSEAs) that lead into fifth-order system is a challenging task. As a novelty, a full state feedback controller design for the developed fifth-order HSEA system is presented to serve as an inner-loop controller to handle highly nonlinear dynamics behavior. In addition, as an outer-loop impedance controller for HSEAs in heavy-duty applications, the position-based impedance controller is designed to handle control of the HSEA system during the contact motion. Experimental results with a one-degree-of-freedom real-size experimental setup with a payload of 200 kilos demonstrates the effectiveness of the proposed HSEA control methods both in the free-space motion and in a contact impedance motion.

This paper presents a nonlinear, universal, path-following controller for Wheeled Mobile Robots (WMRs). This approach, unlike previous algorithms, solves the path-following problem for all common categories of holonomic and nonholonomic WMRs, such as omnidirectional, unicycle, car-like, and all steerable wheels. This generality is the consequence of a two-stage solution that tackles separately the platform path-following and wheels’ kinematic constraints. In the first stage, for a mobile platform divested of the wheels’ constraints, we develop a general paradigm of a path-following controller that plans asymptotic paths from the WMR to the desired path and, accordingly, we derive a realization of the presented paradigm. The second stage accounts for the kinematic constraints imposed by the wheels. In this stage, we demonstrate that the designed controller simplifies the otherwise impenetrable wheels’ kinematic and nonholonomic constraints into explicit proportional functions between the velocity of the platform and that of the wheels. This result enables us to derive a closed-form trajectory generation scheme for the asymptotic path that constantly keeps the wheels’ steering and driving velocities within their corresponding, pre-specified bounds. Extensive experimental results on several types of WMRs, along with simulation results for the other types, are provided to demonstrate the performance and the efficacy of the method.

Surface extraction from noisy volumetric images is a problem commonly encountered in medical image analysis. Deformable surface models can, in principle, solve the problem in an automatic manner. However, it is often essential that a reasonably close initialization and good parameter values for deformable models are provided. In this paper, novel algorithms for global minimization of the energy of deformable meshes are presented. We demonstrate that global optimization by these algorithms reduces the sensitivity of the deformable mesh to its initialization and its parameter values. Consequently, it becomes easier to automate the initialization process and the selection of parameter values. As the second contribution, the internal energy function is derived in a novel way in the framework of deformable surface models. The construction of the internal energy in this way features a simple way to derive the variants of our global optimization algorithm. The experiments with synthetic images are performed to compare variants of the proposed optimization algorithm. Also, we present a practical application of our deformable model to automatic segmentation of positron emission tomography images. [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). Objective: The aim of this study was to investigate CB1 receptors in PD with [18F]FMPEP‐d2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18F]FMPEP‐d2 binding. Methods: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18F]FMPEP‐d2 high‐resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [18F]FMPEP‐d2 binding, 15 subjects with PD underwent [18F]FMPEP‐d2 PET twice, both on and off antiparkinsonian medication. Results: [18F]FMPEP‐d2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region. Conclusions: Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

This paper describes one of the challenging issues implied by scientific infrastructures on a mobile robot cognition architecture. For a generally applicable cognition architecture, we study the dependencies and logical relations between several tasks and subsystems. The overall view of the software modules is described, including their relationship with a fault management module that monitors the consistency of the data flow among the modules. The fault management module is the solution of the deliberative architecture for the single point failures, and the safety anchor is the reactive solution for the faults by redundant equipment. In addition, a hardware architecture is proposed to ensure safe robot movement as a redundancy for the cognition of the robot. The method is designed for a four-wheel steerable (4WS) mobile manipulator (iMoro) as a case study.

This paper addresses the energy-inefficiency problem of four-degrees-of-freedom (4-DOF) hydraulic manipulators through redundancy resolution in robotic closed-loop controlled applications. Because conventional methods typically are local and have poor performance for resolving redundancy with respect to minimum hydraulic energy consumption, global energy-optimal redundancy resolution is proposed at the valve-controlled actuator and hydraulic power system interaction level. The energy consumption of the widely popular valve-controlled load-sensing (LS) and constant-pressure (CP) systems is effectively minimised through cost functions formulated in a discrete-time dynamic programming (DP) approach with minimum state representation. A prescribed end-effector path and important actuator constraints at the position, velocity and acceleration levels are also satisfied in the solution. Extensive field experiments performed on a forestry hydraulic manipulator demonstrate the performance of the proposed solution. Approximately 15–30% greater hydraulic energy consumption was observed with the conventional methods in the LS and CP systems. These results encourage energy-optimal redundancy resolution in future robotic applications of hydraulic manipulators.

Mobile manipulators are one of the most complicated types of mechatronics systems. The performance of these robots in performing complex manipulation tasks is highly correlated with the synchronization and integration of their low-level components. This paper discusses in detail the mechatronics design of a four wheel steered mobile manipulator. It presents the manipulator's mechanical structure and electrical interfaces, designs low-level software architecture based on embedded PC-based controls, and proposes a systematic solution based on code generation products of MATLAB and Simulink. The remote development environment described here is used to develop real-time controller software and modules for the mobile manipulator under a POSIX-compliant, real-time Linux operating system. Our approach enables developers to reliably design controller modules that meet the hard real-time constraints of the entire low-level system architecture. Moreover, it provides a systematic framework for the development and integration of hardware devices with various communication mediums and protocols, which facilitates the development and integration process of the software controller.

The Super-FRS, Superconducting Fragment Separator, is a unique machine that presents several challenging technical problems. One of these is regarding how to conduct maintenance in the target area where high levels of radiation will be generated and human access is forbidden. To address this problem the use of a remote maintenance system is foreseen. The objective of this paper is to develop a systems engineering (SE) research and development (R&D) approach suitable to develop the Super-FRS Target Area Remote Maintenance Systems (TARMS) and the RH design adaptation of the components in the target area. The Super-FRS target area is described in detail in order to introduce the need for a remote maintenance system. Components in the target area are classified by adopting ITER RH maintenance classification. The general scenario of remote handling and the current target area remote maintenance system are described. Finally, the proposed systems engineering approach is presented.

Remote Handling (RH) systems are now frequently used to conduct inspections and maintenance in hazardous environments. New particle accelerator facilities present unique logistic challenges due to high radiation levels, a hazardous environment and heavy loads. The Facility for Antiproton and Ion Research (FAIR) will deliver a beam of all ions up to uranium with intensities up to 10 12 238 U ions/s, which will cause high levels of radiation during operation so human access is limited. This paper contains a survey on RH logistics for existing High Intensity Beam (HIB) facilities to determine state of the art RH practices and to draw a conclusion based on the analysis. The second part of this paper presents a detailed study of beam losses, the radiation environment, RH logistic challenges and some proposed solutions for Super-FRS. This paper will also suggest a Systems Engineering (SE) approach for developing Super-FRS RH logistics.

Maintenance in scientific facilities is a difficult issue, especially in large and hazardous facilities, due to the complexity of tasks and equipment. Augmented reality is a technology that has already shown great promise in the maintenance field. With the help of augmented reality applications, maintenance tasks can be carried out faster and more safely. The problem with current applications is that they are small-scale prototypes that do not easily scale to large facility maintenance applications. This paper presents a new hybrid approach that enables the creation of augmented reality maintenance applications for large and hazardous scientific facilities. In this paper, a new augmented reality marker and the algorithm for its recognition is proposed. The performance of the algorithm is verified in three test cases, showing promising results in two of them. Improvements in robustness in the third test case in which the camera is moving quickly or when light conditions are extreme are subject to further studies. The proposed new approach will be integrated into an existing augmented reality maintenance system.

We show that electric-dipole-allowed surface second-harmonic (SH) generation with focused Gaussian beams can be described in terms of Mie-type multipolar contributions to the SH signal. In contrast to the traditional case, where Mie multipoles arise from field retardation across nanoparticles, the multipoles here arise from the confined source volume and the tensorial properties of the SH response. We demonstrate this by measuring strongly asymmetric SH emission into reflected and transmitted directions from a nonlinear thin film with isotropic surface symmetry, where symmetric emission is expected using traditional formalisms based on plane-wave excitation. The proposed multipole approach provides a convenient way to explain the measured asymmetric emission. Our results suggest that the separation of surface and bulk responses, which have dipolar and higher-multipolar character, respectively, may be even more difficult than thought. On the other hand, the multipolar approach may allow tailoring of focal conditions in order to design confined and thin nonlinear sources with desired radiation patterns.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) recapitulate numerous disease and drug response phenotypes, but cell immaturity may limit their accuracy and fidelity as a model system. Cell culture medium modification is a common method for enhancing maturation, yet prior studies have used complex media with little understanding of individual component contribution, which may compromise long-term hiPSC-CM viability. Here, we developed high-throughput methods to measure hiPSC-CM maturation, determined factors that enhanced viability, and then systematically assessed the contribution of individual maturation medium components. We developed a medium that is compatible with extended culture. We discovered that hiPSC-CM maturation can be sub-specified into electrophysiological/EC coupling, metabolism, and gene expression and that induction of these attributes is largely independent. In this work, we establish a defined baseline for future studies of cardiomyocyte maturation. Furthermore, we provide a selection of medium formulae, optimized for distinct applications and priorities, that promote measurable attributes of maturation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies and candidate gene association studies have identified more than 180 genetic variants statistically associated with anthracycline-induced cardiotoxicity (AIC). However, the lack of functional validation has hindered the clinical translation of these findings., Objectives: The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)., Methods: Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC ( GSTM1 , CBR1 , and ERBB2 ) were included. Of these, 38 genes exhibited expression in human fetal heart, adult heart, and hiPSC-CMs. Using clustered regularly interspaced short palindromic repeats/Cas9-based genome editing, each of these 38 genes was systematically knocked out in control hiPSC-CMs, and the resulting doxorubicin-induced cardiotoxicity (DIC) phenotype was assessed using hiPSC-CMs. Subsequently, functional assays were conducted for each gene knockout on the basis of hypothesized mechanistic implications in DIC., Results: Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters ( ABCC10 , ABCC2 , ABCB4 , ABCC5 , and ABCC9 ), well-established DIC-associated genes ( CBR1 , CBR3 , and RAC2 ), and genome-wide association study-discovered genes ( RARG and CELF4 ). Conversely, knockout of ATP2B1 , HNMT , POR , CYBA , WDR4 , and COL1A2 had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters ( SLC28A3 , SLC22A17 , and SLC28A1 ) demonstrated a protective effect against DIC., Conclusions: The present findings establish a comprehensive platform for the functional validation of DIC-associated genes, providing insights for future studies in DIC variant associations and potential mechanistic targets for the development of cardioprotective drugs., Competing Interests: This work was supported by National Institutes of Health grants R01 CA220002 and R01 CA261898, American Heart Association Transformational Project Award 18TPA34230105, and the Leducq Foundation (to Dr Burridge). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2 , which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome., Methods: A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively., Results: Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential., Conclusions: Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction., Competing Interests: Disclosures None.

The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has shown promise in preclinical models of myocardial infarction, but graft myocardium exhibits incomplete host-graft electromechanical integration and a propensity for pro-arrhythmic behavior. Perhaps contributing to this situation, hPSC-CM grafts show low expression of connexin 43 (Cx43), the major gap junction (GJ) protein, in ventricular myocardia. We hypothesized that Cx43 expression and function could be rescued by engineering Cx43 in hPSC-CMs with a series of phosphatase-resistant mutations at three casein kinase 1 phosphorylation sites (Cx43-S3E) that have been previously reported to stabilize Cx43 GJs and reduce arrhythmias in transgenic mice. However, contrary to our predictions, transgenic Cx43-S3E hPSC-CMs exhibited reduced Cx43 expression relative to wild-type cells, both at baseline and following ischemic challenge. Cx43-S3E hPSC-CMs showed correspondingly slower conduction velocities, increased automaticity, and differential expression of other connexin isoforms and various genes involved in cardiac excitation-contraction coupling. Cx43-S3E hPSC-CMs also had phosphorylation marks associated with Cx43 GJ internalization, a finding that may account for their impaired GJ localization. Taken collectively, our data indicate that the Cx43-S3E mutation behaves differently in hPSC-CMs than in adult mouse ventricular myocytes and that multiple biological factors likely need to be addressed synchronously to ensure proper Cx43 expression, localization, and function.

Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A ( LDHA ) and cluster of differentiation 36 ( CD36 ) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 ( IL1R1 , IL1R2 ), and matrix metalloproteinase 8, 9 ( MMP8, MMP9 ) appeared in multiple canonical pathways. LDHA -knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy., (© 2023. Springer Nature Limited.)

Background: The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD)., Objective: The aim of this study was to investigate CB1 receptors in PD with [ 18 F]FMPEP-d 2 positron emission tomography (PET) and the effect of dopaminergic medication on the [ 18 F]FMPEP-d 2 binding., Methods: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [ 18 F]FMPEP-d 2 high-resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [ 18 F]FMPEP-d 2 binding, 15 subjects with PD underwent [ 18 F]FMPEP-d 2 PET twice, both on and off antiparkinsonian medication., Results: [ 18 F]FMPEP-d 2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region., Conclusions: Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)