The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells
. This process requires major molecular adaptations to allow HSCs to meet ...the regulatory and metabolic requirements for cell division
. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)
, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.
Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. The mechanisms by which these critical ...activities are balanced are still unclear. Here, we report that Macrophage-Erythroblast Attacher (MAEA, also known as EMP), a receptor thus far only identified in erythroblastic island, is a membrane-associated E3 ubiquitin ligase subunit essential for HSC maintenance and lymphoid potential. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and leads to a lethal myeloproliferative syndrome. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in the absence of Maea, thereby prolonging their intracellular signalling. This is associated with impaired autophagy flux in HSCs but not in mature haematopoietic cells. Administration of receptor kinase inhibitor or autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. Our results suggest that MAEA provides E3 ubiquitin ligase activity, guarding HSC function by restricting cytokine receptor signalling via autophagy.
Convolutional neural networks (CNNs) can automatically learn features from the hyperspectral image (HSI) data, avoiding the difficulty of manually extracting features. However, the number of training ...samples for the classification of HSIs is always limited, making it difficult for CNN to obtain effective features and resulting in low classification accuracy. To solve this problem, a pixel cluster CNN and spectral-spatial fusion (SSF) algorithm for hyperspectral image classification with small-size training samples is proposed in this article. First, spatial information is extracted by the gray level co-occurrence matrix. Then, spatial information and spectral information are fused by means of bands superposition, forming spectral-spatial features. To expand the number of training samples, the pixels after SSF are combined into pixel clusters according to a certain rule. Finally, a CNN framework is utilized to extract effective features from the pixel clusters. Experiments based on three standard HSIs demonstrate that the proposed algorithm can get better performance than the conventional CNN and also outperforms other studied algorithms in the case of small training set.
Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. ...Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and ...cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGγ-dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGγ knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGγ-proteasome inhibition has a potential to provide tumour-starving benefits.
•The proposed co-prime MIMO radar model is based on the transmit energy focusing technique, which improves the signal-to-noise ratio (SNR) gain in the desired sector.•The transmit beamspace matrix ...with a specific structure is designed to ensure the number of DOFs is not sacrificed.•The CRB of the DOA estimation for the TEF-based co-prime MIMO radar has a lower bound than the traditional co-prime MIMO radar.
In this paper, we propose a novel co-prime multiple-input multiple-output (MIMO) radar model based on the transmit energy focusing (TEF) technique for direction of arrival (DOA) estimation. Compared with omnidirectional radiation of the transmit energy of the traditional co-prime MIMO radar, the proposed model can focus the transmit energy in the desired spatial sector. To obtain more degrees of freedom (DOFs), we design the transmit beamspace matrix with a specific structure. Then, the sum and difference co-array (SDC) is given by vectorizing the sampling covariance matrix of the received data. Subsequently, the maximum number of consecutive lags and unique lags for SDC is derived. Besides, we also derive the Cramer–Rao bound (CRB) of our model. Moreover, the DOA estimation performance of the TEF-based co-prime MIMO radar and traditional co-prime MIMO radar is compared by using forward-backward spatial smoothing (FBSS), sparse recovery (SR), and fast iterative interpolated beamformer (FIIB) algorithms. Simulation results show the superiority of the proposed model.
With the development of new active deception jamming, radar antijamming has become a major research hotspot, and the recognition of jamming type is one of its key steps. In recent years, deep ...learning has been successfully applied in the field of radar jamming recognition, such as convolutional neural networks (CNNs). However, it is difficult to effectively improve the accuracy of deep learning algorithms in the case of small sample. Furthermore, ensemble learning and transfer learning can effectively improve the model generalization performance. For the small sample problem, this article proposes a weighted ensemble CNN with transfer learning (WECNN-TL)-based radar active deception jamming recognition algorithm. The main idea of this method is to obtain the time-frequency distribution maps of jamming signals by the short-time Fourier transform (STFT), and then, their real parts, imaginary parts, moduli, and phases are combined differently to construct multiple datasets. Finally, an ensemble CNN (ECNN) model with weighted voting and transfer learning is constructed to realize jamming recognition. Experiments on the simulated and measured mixed datasets (including 12 types of samples) show that the proposed method can get better recognition performance than random forest (RF), support vector machine (SVM), and some CNN-based methods.
Hematopoietic stem cells (HSC) harbor extensive self-renewal capabilities along with multilineage differentiation plasticity to sustain blood production over a lifetime. Maintenance of a fully ...functional proteome that can rapidly change to adjust to the status of HSC activation is facilitated in part by two major intracellular proteolytic pathways, the ubiquitin proteasome system and the autophagy/lysosomal system. Alterations in HSC proteostasis have been associated with a number of degenerative and malignant diseases, underscoring the importance of elucidating the precise contribution of components of the cellular proteostasis network to HSC maintenance.
In this work, we have focused in a highly selective type of autophagy, known as chaperone-mediated autophagy (CMA), whereby individual proteins bearing a unique pentapeptide motif (KFERQ-like) are targeted for degradation in lysosomes upon binding to the heat shock cognate protein of 70 kDa (HSC70). Substrate proteins are directly translocated into the lysosomal lumen through a dedicated multiprotein translocation complex. The main component of this complex is the lysosome-associated membrane protein type 2A (LAMP-2A) that also serves as substrate receptor and is the limiting component of CMA. Using novel mouse models that allow for CMA tracking (KFERQ-Dendra mice) and for selective depletion of LAMP-2A in hematopoietic cells (Vav-iCre:LAMP2Af/f mice), we have investigated the physiological role of CMA in HSCs during steady-state and upon activation and gained novel insights on the consequences of CMA failure in these cells in aging.
Our work revealed that the basal CMA activity detected in quiescent HSC under steady-state conditions is significantly stimulated upon HSC activation following 5-fluorouracil (5-FU) in vivo exposure. This upregulation of CMA is necessary to ensure HSCs persistence during activation because, upon serial 5-FU injections, CMA-deficient HSCs had a significantly reduced multilineage reconstitution ability with premature bone marrow failure. We found reduced long-term colony formation of CMA-deficient HSCs in serial colony formation assays and demonstrated that these cells had a significant and progressive disadvantage of repopulating lethally-irradiated congenic recipient mice upon serial bone marrow transplantation. We also found that CMA becomes increasingly important for the maintenance of functional HSCs in aging, since as mice age, CMA-deficient HSCs showed an even greater functional defect compared to age-mated control-derived HSCs.
Using comparative transcriptomics and metabolomics on HSCs from control and LAMP-2A-deficient mice, we found evidence for metabolic alterations and dysfunctional redox signaling. We confirmed that CMA-deficient HSCs have reduced rates of glycolysis, lower ATP production and higher reactive oxygen species levels than control cells. Deficient cellular energetics and increased oxidative stress are important consequences of CMA failure in HSC, since supplementation with pyruvate or treatment with anti-oxidant agents (i.e. N-acetyl-cysteine) was sufficient to restore CMA-deficient HSC function, as measured by serial colony formation. Proteomic analysis of CMA-deficient Lin-Scal+c-Kit+ (LSK) cells revealed an overall increase of acetylated and oxidized proteins, including key metabolic enzymes and proteins required for the cellular response to oxidative stress. We propose that, upon CMA failure, the inability of HSC cells to timely turning over these regulatory proteins, favors accumulation of unwanted post-translational modifications that interfere with their normal functioning.
Together, our findings suggest that CMA upregulation during HSCs activation is required for the proteome remodeling that facilitates transition from quiescent to activated cells. By assuring timely turnover of selected proteins, CMA sustains the metabolic adaptation required to meet these cells' energetic needs and assures an efficient cellular response to stress.
No relevant conflicts of interest to declare.
To overcome the shortcomings of whale optimization algorithm (WOA) such as the slow convergence rate, and low convergence accuracy, and being easy to fall into the local optimum, an improved whale ...optimization algorithm based on the tent chaotic mapping and nonlinear convergence factor (TNWOA)is proposed. Firstly, In this algorithm, tent chaotic mapping, which enhances the diversity of the initialization population, is introduced into the initialization of population, therefore, the search space can be searched more thoroughly; Secondly, trigonometric function and the beta distribution are introduced in the convergence factor 'a', which balance the global search ability as well as local optimization ability and speed up the convergence speed of the algorithm. Simulation experiments on the four kinds of common test functions on CEC2017 show that under the same experimental conditions, the improved whale optimization algorithm improves the solution accuracy and convergence speed significantly, and its performance is obviously better than other smart optimization algorithms and other improved WOA algorithms.
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