We consider Device-to-Device (D2D)-enabled mobile edge computing offloading scenario, where a device can partially offload its computation task to the edge server or exploit the computation resources ...of proximal devices. Keeping in view the millisecond-scale latency requirement in 5G service scenarios and the spectrum scarcity, we focus on minimizing the sum of task execution latency of all the devices in a shared spectrum with interference. In particular, we provide an integrated framework for partial offloading and interference management using orthogonal frequency-division multiple access (OFDMA) scheme. Accordingly, we formulate total latency minimization as a mixed integer nonlinear programming (MINLP) problem by considering desired energy consumption, partial offloading, and resource allocation constraints. We use decomposition approach to solve our problem and propose a novel scheme named Joint Partial Offloading and Resource Allocation (JPORA). With aim to reduce the task execution latency, JPORA iteratively adjusts data segmentation and solves the underlying problem of quality of service (QoS)-aware communication resource allocation to the cellular links, and interference-aware communication resource allocation to D2D links. Extensive evaluation results demonstrate that JPORA achieves the lowest latency as compared to the other baseline schemes, meanwhile limiting the local energy consumption of user devices.
Mobile edge computing (MEC) has emerged as a new paradigm to assist low latency services by enabling computation offloading at the network edge. Nevertheless, human mobility can significantly impact ...the offloading decision and performance in MEC networks. In this context, we propose device-to-device (D2D) cooperation based MEC to expedite the task execution of mobile user by leveraging proximity-aware task offloading. However, user mobility in such distributed architecture results in dynamic offloading decision that instigates mobility-aware task scheduling in our proposed framework. We jointly formulate task assignment and power allocation to minimize the total task execution latency by taking account of user mobility, distributed resources, tasks properties, and energy constraint of the user device. We first propose Genetic Algorithm (GA)-based evolutionary scheme to solve our formulated mixed-integer non-linear programming (MINLP) problem. Then we propose a heuristic named mobility-aware task scheduling (MATS) to obtain effective task assignment with low complexity. The extensive evaluation under realistic human mobility trajectories provides useful insights into the performance of our schemes and demonstrates that, both GA and MATS achieve better latency than other baseline schemes while satisfying the energy constraint of mobile device.
Abstract
Aims
Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated ...markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection.
Methods and results
Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir.
Conclusion
This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.
Graphical Abstract
Background and Purpose
Phosphodiesterases (PDEs) are important regulators of β‐adrenoceptor signalling in the heart. While PDE4 is the most important isoform that regulates ICa,L and force in rodent ...cardiomyocytes, the dominant isoform in adult human cardiomyocytes is PDE3.
Experimental Approach
Given the potential of human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) for biomedical research, this study characterized the contribution of PDE3 and PDE4 isoforms to the regulation of ICa,L and force in hiPSC‐CMs in an engineered heart tissue (EHT) model.
Key Results
There was a lower abundance of mRNA for PDE3A and 4A in hiPSC‐CM EHT than in non‐failing human heart samples. Selective inhibition of PDE3 and 4 with cilostamide and rolipram, respectively, showed that, in hiPSC‐CM, PDE4 was the predominant isoform for the regulation of ICa,L (cilostamide: +1.44‐fold; rolipram: +1.77‐fold). Furthermore, in contrast to cilostamide, rolipram decreased the EC50 of isoprenaline about 15‐fold.
Conclusion and implications
The predominance of PDE4 over PDE3 is a peculiarity of hiPSC‐CMs and is probably an indicator of immaturity. This finding has implications for the use of hiPSC‐CM as pharmacological models to investigate and assess the effects of PDE inhibitors.
Force measurements in ex vivo and engineered heart tissues are well established. Analysis of calcium transients (CaT) is complementary to force, and the combined analysis is meaningful to the study ...of cardiomyocyte biology and disease. This article describes a model of human induced pluripotent stem cell cardiomyocyte-derived engineered heart tissues (hiPSC-CM EHTs) transduced with the calcium sensor GCaMP6f followed by sequential analysis of force and CaT. Average peak analysis demonstrated the temporal sequence of the CaT preceding the contraction twitch. The pharmacological relevance of the test system was demonstrated with inotropic indicator compounds. Force-frequency relationship was analyzed in the presence of ivabradine (300 nM), which reduced spontaneous frequency and unmasked a positive correlation of force and CaT at physiological human heart beating frequency with stimulation frequency between 0.75 and 2.5 Hz (force +96%; CaT +102%). This work demonstrates the usefulness of combined force/CaT analysis and demonstrates a positive force-frequency relationship in hiPSC-CM EHTs.
•Analysis of calcium transients and force in engineered heart tissues•Accurate replications of drug effects on calcium transients and force analysis•Positive force- and calcium transients-frequency relationship•Reverse correlation between omecamtiv mecarbil's inotropic effect and frequency
In this article, Hansen and colleagues establish a system using human induced pluripotent stem cell-derived cardiomyocytes to sequentially analyze force and calcium transients (CaTs) in an engineered heart tissue model by using genetically encoded calcium indicator (GCaMP6f) and demonstrate a positive force- and CaT-frequency relationship at physiological human heart beat frequencies.
Abstract
Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived ...cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these “secondary” parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.
Driven by the soaring traffic demand and the growing diversity of mobile services, wireless networks are evolving to be increasingly dense and heterogeneous. Accordingly, in such large-scale and ...complicated wireless networks, optimal controlling is reaching unprecedented levels of complexity while its traditional solutions of handcrafted offline algorithms become inefficient due to high complexity, low robustness, and high overhead. Therefore, reinforcement learning (RL), which enables network entities to learn from their actions and consequences in the interactive network environment, attracts significant attention. In this article, we comprehensively review the applications of RL in wireless networks from a layering perspective. First, we present an overview of the principle, fundamentals, and several advanced models of RL. Then, we review the up-to-date applications of RL in various functionality blocks of different network layers, ranging from the low-level physical layer to the high-level application layer. Finally, we outline a broad spectrum of challenges, open issues, and future research directions of RL-empowered wireless networks.
We review harvested energy prediction schemes to be used in wireless sensor networks and explore the relative merits of landmark solutions. We propose enhancements to the well-known Profile-Energy ...(Pro-Energy) model, the so-called Improved Profile-Energy (IPro-Energy), and compare its performance with Accurate Solar Irradiance Prediction Model (ASIM), Pro-Energy, and Weather Conditioned Moving Average (WCMA). The performance metrics considered are the prediction accuracy and the execution time which measure the implementation complexity. In addition, the effectiveness of the considered models, when integrated in an energy management scheme, is also investigated in terms of the achieved throughput and the energy consumption. Both solar irradiance and wind power datasets are used for the evaluation study. Our results indicate that the proposed IPro-Energy scheme outperforms the other candidate models in terms of the prediction accuracy achieved by up to 78% for short term predictions and 50% for medium term prediction horizons. For long term predictions, its prediction accuracy is comparable to the Pro-Energy model but outperforms the other models by up to 64%. In addition, the IPro scheme is able to achieve the highest throughput when integrated in the developed energy management scheme. Finally, the ASIM scheme reports the smallest implementation complexity.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are commercially available, and cardiac differentiation established routine. Systematic evaluation of several control hiPSC-CM is ...lacking. We investigated 10 different control hiPSC-CM lines and analyzed function and suitability for drug screening. Five commercial and 5 academic hPSC-CM lines were casted in engineered heart tissue (EHT) format. Spontaneous and stimulated EHT contractions were analyzed, and 7 inotropic indicator compounds investigated on 8 cell lines. Baseline contractile force, kinetics, and rate varied widely among the different lines (e.g., relaxation time range: 118-471 ms). In contrast, the qualitative correctness of responses to BayK-8644, nifedipine, EMD-57033, isoprenaline, and digoxin in terms of force and kinetics varied only between 80% and 93%. Large baseline differences between control cell lines support the request for isogenic controls in disease modeling. Variability appears less relevant for drug screening but needs to be considered, arguing for studies with more than one line.
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•EHTs are stable from all tested hPSC-CM control lines•EHT baseline contractility shows high levels of variability between cell lines•Batch-to-batch variability is a large confounder of contractile parameters•Despite baseline variability, canonical drug responses were seen in all lines
In this article, Mannhardt and colleagues show that a systematic evaluation of 10 control hPSC-CM lines (commercial and academic) revealed high levels of variability regarding baseline contractility between the lines. In contrast, inotropic drug effects showed less prominent variability in canonical responses, arguing for a smaller relevance in drug screening.
The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, ...isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca2+ transient decay time, Ca2+‐load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow‐up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end‐stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non‐failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca2+‐binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca2+‐scavenging, suggesting impaired local Ca2+ cycling as an important disease culprit.
Synopsis
The disease mechanism linking the phospholamban (PLN) p.Arg14del mutation to dilated cardiomyopathy is incompletely understood. In this study, patient‐derived human induced pluripotent stem cell‐cardiomyocytes were used to elucidate this molecular mechanism.
Sarcoplasmic reticulum function remained unaltered in PLN p.Arg14del human cardiomyocytes.
Impairment of the interface between endoplasmic reticulum and mitochondria was discovered as a novel disease phenotype.
Cytoplasmic calcium‐scavenging improved the cardiomyopathy phenotype and revealed the role for cytoplasmic calcium in disease development.
The disease mechanism linking the phospholamban (PLN) p.Arg14del mutation to dilated cardiomyopathy is incompletely understood. In this study, patient‐derived human induced pluripotent stem cell‐cardiomyocytes were used to elucidate this molecular mechanism.
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