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Maksymenko, K.

Publications and source records attributed to Maksymenko, K..

3 recordsLinked to original sources

Tuning of granulopoietic signaling by de novo designed agonists

Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune the granulocyte-colony stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. Unlike G-CSF, they achieve selective activation of gene sets with hematopoietic functions with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and open up ways for new therapeutic applications for designed cytokines. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/568662v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@af56e3org.highwire.dtl.DTLVardef@171920forg.highwire.dtl.DTLVardef@12c2c0aorg.highwire.dtl.DTLVardef@ff7556_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

NeuroMotion: Open-source Simulator with Neuromechanical and Deep Network Models to Generate Surface EMG signals during Voluntary Movement

Neuromechanical studies investigate how the nervous system interacts with the musculoskeletal (MSK) system to generate volitional movements. Such studies have been supported by simulation models that provide insights into variables that cannot be measured experimentally and allow a large number of conditions to be tested before the experimental analysis. However, current simulation models of electromyography (EMG), a core physiological signal in neuromechanical analyses, are mainly limited to static contractions and cannot fully represent the dynamic modulation of EMG signals during volitional movements. Here, we overcome these limitations by presenting NeuroMotion, an open-source simulator that provides a full-spectrum synthesis of EMG signals during voluntary movements. NeuroMotion is comprised of three modules. The first module is an upper-limb MSK model with OpenSim API to estimate the muscle fibre lengths and muscle activations during movements. The second module is BioMime, a deep neural network-based EMG generator that receives nonstationary physiological parameter inputs, such as muscle fibre lengths, and efficiently outputs motor unit action potentials (MUAPs). The third module is a motor unit pool model that transforms the muscle activations into discharge timings of motor units. The discharge timings are convolved with the output of BioMime to simulate EMG signals during the movement. Here we also provide representative applications of NeuroMotion. We first show how simulated MUAP waveforms change during different levels of physiological parameter variations and different movements. We then show that the synthetic EMG signals during two-degree-of-freedom hand and wrist movements can be used to augment experimental data for regression. Ridge regressors trained on the synthetic dataset were directly used to predict joint angles from experimental data. NeuroMotion is the first full-spectrum EMG generative model to simulate human forearm electrophysiology during voluntary hand, wrist, and forearm movements. All intermediate variables are available, which allows the user to study cause-effect relationships in the complex neuromechanical system, fast iterate algorithms before collecting experimental data, and validate algorithms that estimate non-measurable parameters in experiments. We expect this full-spectrum model will complement experimental approaches and facilitate neuromechanical research. Author summaryNeuromechanical studies investigate how the nervous system and musculoskeletal system interact to generate movements. Such studies heavily rely on simulation models, which provide non-measurable variables to complement the experimental analyses. However, the simulation models of surface electromyography (EMG), the core physiological signal widely used in neuromechanical analyses, are limited to static conditions. We bridged this gap by proposing NeuroMotion, the first full-spectrum EMG simulator that can be used to generate EMG signals during voluntary movements. NeuroMotion integrates a musculoskeletal model, a neural network-based EMG generator, and an advanced motoneuron model. With representative applications of this simulator, we show that it can be used to investigate the variabilities of EMG signals during voluntary movement. We also demonstrate that the synthetic signals generated by NeuroMotion can be used to augment experimental data for regressing joint angles. We expect the functionality provided by NeuroMotion, which is provided open-source, will stimulate progress in neuromechanics.

bioengineering↗

Ultra fast and highly realistic numerical modelling of the surface EMG

Muscle electrophysiology has emerged as a powerful tool to drive human machine interfaces, with many new recent applications outside the traditional clinical domains. It is currently a crucial component of control systems in robotics and virtual reality. However, more sophisticated, functional, and robust decoding algorithms are required to meet the fine control requirements of these new applications. Deep learning approaches have shown the highest potential in this regard. To be effective, deep learning requires a large amount of high-quality annotated data for training; the only option today is the use of experimental electromyography data. Yet the acquisition and labelling of training data is time-consuming and expensive. Moreover, the high-quality annotation of this data is often not possible because the ground truth labels are hidden. Data augmentation using simulations, a strategy applied in other deep learning applications, has never been attempted in electromyography due to the absence of computationally efficient and realistic models. Here, we present a new highly realistic and ultra-fast computational model tailored for the training of deep learning algorithms. For the first time, we are able to simulate arbitrary large datasets of realistic electromyography signals with high internal variability and leverage it to train deep learning algorithms. Because the computational model provides access to all the hidden parameters of the simulation, it also allows us to use some annotation strategies that are impossible with experimental data. We believe that this concept of Myoelectric Digital Twin allows new unprecedented approaches to muscular signals decoding and will accelerate the development of human-machine interfaces.

bioengineering↗