A Study on Dimensionality Reduction and Parameters for Hyperspectral Imagery Based on Manifold Learning.

With the rapid advancement of remote-sensing technology, the spectral information obtained from hyperspectral remote-sensing imagery has become increasingly rich, facilitating detailed spectral analysis of Earth's surface objects. However, the abundance of spectral information presents certain challenges for data processing, such as the "curse of dimensionality" leading to the "Hughes phenomenon", "strong correlation" due to high resolution, and "nonlinear characteristics" caused by varying surface reflectances. Consequently, dimensionality reduction of hyperspectral data emerges as a critical task. This paper begins by elucidating the principles and processes of hyperspectral image dimensionality reduction based on manifold theory and learning methods, in light of the nonlinear structures and features present in hyperspectral remote-sensing data, and formulates a dimensionality reduction process based on manifold learning. Subsequently, this study explores the capabilities of feature extraction and low-dimensional embedding for hyperspectral imagery using manifold learning approaches, including principal components analysis (PCA), multidimensional scaling (MDS), and linear discriminant analysis (LDA) for linear methods; and isometric mapping (Isomap), locally linear embedding (LLE), Laplacian eigenmaps (LE), Hessian locally linear embedding (HLLE), local tangent space alignment (LTSA), and maximum variance unfolding (MVU) for nonlinear methods, based on the Indian Pines hyperspectral dataset and Pavia University dataset. Furthermore, the paper investigates the optimal neighborhood computation time and overall algorithm runtime for feature extraction in hyperspectral imagery, varying by the choice of neighborhood k and intrinsic dimensionality d values across different manifold learning methods. Based on the outcomes of feature extraction, the study examines the classification experiments of various manifold learning methods, comparing and analyzing the variations in classification accuracy and Kappa coefficient with different selections of neighborhood k and intrinsic dimensionality d values. Building on this, the impact of selecting different bandwidths t for the Gaussian kernel in the LE method and different Lagrange multipliers λ for the MVU method on classification accuracy, given varying choices of neighborhood k and intrinsic dimensionality d, is explored. Through these experiments, the paper investigates the capability and effectiveness of different manifold learning methods in feature extraction and dimensionality reduction within hyperspectral imagery, as influenced by the selection of neighborhood k and intrinsic dimensionality d values, identifying the optimal neighborhood k and intrinsic dimensionality d value for each method. A comparison of classification accuracies reveals that the LTSA method yields superior classification results compared to other manifold learning approaches. The study demonstrates the advantages of manifold learning methods in processing hyperspectral image data, providing an experimental reference for subsequent research on hyperspectral image dimensionality reduction using manifold learning methods.

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation.

BACKGROUND: Erythroid and myeloid differentiation disorders are commonly occurred in leukemia. Given that the relationship between erythroid and myeloid lineages is still unclear. To find the co-regulators in erythroid and myeloid differentiation might help to find new target for therapy of myeloid leukemia. In hematopoiesis, ALA (alpha lipoic acid) is reported to inhibit neutrophil lineage determination by targeting transcription factor ELK1 in granulocyte-monocyte progenitors via splicing factor SF3B1. However, further exploration is needed to determine whether ELK1 is a common regulatory factor for erythroid and myeloid differentiation. METHODS: In vitro culture of isolated CD34+, CMPs (common myeloid progenitors) and CD34+ CD371- HSPCs (hematopoietic stem progenitor cells) were performed to assay the differentiation potential of monocytes, neutrophils, and erythrocytes. Overexpression lentivirus of long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 transduced CD34+ HSPCs were transplanted into NSG mice to assay the human lymphocyte and myeloid differentiation differences 3 months after transplantation. Knocking down of SRSF11, which was high expressed in CD371+GMPs (granulocyte-monocyte progenitors), upregulated by ALA and binding to ELK1-RNA splicing site, was performed to analyze the function in erythroid differentiation derived from CD34+ CD123mid CD38+ CD371- HPCs (hematopoietic progenitor cells). RNA sequencing of L-ELK1 and S-ELK1 overexpressed CD34+ CD123mid CD38+ CD371- HPCs were performed to assay the signals changed by ELK1. RESULTS: Here, we presented new evidence that ALA promoted erythroid differentiation by targeting the transcription factor ELK1 in CD34+ CD371- hematopoietic stem progenitor cells (HSPCs). Overexpression of either the long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 inhibited erythroid-cell differentiation, but knockdown of ELK1 did not affect erythroid-cell differentiation. RNAseq analysis of CD34+ CD123mid CD38+ CD371- HPCs showed that L-ELK1 upregulated the expression of genes related to neutrophil activity, phosphorylation, and hypoxia signals, while S-ELK1 mainly regulated hypoxia-related signals. However, most of the genes that were upregulated by L-ELK1 were only moderately upregulated by S-ELK1, which might be due to a lack of serum response factor interaction and regulation domains in S-ELK1 compared to L-ELK1. In summary, the differentiation of neutrophils and erythrocytes might need to rely on the dose of L-ELK1 and S-ELK1 to achieve precise regulation via RNA splicing signals at early lineage commitment. CONCLUSIONS: ALA and ELK1 are found to regulate both human granulopoiesis and erythropoiesis via RNA spliceosome, and ALA-ELK1 signal might be the target of human leukemia therapy.

Point Cloud Denoising and Feature Preservation: An Adaptive Kernel Approach Based on Local Density and Global Statistics.

Noise removal is a critical stage in the preprocessing of point clouds, exerting a significant impact on subsequent processes such as point cloud classification, segmentation, feature extraction, and 3D reconstruction. The exploration of methods capable of adapting to and effectively handling the noise in point clouds from real-world outdoor scenes remains an open and practically significant issue. Addressing this issue, this study proposes an adaptive kernel approach based on local density and global statistics (AKA-LDGS). This method constructs the overall framework for point cloud denoising using Bayesian estimation theory. It dynamically sets the prior probabilities of real and noise points according to the spatial function relationship, which varies with the distance from the points to the center of the LiDAR. The probability density function (PDF) for real points is constructed using a multivariate Gaussian distribution, while the PDF for noise points is established using a data-driven, non-parametric adaptive kernel density estimation (KDE) approach. Experimental results demonstrate that this method can effectively remove noise from point clouds in real-world outdoor scenes while maintaining the overall structural features of the point cloud.

Mesenchymal stem/stromal cells from human pluripotent stem cell-derived brain organoid enhance the ex vivo expansion and maintenance of hematopoietic stem/progenitor cells.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) are of great therapeutic value due to their role in maintaining the function of hematopoietic stem/progenitor cells (HSPCs). MSCs derived from human pluripotent stem cells represent an ideal alternative because of their unlimited supply. However, the role of MSCs with neural crest origin derived from HPSCs on the maintenance of HSPCs has not been reported. METHODS: Flow cytometric analysis, RNA sequencing and differentiation ability were applied to detect the characteristics of stromal cells from 3D human brain organoids. Human umbilical cord blood CD34+ (UCB-CD34+) cells were cultured in different coculture conditions composed of stromal cells and umbilical cord MSCs (UC-MSCs) with or without a cytokine cocktail. The hematopoietic stroma capacity of stromal cells was tested in vitro with the LTC-IC assay and in vivo by cotransplantation of cord blood nucleated cells and stroma cells into immunodeficient mice. RNA and proteomic sequencing were used to detect the role of MSCs on HSPCs. RESULTS: The stromal cells, derived from both H1-hESCs and human induced pluripotent stem cells forebrain organoids, were capable of differentiating into the classical mesenchymal-derived cells (osteoblasts, chondrocytes, and adipocytes). These cells expressed MSC markers, thus named pluripotent stem cell-derived MSCs (pMSCs). The pMSCs showed neural crest origin with CD271 expression in the early stage. When human UCB-CD34+ HSPCs were cocultured on UC-MSCs or pMSCs, the latter resulted in robust expansion of UCB-CD34+ HSPCs in long-term culture and efficient maintenance of their transplantability. Comparison by RNA sequencing indicated that coculture of human UCB-CD34+ HSPCs with pMSCs provided an improved microenvironment for HSC maintenance. The pMSCs highly expressed the Wnt signaling inhibitors SFRP1 and SFRP2, indicating that they may help to modulate the cell cycle to promote the maintenance of UCB-CD34+ HSPCs by antagonizing Wnt activation. CONCLUSIONS: A novel method for harvesting MSCs with neural crest origin from 3D human brain organoids under serum-free culture conditions was reported. We demonstrate that the pMSCs support human UCB-HSPC expansion in vitro in a long-term culture and the maintenance of their transplantable ability. RNA and proteomic sequencing indicated that pMSCs provided an improved microenvironment for HSC maintenance via mechanisms involving cell-cell contact and secreted factors and suppression of Wnt signaling. This represents a novel method for large-scale production of MSCs of neural crest origin and provides a potential approach for development of human hematopoietic stromal cell therapy for treatment of dyshematopoiesis.

Integrated modelling of flow-sediment transport and power generation in the Three Gorges Reservoir.

Reservoirs play a crucial role in regulating runoff and generating energy. However, they also lead to significant sedimentation in the reservoir area. In this study, we propose an integrated model that combines a 1-D hydro- and sediment dynamic module with a power generation module. The model considers both suspended and bed load transports. This model is applied to the Three Gorges Reservoir (TGR) and evaluate its performance against corresponding measurements. The results demonstrate that:① the proposed model accurately reproduces the processes of flow and sediment transport, bed deformation, and power generation during the hydrological years of 2019 and 2020. The relative errors for average discharge and bed deformation volume are <6 % and 10 %, respectively. Moreover, the calculated total power (982 × 108-1115 × 108 kW·h) closely agree with the measured values (969 × 108-1118 × 108 kW·h); ② the inflows of small tributaries have a noticeable impact on the calculated water discharge in the TGR. This impact will lead to a 16 % increase in average discharge and alter the magnitudes and occurrence times of flood peaks; ③ the flocculation of fine sediment particles significantly affects sediment transport, particularly in the sub-reach close to the dam. This flocculation will result in a 37 %-57 % reduction in average suspended sediment discharge and a 63 %-93 % reduction in peak sediment discharge. This research provides a comprehensive tool for simulating flow and sediment transport as well as power generation, which can support the optimal regulation of the TGR.

Laboratory and Semi-Field Evaluation on S-Methoprene Formulations Against Anopheles sinensis (Diptera: Culicidae) - Yuxi City, Yunnan Province, China.

What is already known about this topic?: Anopheles sinensis (An. sinensis) is the predominant malaria vector in China. The impact of S-methoprene on the emergence process of mosquito larvae suggests its potential as a control method for vector mosquitoes. However, the efficacy of S-methoprene in controlling An. sinensis has not yet been demonstrated. What is added by this report?: The effectiveness of S-methoprene against An. sinensis was assessed in laboratory and semi-field conditions in Yunnan Province. What are the implications for public health practice?: These results offer valuable options and guidance for utilizing S-methoprene products in malaria reimportation prevention areas within Yunnan Province.

Maternal nitric oxide homeostasis impacts female gametophyte development under optimal and stress conditions.

In adverse environments, the number of fertilizable female gametophytes (FGs) in plants is reduced, leading to increased survival of remaining offspring. How the maternal plant perceives internal growth cues and external stress conditions to alter FG development remains largely unknown. We report that homeostasis of the stress signaling molecule nitric oxide (NO) plays a key role in controlling FG development under both optimal and stress conditions. NO homeostasis is precisely regulated by S-nitrosoglutathione reductase (GSNOR). Prior to fertilization, GSNOR protein is exclusively accumulated in sporophytic tissues and indirectly controls FG development in Arabidopsis (Arabidopsis thaliana). In GSNOR null mutants, NO species accumulated in the degenerating sporophytic nucellus and auxin efflux into the developing FG was restricted, which inhibited FG development, resulting in reduced fertility. Importantly, restoring GSNOR expression in maternal, but not gametophytic tissues, or increasing auxin efflux substrate significantly increased the proportion of normal FGs and fertility. Furthermore, GSNOR overexpression or added auxin efflux substrate increased fertility under drought and salt stress. These data indicate that NO homeostasis is critical to normal auxin transport and maternal control of FG development, which in turn determine seed yield. Understanding this aspect of fertility control could contribute to mediating yield loss under adverse conditions.

Performance of ChatGPT incorporated chain-of-thought method in bilingual nuclear medicine physician board examinations.

Objective: This research explores the performance of ChatGPT, compared to human doctors, in bilingual, Mandarin Chinese and English, medical specialty exam in Nuclear Medicine in Taiwan. Methods: The study employed generative pre-trained transformer (GPT-4) and integrated chain-of-thoughts (COT) method to enhance performance by triggering and explaining the thinking process to answer the question in a coherent and logical manner. Questions from the Taiwanese Nuclear Medicine Specialty Exam served as the basis for testing. The research analyzed the correctness of AI responses in different sections of the exam and explored the influence of question length and language proportion on accuracy. Results: AI, especially ChatGPT with COT, exhibited exceptional capabilities in theoretical knowledge, clinical medicine, and handling integrated questions, often surpassing, or matching human doctor performance. However, AI struggled with questions related to medical regulations. The analysis of question length showed that questions within the 109-163 words range yielded the highest accuracy. Moreover, an increase in the proportion of English words in questions improved both AI and human accuracy. Conclusions: This research highlights the potential and challenges of AI in the medical field. ChatGPT demonstrates significant competence in various aspects of medical knowledge. However, areas like medical regulations require improvement. The study also suggests that AI may help in evaluating exam question difficulty and maintaining fairness in examinations. These findings shed light on AI role in the medical field, with potential applications in healthcare education, exam preparation, and multilingual environments. Ongoing AI advancements are expected to further enhance AI utility in the medical domain.

Cardiac cellular diversity and functionality in cardiac repair by single-cell transcriptomics.

Cardiac repair after myocardial infarction (MI) is orchestrated by multiple intrinsic mechanisms in the heart. Identifying cardiac cell heterogeneity and its effect on processes that mediate the ischemic myocardium repair may be key to developing novel therapeutics for preventing heart failure. With the rapid advancement of single-cell transcriptomics, recent studies have uncovered novel cardiac cell populations, dynamics of cell type composition, and molecular signatures of MI-associated cells at the single-cell level. In this review, we summarized the main findings during cardiac repair by applying single-cell transcriptomics, including endogenous myocardial regeneration, myocardial fibrosis, angiogenesis, and the immune microenvironment. Finally, we also discussed the integrative analysis of spatial multi-omics transcriptomics and single-cell transcriptomics. This review provided a basis for future studies to further advance the mechanism and development of therapeutic approaches for cardiac repair.

Aldehyde dehydrogenase 2 gene rs671 G>A polymorphism is associated with an increased risk of digestive tract cancer.

OBJECTIVE: Acetaldehyde can accumulate in cells and form acetaldehyde-DNA adducts that result in digestive tract cancer development. Acetaldehyde dehydrogenase 2 (ALDH2) enzymatic activity is involved in this process. Here, we aimed to analyze the relationship between an ALDH2 gene polymorphism and the digestive tract cancer risk in the Hakka population in China. METHODS: This was a retrospective study, with the ALDH2 rs671 genotype and medical record information collected from all subjects. The relationships between these factors, including various blood cell parameters, and digestive tract cancer susceptibility were analyzed. RESULTS: Overall, 307 cancer patients and 317 controls were included. The cancer patients had significantly higher percentages with a history of smoking and drinking alcohol, as well as an increased platelet to lymphocyte ratio and lower lymphocyte to monocyte ratio, compared with the controls. The ALDH2 rs671 genotype and allele distributions were significantly different between the cancer patients and controls. Logistic regression analysis showed that the ALDH2 G/A genotype (G/A vs. G/G) and A/A genotype (A/A vs. G/G) in the co-dominant mode were risk factors for digestive tract cancer susceptibility. CONCLUSIONS: ALDH2 rs671 G/A or A/A genotype carriers may have an increased risk of developing digestive tract cancers among the Hakka people.

Generating hematopoietic cells from human pluripotent stem cells: approaches, progress and challenges.

Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the production of blood cells for clinical application. In two decades, almost all types of blood cells can be successfully generated from hPSCs through various differentiated strategies. Meanwhile, with a deeper understanding of hematopoiesis, higher efficiency of generating progenitors and precursors of blood cells from hPSCs is achieved. However, how to generate large-scale mature functional cells from hPSCs for clinical use is still difficult. In this review, we summarized recent approaches that generated both hematopoietic stem cells and mature lineage cells from hPSCs, and remarked their efficiency and mechanisms in producing mature functional cells. We also discussed the major challenges in hPSC-derived products of blood cells and provided some potential solutions. Our review summarized efficient, simple, and defined methodologies for developing good manufacturing practice standards for hPSC-derived blood cells, which will facilitate the translation of these products into the clinic.

Comparison of holmium laser enucleation and transurethral resection of prostate in benign prostatic hyperplasia: a systematic review and meta-analysis.

Transurethral resection of the prostate (TURP) is the gold-standard classical method for the treatment of benign prostatic hyperplasia (BPH). In minimally invasive surgery, holmium laser enucleation of the prostate (HoLEP) is considered an alternative option. In this systematic review and meta-analysis, we aimed to comprehensively evaluate the advantages and disadvantages of TURP and HoLEP the treating BPH. We comprehensively searched PubMed, Cochrane Library, EMBASE, and Web of Science databases for all randomized controlled trials published before 1 December 2022 comparing HoLEP and TURP. The study protocol is registered on INPLASY (DOI: 10.37766/inplasy2023.5.0065). Compared with TURP, HoLEP required longer operation time but shorter catheter duration, hospital stay, and bladder irrigation time, as well as less postoperative irrigation. With HoLEP, maximum urinary flow rate at 12 and 24 months after surgery; post-void residual volume at 1, 6, and 12 months; and International Prostate Symptom Score at 12 months after surgery were superior to those with TURP. HoLEP was associated with significantly lower risk of hyponatremia, blood transfusion, and urethral stricture but greater risk of postoperative dysuria. Compared with TURP, HoLEP had better curative efficacy at 6, 12, and 24 months after operation and lower incidence of adverse events in patients with BPH.

Predicting Overall Survival with Deep Learning from 18F-FDG PET-CT Images in Patients with Hepatocellular Carcinoma before Liver Transplantation.

Positron emission tomography and computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET-CT) were used to predict outcomes after liver transplantation in patients with hepatocellular carcinoma (HCC). However, few approaches for prediction based on 18F-FDG PET-CT images that leverage automatic liver segmentation and deep learning were proposed. This study evaluated the performance of deep learning from 18F-FDG PET-CT images to predict overall survival in HCC patients before liver transplantation (LT). We retrospectively included 304 patients with HCC who underwent 18F-FDG PET/CT before LT between January 2010 and December 2016. The hepatic areas of 273 of the patients were segmented by software, while the other 31 were delineated manually. We analyzed the predictive value of the deep learning model from both FDG PET/CT images and CT images alone. The results of the developed prognostic model were obtained by combining FDG PET-CT images and combining FDG CT images (0.807 AUC vs. 0.743 AUC). The model based on FDG PET-CT images achieved somewhat better sensitivity than the model based on CT images alone (0.571 SEN vs. 0.432 SEN). Automatic liver segmentation from 18F-FDG PET-CT images is feasible and can be utilized to train deep-learning models. The proposed predictive tool can effectively determine prognosis (i.e., overall survival) and, thereby, select an optimal candidate of LT for patients with HCC.

ALDH2 gene rs671 G > a polymorphism and the risk of colorectal cancer: A hospital-based study.

BACKGROUND: The susceptibility to some cancers is linked to genetic factors, such as aldehyde dehydrogenase 2 (ALDH2) polymorphisms. The relationship between ALDH2 rs671 and colorectal cancer (CRC) is not clear in Hakka population. METHODS: Between October 2015 and December 2020, a total of 178 CRC patients and 261 controls were recruited. ALDH2 rs671 was genotyped in these subjects, medical records (smoking history, drinking history and blood cell parameters) were collected, and the relationship between these information and CRC was analyzed. RESULTS: The proportion of the ALDH2 rs671 G/G, G/A, and A/A genotype was 48.3%, 44.4%, and 7.3% in patients; 62.1%, 34.1%, and 3.8% in controls, respectively. The difference of ALDH2 genotypes distribution between cases and controls was statistically significant (p = 0.011). The higher percentage of smokers and alcoholics, higher level of neutrophil to lymphocyte ratio (NLR), platelet count, and platelet to lymphocyte ratio (PLR), and lower level of lymphocyte count, lymphocyte to monocyte ratio (LMR), and mean hemoglobin concentration were observed in patients. Logistic regression analysis indicated that ALDH2 rs671 G/A genotype (G/A vs. G/G) (adjusted OR 1.801, 95% CI 1.160-2.794, p = 0.009) and A/A genotype (A/A vs. G/G) (adjusted OR 2.630, 95% CI 1.041-6.645, p = 0.041) in the co-dominant model, while G/A + A/A genotypes (G/A + A/A vs. G/G) (adjusted OR 1.883, 95% CI 1.230-2.881, p = 0.004) in the dominant model were risk factors for CRC. CONCLUSIONS: Individuals carrying ALDH2 rs671 A allele (G/A, A/A genotypes) may be at increased risk of colorectal cancer.

Study on the Effect of Different Endoscopic Auxiliary Treatment of Gastric Mucosal Microtumor.

Objective: To explore the effect of endoscopy in the treatment of gastric mucosal microtumors. Methods: A total of 229 patients with gastric mucosal microtumors were treated in our hospital from January 2016 to December 2021. All patients were divided into three groups group A, group B, and group C. Group A was treated with a transparent cap combined with circle-assisted endoscopic resection, group B with ligator combined with circle-assisted endoscopic resection, and group C with endoscopic mucosal tumor resection. The effects of the three groups were observed. Results: There were 47 patients in group A, 17 males, and 30 females, aged 36-69 years, with an average age of 55.6 ± 9.2 years. There were 54 patients in group B, 18 males, and 36 females, aged 38-72 years, with an average age of 57.6 ± 7.7 years. There were 128 patients in group C, 29 males, and 99 females, aged 33-78 years, with an average age of 55.6 ± 8.4 years. There is no significant difference in age and sex between group A, group B, and group C (P > 0.05). The incidence of postoperative complications in group B (66.7%) was significantly higher than that in group A (57.4%) and group C (53.9%) (all P < 0.05). The incidence of postoperative complications in group A (57.4%) was higher than that in group C (53.9%), and the difference was statistically significant (P < 0.05). Conclusion: Endoscopic mucosal resection and ligation combined with circle-assisted endoscopic resection are effective and safe in the treatment of gastric mucosal microtumors, but it needs to be combined with targeted nursing measures. The transparent cap combined with ring-assisted endoscopic resection has a significant effect on the treatment of gastric mucosal micromasses, reducing operative complications.

LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization.

AIMS: Metabolic switching during heart development contributes to postnatal cardiomyocyte (CM) cell cycle exit and loss of regenerative capacity in the mammalian heart. Metabolic control has potential for developing effective CM proliferation strategies. We sought to determine whether lactate dehydrogenase A (LDHA) regulated CM proliferation by inducing metabolic reprogramming. METHODS AND RESULTS: LDHA expression was high in P1 hearts and significantly decreased during postnatal heart development. CM-specific LDHA knockout mice were generated using CRISPR/Cas9 technology. CM-specific LDHA knockout inhibited CM proliferation, leading to worse cardiac function and a lower survival rate in the neonatal apical resection model. In contrast, CM-specific overexpression of LDHA promoted CM proliferation and cardiac repair post-MI. The α-MHC-H2B-mCh/CAG-eGFP-anillin system was used to confirm the proliferative effect triggered by LDHA on P7 CMs and adult hearts. Metabolomics, proteomics and Co-IP experiments indicated that LDHA-mediated succinyl coenzyme A reduction inhibited succinylation-dependent ubiquitination of thioredoxin reductase 1 (Txnrd1), which alleviated ROS and thereby promoted CM proliferation. In addition, flow cytometry and western blotting showed that LDHA-driven lactate production created a beneficial cardiac regenerative microenvironment by inducing M2 macrophage polarization. CONCLUSIONS: LDHA-mediated metabolic reprogramming promoted CM proliferation by alleviating ROS and inducing M2 macrophage polarization, indicating that LDHA might be an effective target for promoting cardiac repair post-MI.

Dissecting the process of human neutrophil lineage determination by using alpha-lipoic acid inducing neutrophil deficiency model.

Granulocyte-monocyte progenitors (GMPs) differentiate into both neutrophils and monocytes. Recently, uni-potential neutrophil progenitors have been identified both in mice and humans using an array of surface markers. However, how human GMPs commit to neutrophil progenitors and the regulatory mechanisms of fate determination remain incompletely understood. In the present study, we established a human neutrophil deficiency model using the small molecule alpha-lipoic acid. Using this neutrophil deficiency model, we determined that the neutrophil progenitor commitment process from CD371+ CD115- GMPs defined by CD34 and CD15 and discovered that critical signals generated by RNA splicing and rRNA biogenesis regulate the process of early commitment for human early neutrophil progenitors derived from CD371+ CD115- GMPs. These processes were elucidated by single-cell RNA sequencing both in vitro and in vivo derived cells. Sequentially, we identified that the transcription factor ELK1 is essential for human neutrophil lineage commitment using the alpha-lipoic acid (ALA)-inducing neutrophil deficiency model. Finally, we also revealed differential roles for long-ELK1 and short-ELK1, balanced by SF3B1, in the commitment process of neutrophil progenitors. Taken together, we discovered a novel function of ALA in regulating neutrophil lineage specification and identified that the SF3B1-ELK axis regulates the commitment of human neutrophil progenitors from CD371+ CD115- GMPs.

CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output.

Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.