Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSIONS: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

Nr4a1 marks a distinctive ILC2 activation subset in the mouse inflammatory lung.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical sources of type 2 cytokines and represent one of the major tissue-resident lymphoid cells in the mouse lung. However, the molecular mechanisms underlying ILC2 activation under challenges are not fully understood. RESULTS: Here, using single-cell transcriptomics, genetic reporters, and gene knockouts, we identify four ILC2 subsets, including two non-activation subsets and two activation subsets, in the mouse acute inflammatory lung. Of note, a distinct activation subset, marked by the transcription factor Nr4a1, paradoxically expresses both tissue-resident memory T cell (Trm), and effector/central memory T cell (Tem/Tcm) signature genes, as well as higher scores of proliferation, activation, and wound healing, all driven by its particular regulons. Furthermore, we demonstrate that the Nr4a1+ILC2s are restrained from activating by the programmed cell death protein-1 (PD-1), which negatively modulates their activation-related regulons. PD-1 deficiency places the non-activation ILC2s in a state that is prone to activation, resulting in Nr4a1+ILC2 differentiation through different activation trajectories. Loss of PD-1 also leads to the expansion of Nr4a1+ILC2s by the increase of their proliferation ability. CONCLUSIONS: The findings show that activated ILC2s are a heterogenous population encompassing distinct subsets that have different propensities, and therefore provide an opportunity to explore PD-1's role in modulating the activity of ILC2s for disease prevention and therapy.

RGCC balances self-renewal and neuronal differentiation of neural stem cells in the developing mammalian neocortex.

During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations.

Association between copy number variation of SERPINA3-1 gene and growth traits in Chinese cattle.

Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (SERPINA3) belongs to the serine protease inhibitor family A subtype, and contains 8 genes from SERPINA3-1 to SERPINA3-8. Although the regulatory effects of these 8 genes have been revealed one by one in recent years, the related effects of SERPINA3-1 gene on cattle growth is still unclear. This study used quantitative Real time PCR (qPCR) to detect the type of copy number variation (CNV) of SERPINA3-1 gene in a total of 542 Chinese cattle, and expression of SERPINA3-1 gene in different tissues of Qinchuan cattles (adult) on mRNA level. Then association analysis was conducted between the detection results and cattle growth traits. The results showed that the Duplication type in SERPINA3-1 gene performed better on the growth traits and the CNV was significantly correlated with multiple growth traits (p < 0.05). In addition, SERPINA3-1 gene has different expression conditions in different tissues, results showed that SERPINA3-1 gene has a low expression in muscle. In conclusion, we speculate that the SERPINA3-1 gene can be used as a molecular marker and the result of this study could be a basic material for candidate functional genes for beef cattle growth and development.

In order to detect the gene expression diversification of the SERPINA3-1 gene, blood samples were collected from five Chinese cattle breeds, we detected related signal and made an associated analyze with cattle growth traits. We determined the copy number variation distribution of the SERPINA3-1 gene in cattle populations and found that the SERPINA3-1 gene has a certain promoting effect on the growth and development of Chinese cattle. For example, Pinan cattle with Duplication type copy number have a better performance on growth traits. This study has enriched the candidate genes of Chinese cattle molecular breeding and provided basic data for Chinese cattle breeding.

VIDAR-Based Road-Surface-Pothole-Detection Method.

This paper presents a VIDAR (a Vision-IMU based detection and ranging method)-based approach to road-surface pothole detection. Most potholes on the road surface are caused by the further erosion of cracks in the road surface, and tires, wheels and bearings of vehicles are damaged to some extent as they pass through the potholes. To ensure the safety and stability of vehicle driving, we propose a VIDAR-based pothole-detection method. The method combines vision with IMU to filter, mark and frame potholes on flat pavements using MSER to calculate the width, length and depth of potholes. By comparing it with the classical method and using the confusion matrix to judge the correctness, recall and accuracy of the method proposed in this paper, it is verified that the method proposed in this paper can improve the accuracy of monocular vision in detecting potholes in road surfaces.

Obstacle Detection Method Based on RSU and Vehicle Camera Fusion.

Road obstacle detection is an important component of intelligent assisted driving technology. Existing obstacle detection methods ignore the important direction of generalized obstacle detection. This paper proposes an obstacle detection method based on the fusion of roadside units and vehicle mounted cameras and illustrates the feasibility of a combined monocular camera inertial measurement unit (IMU) and roadside unit (RSU) detection method. A generalized obstacle detection method based on vision IMU is combined with a roadside unit obstacle detection method based on a background difference method to achieve generalized obstacle classification while reducing the spatial complexity of the detection area. In the generalized obstacle recognition stage, a VIDAR (Vision-IMU based identification and ranging) -based generalized obstacle recognition method is proposed. The problem of the low accuracy of obstacle information acquisition in the driving environment where generalized obstacles exist is solved. For generalized obstacles that cannot be detected by the roadside unit, VIDAR obstacle detection is performed on the target generalized obstacles through the vehicle terminal camera, and the detection result information is transmitted to the roadside device terminal through the UDP (User Data Protocol) protocol to achieve obstacle recognition and pseudo-obstacle removal, thereby reducing the error recognition rate of generalized obstacles. In this paper, pseudo-obstacles, obstacles with a certain height less than the maximum passing height of the vehicle, and obstacles with a height greater than the maximum passing height of the vehicle are defined as generalized obstacles. Pseudo-obstacles refer to non-height objects that appear to be "patches" on the imaging interface obtained by visual sensors and obstacles with a height less than the maximum passing height of the vehicle. VIDAR is a vision-IMU-based detection and ranging method. IMU is used to obtain the distance and pose of the camera movement, and through the inverse perspective transformation, it can calculate the height of the object in the image. The VIDAR-based obstacle detection method, the roadside unit-based obstacle detection method, YOLOv5 (You Only Look Once version 5), and the method proposed in this paper were applied to outdoor comparison experiments. The results show that the accuracy of the method is improved by 2.3%, 17.4%, and 1.8%, respectively, compared with the other four methods. Compared with the roadside unit obstacle detection method, the speed of obstacle detection is improved by 1.1%. The experimental results show that the method can expand the detection range of road vehicles based on the vehicle obstacle detection method and can quickly and effectively eliminate false obstacle information on the road.

Copy number variation of MYLK4 gene and its growth traits of Capra hircus (goat).

Copy number variation (CNV) is a form of genetic variation caused by genome rearrangement, with abnormal fragments ranging from 50 bp to Mb. And, CNV is closely related to disease, growth and reproductive shape of livestock. As a member of myosin light chain kinase (MYLK) family with serine/threonine specificity, MYLK4 belongs to an enzyme encoded by MYLK4 gene. Although MYLK4 is a recognized kinase, its function has yet to be revealed in subsequent studies. This study aims to analyze CNV and genetic effects of MYLK4 gene in goats. We used qPCR to detect CNV of MYLK4 gene in African Nubian goat (n = 32), Guizhou black goat (n = 196) and Guizhou white goat (n = 95), respectively, and correlated CNV data of MYLK4 gene with goat growth traits in Chinese goats. The results showed that the effect of MYLK4 gene CNV on body weight, body length and body height of goats had significantly different (p < 0.05, Q < 0.05), in which CNV showed better growth traits in type of deletion. Therefore, CNV of MYLK4 gene can be used as a molecular marker for assisted selection of goat growth traits, which provides a theoretical basis for the genetic improvement of goat breeds in China.

Radiomics in RayPlus: a Web-Based Tool for Texture Analysis in Medical Images.

Radiomics has been shown to have considerable potential and value in quantifying the tumor phenotype and predicting the treatment response. In most scenarios, the commercial and open-source software programs are available for quantitative analysis in medical images to streamline radiomics research. However, at this stage, most of these programs are local applications and require users to have experience in programming and software engineering, which clinicians usually do not have. Therefore, in this article, a web-based tool was proposed to flexibly support radiomics research workflow tasks. Radiomics in RayPlus requires zero installation, is easy to maintain, and accessible anywhere via any PC or MAC with an Internet connection. The system provides functions including multimodality image import and viewing, ROI definition, feature extraction, and data sharing. As a web application, it appears an effective way to multi-institution and multi-department collaborative radiomics research and moreover, its transparency, flexibility, and portability can greatly accelerate the pace of clinical data analysis.

RayPlus: a Web-Based Platform for Medical Image Processing.

Medical image can provide valuable information for preclinical research, clinical diagnosis, and treatment. As the widespread use of digital medical imaging, many researchers are currently developing medical image processing algorithms and systems in order to accommodate a better result to clinical community, including accurate clinical parameters or processed images from the original images. In this paper, we propose a web-based platform to present and process medical images. By using Internet and novel database technologies, authorized users can easily access to medical images and facilitate their workflows of processing with server-side powerful computing performance without any installation. We implement a series of algorithms of image processing and visualization in the initial version of Rayplus. Integration of our system allows much flexibility and convenience for both research and clinical communities.

Association Analysis to Copy Number Variation (CNV) of Opn4 Gene with Growth Traits of Goats.

Extensive research has been carried out regarding the correlation between the growth traits of livestock and genetic polymorphisms, including single nucleotide polymorphisms and copy number variations (CNV). The purpose of this study was to analyze the CNV and its genetic effects of the Opn4 gene in 284 Guizhou goats (Guizhou black goat: n = 186, Guizhou white goat: n = 98). We used qPCR to detect the CNV of the Opn4 gene in Guizhou goats, and the classification results were correlated with the corresponding individual growth traits by SPSS software. The results showed that the Opn4 gene had a superior effect on growth traits with multiple copy variants in Guizhou black goats, and there was a significant correlation between copy number variation sites and body length traits. Contrary to the former conclusion, in Guizhou white goats, individuals with the Normal copy number type showed superior growth traits and copy number variant sites were significantly associated with body weight traits. Therefore, the CNV of the Opn4 gene can be used as a candidate molecular genetic marker to improve goat growth traits, speeding up the breeding process of goat elite varieties.

A novel SNP of PLAG1 gene and its association with growth traits in Chinese cattle.

Genetic polymorphism has great influences on the improvement of cattle traits. The polymorphism of the same gene family will greatly change the growth traits of cattle, such as the pleomorphic adenoma gene (PLAG) family. Many studies have shown that the PLAG family proteins are the transcription regulators of nuclear protein, which mainly regulates the expression of many important genes in the body. In cattle, single nucleotide polymorphisms (SNPs) within or near the PLAG1 gene is associated with economic traits of height in cattle. Here we investigate a SNPs of bovine PLAG1 in 646 cattle from five breeds. We found three different genotypes by using cleaved amplification polymorphism sequence-tagged sites (CAPs), includes some significant differences in body height, chest circumference and other shapes (P < 0.05), also we found that the TT genotype had no advantage in body shape. These results indicate that the selection of PLAG1 gene could be used to ensure the breeding direction for growth traits of the beef cattle.

DNA methylation status of CRABP2 promoter down-regulates its expression.

As an important epigenetic modification DNA methylation is catalyzed by DNA methylation transferases (DNMTs) and occurs mainly in CpG islands. DNA methylation plays an important role in regulates gene expression, cell differentiation, genetic imprinting and tumor therapy. Retinoic acid-binding proteins (RAC) is vital for the absorption, transport, metabolism and maintenance of homeostasis of retinoic acid, which in turn regulates the differentiation and proliferation of cells by regulating the transcription of many target genes, therefore, these proteins influence differentiation and proliferation of adipocytes and muscle fibroblasts. Thus, cellular retinoic acid binding protein 2 (CRABP2) may be a candidate gene which affects beef quality, yield and fat deposition. The aim of this study was to evaluate the expression and the methylation pattern on the differentially methylated region (DMR) of the promoter of CRABP2. The DNA methylation pattern was tested by bisulfite sequencing polymerase chain reaction (BSP), the quantitative real-time PCR (qPCR) was used to analysis the expression of CRABP2 gene. The results showed that the DNA methylation level was higher in purebred cattle breed than that in hybrid cattle breeds which was negative correlation with the expression of the gen. These results indicate that the methylation status of the CRABP2 DMR can regulate mRNA expression. What's more, there are different methylation and expression patterns in different breeds and tissues which may influence the phenotype, and the results may be a useful parameter to investigate the function of CRABP2 in muscle and fat developmental in Chinese cattle.