BiLSTM-Based Joint Torque Prediction From Mechanomyogram During Isometric Contractions: A Proof of Concept Study.

Quantifying muscle strength is an important measure in clinical settings; however, there is a lack of practical tools that can be deployed for routine assessment. The purpose of this study is to propose a deep learning model for ankle plantar flexion torque prediction from time-series mechanomyogram (MMG) signals recorded during isometric contractions (i.e., a similar form to manual muscle testing procedure in clinical practice) and to evaluate its performance. Four different deep learning models in terms of model architecture (based on a stacked bidirectional long short-term memory and dense layers) were designed with different combinations of the number of units (from 32 to 512) and dropout ratio (from 0.0 to 0.8), and then evaluated for prediction performance by conducting the leave-one-subject-out cross-validation method from the 10-subject dataset. As a result, the models explained more variance in the untrained test dataset as the error metrics (e.g., root-mean-square error) decreased and as the slope of the relationship between the measured and predicted joint torques became closer to 1.0. Although the slope estimates appear to be sensitive to an individual dataset, >70% of the variance in nine out of 10 datasets was explained by the optimal model. These results demonstrated the feasibility of the proposed model as a potential tool to quantify average joint torque during a sustained isometric contraction.

Molecular mechanism governing RNA-binding property of mammalian TRIM71 protein.

TRIM71 is an RNA-binding protein with ubiquitin ligase activity. Numerous functions of mammalian TRIM71, including cell cycle regulation, embryonic stem cell (ESC) self-renewal, and reprogramming of pluripotent stem cells, are related to its RNA-binding property. We previously reported that a long noncoding RNA (lncRNA) Trincr1 interacts with mouse TRIM71 (mTRIM71) to repress FGF/ERK pathway in mouse ESCs (mESCs). Herein, we identify an RNA motif specifically recognized by mTRIM71 from Trincr1 RNA, and solve the crystal structure of the NHL domain of mTRIM71 complexed with the RNA motif. Similar to the zebrafish TRIM71, mTRIM71 binds to a stem-loop structured RNA fragment of Trincr1, and an adenosine base at the loop region is crucial for the mTRIM71 interaction. We map similar hairpin RNAs preferably bound by TRIM71 in the mRNA UTRs of the cell-cycle related genes regulated by TRIM71. Furthermore, we identify key residues of mTRIM71, conserved among mammalian TRIM71 proteins, required for the RNA-binding property. Single-site mutations of these residues significantly impair the binding of TRIM71 to hairpin RNAs in vitro and to mRNAs of Cdkn1a/p21 and Rbl2/p130 in mESCs. Furthermore, congenital hydrocephalus (CH) specific mutation of mTRIM71 impair its binding to the RNA targets as well. These results reveal molecular mechanism behind the recognition of RNA by mammalian TRIM71 and provide insights into TRIM71 related diseases.

Ankle Joint Angle Influences Relative Torque Fluctuation during Isometric Plantar Flexion.

The purpose of this study was to investigate the influence of changes in muscle length on the torque fluctuations and on related oscillations in muscle activity during voluntary isometric contractions of ankle plantar flexor muscles. Eleven healthy individuals were asked to perform voluntary isometric contractions of ankle muscles at five different contraction intensities from 10% to 70% of maximum voluntary isometric contraction (MVIC) and at three different muscle lengths, implemented by changing the ankle joint angle (plantar flexion of 26°-shorter muscle length; plantar flexion of 10°-neutral muscle length; dorsiflexion of 3°-longer muscle length). Surface electromyogram (EMG) signals were recorded from the skin surface over the triceps surae muscles, and rectified-and-smoothed EMG (rsEMG) were estimated to assess the oscillations in muscle activity. The absolute torque fluctuations (quantified by the standard deviation) were significantly higher during moderate-to-high contractions at the longer muscle length. Absolute torque fluctuations were found to be a linear function of torque output regardless of muscle length. In contrast, the relative torque fluctuations (quantified by the coefficient of variation) were higher at the shorter muscle length. However, both absolute and relative oscillations in muscle activities remained relatively consistent at different ankle joint angles for all plantar flexors. These findings suggest that the torque steadiness may be affected by not only muscle activities, but also by muscle length-dependent mechanical properties. This study provides more insights that muscle mechanics should be considered when explaining the steadiness in force output.

Mechanomyogram amplitude vs. isometric ankle plantarflexion torque of human medial gastrocnemius muscle at different ankle joint angles.

The purpose of this study was to investigate the influence of changes in ankle joint angle on the mechanomyogram (MMG) amplitude of the human medial gastrocnemius (MG) muscle during voluntary isometric plantarflexion contractions. Ten healthy individuals were asked to perform voluntary isometric contractions at six different contraction intensities (from 10% to 100%) and at three different ankle joint angles (plantarflexion of 26°; plantarflexion of 10°; dorsiflexion of 3°). MMG signals were recorded from the surface over the MG muscle, using a 3-axis accelerometer. The relations between root mean square (RMS) MMG and isometric plantarflexion torque at different ankle joint angles were characterized to evaluate the effects of altered muscle mechanical properties on RMS MMG. We found that the relation between RMS MMG and plantarflexion torque is changed at different ankle joint angles: RMS MMG increases monotonically with increasing the plantarflexion torque but decreases as the ankle joint became dorsiflexed. Moreover, RMS MMG shows a negative correlation with muscle length, with passive torque, and with maximum voluntary torque, which were all changed significantly at different ankle joint angles. Our findings demonstrate the potential effects of changing muscle mechanical properties on muscle vibration amplitude. Future studies are required to explore the major sources of this muscle vibration from the perspective of muscle mechanics and muscle activation level, attributable to changes in the neural command.

Exploration of the Substrate Preference of Lysine Methyltransferase SMYD3 by Molecular Dynamics Simulations.

SMYD3, a SET and MYND domain containing lysine methyltransferase, catalyzes the transfer of the methyl group from a methyl donor onto the Nε group of a lysine residue in the substrate protein. Methylation of MAP3 kinase kinase (MAP3K2) by SMYD3 has been implicated in Ras-driven tumorigenesis. The crystal structure of SMYD3 in complex with MAP3K2 peptide reveals a shallow hydrophobic pocket (P-2), which accommodates the binding of a phenylalanine residue at the -2 position of the substrate (F258) is a crucial determinant of substrate specificity of SMYD3. To better understand the substrate preference of SMYD3 at the -2 position, molecular dynamics (MD) simulations and the MM/GBSA method were performed on the crystal structure of SMYD3-MAP3K2 complex (PDB: 5EX0) after substitution of F258 residue of MAP3K2 to each of the other 19 natural residues, respectively. Binding free energy calculations reveal that the P-2 pocket prefers an aromatic hydrophobic group and none of the substitutions behave better than the wild-type phenylalanine residue does. Furthermore, we investigated the structure-activity relationships (SAR) of a series of non-natural phenylalanine derivative substitutions at the -2 position and found that quite a few modifications on the sidechain of F258 residue could strengthen its binding to the P-2 pocket of SMYD3. These explorations provide insights into developing novel SMYD3 inhibitors with high potency and high selectivity against MAP3K2 and cancer.