Muscular dystrophies are a group of genetic muscle disorders that cause progressive muscle weakness and degeneration. Within this group, Duchenne muscular dystrophy (DMD) is the most common and one ...of the most severe. DMD is an X chromosome linked disease that occurs to 1 in 3500 to 1 in 5000 boys. The cause of DMD is a mutation in the dystrophin gene, whose encoded protein provides both structural support and cell signaling capabilities. So far, there are very limited therapeutic options available and there is no cure for this disease. In this review, we discuss the existing cell therapy research, especially stem cell-based, which utilize myoblasts, satellite cells, bone marrow cells, mesoangioblasts and CD133+ cells. Finally, we focus on human pluripotent stem cells (hPSCs) which hold great potential in treating DMD. hPSCs can be used for autologous transplantation after being specified to a myogenic lineage. Over the last few years, there has been a rapid development of isolation, as well as differentiation, techniques in order to achieve effective transplantation results of myogenic cells specified from hPSCs. In this review, we summarize the current methods of hPSCs myogenic commitment/differentiation, and describe the current status of hPSC-derived myogenic cell transplantation.
•Myogenic progenitor cells could provide a source for cell therapy for DMD to regenerate and replace the diseased tissue•An orchestration of signaling molecules directing the lineage determination sets the basis for PSC differentiation in vitro•There is a need to develop more cell therapy options (e.g iPSC) for DMD due to limited success of current ones•The review describes the most recent studies of hiPSC muscle lineage specification and the potential of their application
Speech emotion recognition (SER) is the key to human-computer emotion interaction. However, the nonlinear characteristics of speech emotion are variable, complex, and subtly changing. Therefore, ...accurate recognition of emotions from speech remains a challenge. Empirical mode decomposition (EMD), as an effective decomposition method for nonlinear non-stationary signals, has been successfully used to analyze emotional speech signals. However, the mode mixing problem of EMD affects the performance of EMD-based methods for SER. Various improved methods for EMD have been proposed to alleviate the mode mixing problem. These improved methods still suffer from the problems of mode mixing, residual noise, and long computation time, and their main parameters cannot be set adaptively. To overcome these problems, we propose a novel SER framework, named IMEMD-CRNN, based on the combination of an improved version of the masking signal-based EMD (IMEMD) and convolutional recurrent neural network (CRNN). First, IMEMD is proposed to decompose speech. IMEMD is a novel disturbance-assisted EMD method and can determine the parameters of masking signals to the nature of signals. Second, we extract the 43-dimensional time-frequency features that can characterize the emotion from the intrinsic mode functions (IMFs) obtained by IMEMD. Finally, we input these features into a CRNN network to recognize emotions. In the CRNN, 2D convolutional neural networks (CNN) layers are used to capture nonlinear local temporal and frequency information of the emotional speech. Bidirectional gated recurrent units (BiGRU) layers are used to learn the temporal context information further. Experiments on the publicly available TESS dataset and Emo-DB dataset demonstrate the effectiveness of our proposed IMEMD-CRNN framework. The TESS dataset consists of 2,800 utterances containing seven emotions recorded by two native English speakers. The Emo-DB dataset consists of 535 utterances containing seven emotions recorded by ten native German speakers. The proposed IMEMD-CRNN framework achieves a state-of-the-art overall accuracy of 100% for the TESS dataset over seven emotions and 93.54% for the Emo-DB dataset over seven emotions. The IMEMD alleviates the mode mixing and obtains IMFs with less noise and more physical meaning with significantly improved efficiency. Our IMEMD-CRNN framework significantly improves the performance of emotion recognition.
Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via Tead transcription factors. To investigate their role ...in skeletal muscle stem cells, we analyzed Taz in vivo and ex vivo in comparison with Yap. Small interfering RNA knockdown or retroviral‐mediated expression of wild‐type human or constitutively active TAZ mutants in satellite cells showed that TAZ promoted proliferation, a function shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene Wwtr1–/–) knockout mice, there were no overt effects on regeneration. Conversely, conditional knockout of Yap in satellite cells of Pax7Cre‐ERT2/+: Yapfl°x/fl°x:Rosa26Lacz mice produced a regeneration deficit. To identify potential mechanisms, microarray analysis showed many common TAZ/YAP target genes, but TAZ also regulates some genes independently of YAP, including myogenic genes such as Pax7, Myf5, and Myod1 (ArrayExpress–E‐MTAB‐5395). Proteomic analysis revealed many novel binding partners of TAZ/YAP in myogenic cells, but TAZ also interacts with proteins distinct from YAP that are often involved in myogenesis and aspects of cytoskeleton organization (ProteomeXchange–PXD005751). Neither TAZ nor YAP bind members of the Wnt destruction complex but both regulated expression of Wnt and Wnt‐cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to enhance myogenic differentiation. Stem Cells 2017;35:1958–1972
In skeletal muscle, Taz and Yap both enhance satellite cell derived‐myoblast proliferation, but during the later stages of myogenesis, Taz switches to influence satellite cell fate by promoting myogenic differentiation over self‐renewal.
VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in ...mice. Here, we characterise
in skeletal muscle. We found that mouse
was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans,
was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. However, there was no interaction with proteins from major regulatory systems such as the Hippo kinase cascade, unlike what is found for the TEAD co-factors YAP (encoded by
) and TAZ (encoded by
).
overexpression reduced the activity of the Hippo negative-feedback loop, affecting expression of muscle-regulating genes including
,
and
, and genes encoding certain Wnts and IGFBPs. VGLL3 mainly repressed gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated
knockdown suppressed myoblast proliferation, whereas
overexpression strongly promoted myogenic differentiation. However, skeletal muscle was overtly normal in
-null mice, presumably due to feedback signalling and/or redundancy. This work identifies VGLL3 as a transcriptional co-factor operating with the Hippo signal transduction network to control myogenesis.
Epilepsy is a common chronic brain disorder. Detecting epilepsy by observing electroencephalography (EEG) is the main method neurologists use, but this method is time-consuming. EEG signals are ...non-stationary, nonlinear, and often highly noisy, so it remains challenging to recognize epileptic EEG signals more accurately and automatically. This paper proposes a novel classification system of epileptic EEG signals for single-channel EEG based on the attention network that integrates time-frequency and nonlinear dynamic features. The proposed system has three novel modules. The first module constructs the Hilbert spectrum (HS) with high time-frequency resolution into a two-channel parallel convolutional network. The time-frequency features are fully extracted by complementing the high-dimensional features of the two branches. The second module constructs a grayscale recurrence plot (GRP) that contains more nonlinear dynamic features than traditional RP, fed into the residual-connected convolution module for effective learning of nonlinear dynamic features. The third module is the feature fusion module based on a self-attention mechanism to assign optimal weights to different types of features and further enhance the information extraction capability of the system. Therefore, the system is named HG-SANet. The results of several classification tasks on the Bonn EEG database and the Bern-Barcelona EEG database show that the HG-SANet can effectively capture the contribution degree of the extracted features from different domains, significantly enhance the expression ability of the model, and improve the accuracy of the recognition of epileptic EEG signals. The HG-SANet can improve the diagnosis and treatment efficiency of epilepsy and has broad application prospects in the fields of brain disease diagnosis.
Cells and organisms respond to nutrient deprivation by decreasing global rates of transcription, translation and DNA replication. To what extent such changes can be reversed is largely unknown. We ...examined the effect of maternal dietary restriction on RNA synthesis in the offspring. Low protein diet fed either throughout gestation or for the preimplantation period alone reduced cellular RNA content across fetal somatic tissues during challenge and increased it beyond controls in fetal and adult tissues after challenge release. Changes in transcription of ribosomal RNA, the major component of cellular RNA, were responsible for this phenotype as evidenced by matching alterations in RNA polymerase I density and DNA methylation at ribosomal DNA loci. Cellular levels of the ribosomal transcription factor Rrn3 mirrored the rRNA expression pattern. In cell culture experiments, Rrn3 overexpression reduced rDNA methylation and increased rRNA expression; the converse occurred after inhibition of Rrn3 activity. These observations define novel mechanism where poor nutrition before implantation irreversibly alters basal rates of rRNA transcription thereafter in a process mediated by rDNA methylation and Rrn3 factor.
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•Maternal malnutrition downregulates rDNA transcription in fetal tissues.•Switch to normal diet permanently upregulates rDNA transcription compared to controls.•These changes are mediated by DNA methylation and Pol I transcription factor Rrn3.•This mechanism is activated before implantation.
Cell therapies derived from induced pluripotent stem cells (iPSCs) offer a promising avenue in the field of regenerative medicine due to iPSCs' expandability, immune compatibility, and pluripotent ...potential. An increasing number of preclinical and clinical trials have been carried out, exploring the application of iPSC-based therapies for challenging diseases, such as muscular dystrophies. The unique syncytial nature of skeletal muscle allows stem/progenitor cells to integrate, forming new myonuclei and restoring the expression of genes affected by myopathies. This characteristic makes genome-editing techniques especially attractive in these therapies. With genetic modification and iPSC lineage specification methodologies, immune-compatible healthy iPSC-derived muscle cells can be manufactured to reverse the progression of muscle diseases or facilitate tissue regeneration. Despite this exciting advancement, much of the development of iPSC-based therapies for muscle diseases and tissue regeneration is limited to academic settings, with no successful clinical translation reported. The unknown differentiation process in vivo, potential tumorigenicity, and epigenetic abnormality of transplanted cells are preventing their clinical application. In this review, we give an overview on preclinical development of iPSC-derived myogenic cell transplantation therapies including processes related to iPSC-derived myogenic cells such as differentiation, scaling-up, delivery, and cGMP compliance. And we discuss the potential challenges of each step of clinical translation. Additionally, preclinical model systems for testing myogenic cells intended for clinical applications are described.
Mammalian extra-embryonic lineages perform the crucial role of nutrient provision during gestation to support embryonic and fetal growth. These lineages derive from outer trophectoderm (TE) and ...internal primitive endoderm (PE) in the blastocyst and subsequently give rise to chorio-allantoic and visceral yolk sac placentae, respectively. We have shown maternal low protein diet exclusively during mouse preimplantation development (Emb-LPD) is sufficient to cause a compensatory increase in fetal and perinatal growth that correlates positively with increased adult-onset cardiovascular, metabolic and behavioural disease. Here, to investigate early mechanisms of compensatory nutrient provision, we assessed the influence of maternal Emb-LPD on endocytosis within extra-embryonic lineages using quantitative imaging and expression of markers and proteins involved. Blastocysts collected from Emb-LPD mothers within standard culture medium displayed enhanced TE endocytosis compared with embryos from control mothers with respect to the number and collective volume per cell of vesicles with endocytosed ligand and fluid and lysosomes, plus protein expression of megalin (Lrp2) LDL-family receptor. Endocytosis was also stimulated using similar criteria in the outer PE-like lineage of embryoid bodies formed from embryonic stem cell lines generated from Emb-LPD blastocysts. Using an in vitro model replicating the depleted amino acid (AA) composition found within the Emb-LPD uterine luminal fluid, we show TE endocytosis response is activated through reduced branched-chain AAs (leucine, isoleucine, valine). Moreover, activation appears mediated through RhoA GTPase signalling. Our data indicate early embryos regulate and stabilise endocytosis as a mechanism to compensate for poor maternal nutrient provision.
Empirical mode decomposition (EMD) is a well-established technique to decompose nonstationary signals into intrinsic oscillatory modes, which is essential to catch crucial information hidden in ...nonstationary signals. However, when decomposing signals with intermittency or closely spaced frequency modes, EMD suffers from severe mode mixing problems (MMP). Therefore, we develop a novel adaptively optimized masking EMD (AOMEMD), a generalized, automated method to solve MMP. The work focuses on two aspects: i) Masking signals with different scales are adaptively iteratively generated based on Hilbert analytic solution and applied to raw data to assist EMD in solving MMP. ii) A universal mode mixing measure index (UMI) is proposed to quantitatively evaluate the extent of mode mixing. An optimization routine is then developed to optimize the amplitude and frequency of masking signals with the objective of minimizing the UMI to further improve the frequency separation performance of AOMEMD. Experiments on synthetic and real-world signals demonstrate that AOMEMD outperforms EMD and its variants in effectively addressing MMP, yielding more reasonable and reliable results. AOMEMD can separate modes with frequency ratios up to 0.9.
Environment around conception can influence the developmental programme with lasting effects on gestational and postnatal phenotype and with consequences for adult health and disease risk. ...Peri-conception exposure comprises a crucial part of the 'Developmental Origins of Health and Disease' (DOHaD) concept. In this review, we consider the effects of maternal undernutrition experienced during the peri-conception period in select human models and in a mouse experimental model of protein restriction. Human datasets indicate that macronutrient deprivation around conception affect the epigenome, with enduring effects on cardiometabolic and neurological health. The mouse model, comprising maternal low protein diet exclusively during the peri-conception period, has revealed a stepwise progression in altered developmental programming following induction through maternal metabolite deficiency. This progression includes differential effects in extra-embryonic and embryonic cell lineages and tissues, leading to maladaptation in the growth trajectory and increased chronic disease comorbidities. The timeline embraces an array of mechanisms across nutrient sensing and signalling, cellular, metabolic, epigenetic and physiological processes with a coordinating role for mTORC1 signalling proposed. Early embryos appear active participants in environmental sensing to optimise the developmental programme for survival but with the trade-off of later disease. Similar adverse health outcomes may derive from other peri-conception environmental experiences, including maternal overnutrition, micronutrient availability, pollutant exposure and assisted reproductive treatments (ART) and support the need for preconception health before pregnancy.
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