The implantation of mesenchymal stem cells (MSC) has been reported as a new technique to restore renal tubular structure and improve renal function in acute kidney injury (AKI). Vascular endothelial growth factor (VEGF) plays an important role in the renoprotective function of MSC. Whether upregulation of VEGF by a combination of MSC and VEGF gene transfer could enhance the protective effect of MSC in AKI is not clear. We investigated the effects of VEGF-modified human embryonic MSC (VEGF-hMSC) in healing cisplatin-injured renal tubular epithelial cells (TCMK-1) with a coculture system. We found that TCMK-1 viability declined 3 days after cisplatin pretreatment and that coculture with VEGF-hMSC enhanced cell protection via mitogenic and antiapoptotic actions. In addition, administration of VEGF-hMSC in a nude mouse model of cisplatin-induced kidney injury offered better protective effects on renal function, tubular structure, and survival as represented by increased cell proliferation, decreased cellular apoptosis, and improved peritubular capillary density. These data suggest that VEGF-modified hMSC implantation could provide advanced benefits in the protection against AKI by increasing antiapoptosis effects and improving microcirculation and cell proliferation.
The lack of low frequency information and a good initial model can seriously affect the success of full waveform inversion (FWI), due to the inherent cycle skipping problem. Computational low frequency extrapolation is in principle the most direct way to address this issue. By considering bandwidth extension as a regression problem in machine learning, we propose an architecture of convolutional neural network (CNN) to automatically extrapolate the missing low frequencies without preprocessing and post-processing steps. The bandlimited recordings are the inputs of the CNN and, in our numerical experiments, a neural network trained from enough samples can predict a reasonable approximation to the seismograms in the unobserved low frequency band, both in phase and in amplitude. The numerical experiments considered are set up on simulated P-wave data. In extrapolated FWI (EFWI), the low-wavenumber components of the model are determined from the extrapolated low frequencies, before proceeding with a frequency sweep of the bandlimited data. The proposed deep-learning method of low-frequency extrapolation shows adequate generalizability for the initialization step of EFWI. Numerical examples show that the neural network trained on several submodels of the Marmousi model is able to predict the low frequencies for the BP 2004 benchmark model. Additionally, the neural network can robustly process seismic data with uncertainties due to the existence of noise, poorly-known source wavelet, and different finite-difference scheme in the forward modeling operator. Finally, this approach is not subject to the structural limitations of other methods for bandwidth extension, and seems to offer a tantalizing solution to the problem of properly initializing FWI.
Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possesses their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However, little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health‐related quality of life, disability, and premature death in older people. High‐temperature requirement protein A2 (HtrA2/Omi) is a mitochondrial protease and plays an important role in mitochondrial proteostasis. HtrA2mnd2(−/−) mice harboring protease‐deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in muscle degeneration. Using motor functional, histological, and molecular biological methods, we characterized the phenotype of HtrA2mnd2(−/−) muscle. Furthermore, we isolated the gastrocnemius muscle of HtrA2mnd2(−/−) mice and determined expression of genes in mitochondrial unfolded protein response (UPRmt), mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis. Here, we showed that HtrA2/Omi protease deficiency induced denervation‐independent skeletal muscle degeneration with sarcopenia phenotypes. Despite mitochondrial hypofunction, upregulation of UPRmt and mitohormesis‐related genes and elevated total reactive oxygen species (ROS) production were not observed in HtrA2mnd2(−/−) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nuclear DNA‐ and mitochondrial DNA‐encoded ETC subunits, which is in consistent with their transcription factors, nuclear respiratory factors 1 and 2, and coactivator peroxisome proliferator‐activated receptor γ coactivator 1α. These results reveal that loss of HtrA2/Omi protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.
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