Genetic adaptation of skin pigmentation in highland Tibetans.

Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.

Inhibition of circular JUN prevents the proliferation and invasion of glioblastoma via miR-3064-IGFBP5 axis.

Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumours, characterized by rapid progression and limited treatment options. This study investigated the regulatory roles of circular RNA circJUN, and its functional interaction with microRNA miR-3064 in GBM pathogenesis. We employed bioinformatic analyses and clinical sample validation to identify circJUN as a potential target in GBM. Subsequently, we engineered GBM cell lines with stable circJUN knockout or overexpression, and transfected them with miR-3064 mimic/inhibitor or IGFBP5 small interfering RNA (siRNA)/expression vector to elucidate the molecular mechanisms governing GBM proliferation and invasion. To investigate the in vivo effects, xenograft tumour models were established in nude mice using engineered cells to assess the roles of circJUN in tumour growth regulation. Our analyses revealed significant overexpression of circJUN in GBM tissues compared to healthy controls, which strongly correlated with poor patient prognosis. In vitro and in vivo experiments demonstrated that circJUN overexpression could enhance GBM cell proliferation and invasion. Mechanistic investigations uncovered EIF4A3 as an interacting factor of circJUN which promotes circJUN expression, and circJUN modulates miR-3064 activity to regulate the malignancy of GBM cells. Furthermore, we identified IGFBP5, a crucial regulator of cell growth, as a direct target of miR-3064, thereby establishing an additional layer of control over GBM proliferation and invasion. Our study unveils a complex regulatory network involving circJUN, miR-3064 and IGFBP5 in GBM pathogenesis, underscoring their potential as novel therapeutic targets for improving patient outcomes. Our findings not only contribute to the understanding of GBM biology but also pave the way for innovative therapeutic approaches in the management of this malignancy.

Soybean ZINC FINGER PROTEIN03 targets two SUPEROXIDE DISMUTASE1s and confers resistance to Phytophthora sojae.

Phytophthora sojae causes Phytophthora root and stem rot disease of soybean (Glycine max), leading to huge annual yield loss worldwide, but resistance to Phytophthora sojae (Rps) genes remains elusive. Soybean cultivar "Yudou 29" is resistant to P. sojae strain PsMC1, and this study aimed to clone, identify, and characterize the Rps gene in Yudou 29 (RpsYD29) and clarify its functional mechanism. We map-based cloned RpsYD29 (ZINC FINGER PROTEIN03, GmZFP03) using the families of a cross between Yudou 29 and a P. sojae-susceptible soybean cultivar "Jikedou 2". P. sojae resistance of GmZFP03 was functionally validated by stable soybean genetic transformation and allele-phenotype association analysis. GmZFP03 was identified as a C2H2-type zinc finger protein transcription factor, showing 4 amino acid residue polymorphisms (V79F, G122-, G123-, and D125V) and remarkably different expression patterns between resistant and susceptible soybeans. Notably boosted activity and gene expression of superoxide dismutase (SOD) in resistant-type GmZFP03-expressed transgenic soybean, substantial enhancement of P. sojae resistance of wild-type soybean by exogenous SOD treatment, and GmZFP03 binding to and activation of 2 SOD1 (Glyma.03g242900 and Glyma.19g240400) promoters demonstrated the involvement of SOD1s in GmZFP03-mediated resistance to P. sojae strain PsMC1. Thus, this study cloned the soybean P. sojae-resistant GmZFP03, the product of which specifically targets 2 SOD1 promoters. GmZFP03 can be directly used for precise P. sojae-resistance soybean breeding.

Quantitative genomics-enabled selection for simultaneous improvement of lint yield and seed traits in cotton (Gossypium hirsutum L.).

KEY MESSAGE: A Bayesian linkage disequilibrium-based multiple-locus mixed model identified QTLs for fibre, seed and oil traits and predicted breeding worthiness of test lines, enabling their simultaneous improvement in cotton. Improving cotton seed and oil yields has become increasingly important while continuing to breed for higher lint yield. In this study, a novel Bayesian linkage disequilibrium-based multiple-locus mixed model was developed for QTL identification and genomic prediction (GP). A multi-parent population consisting of 256 recombinant inbred lines, derived from four elite cultivars with distinct combinations of traits, was used in the analysis of QTLs for lint percentage, seed index, lint index and seed oil content and their interrelations. All four traits were moderately heritable and correlated but with no large influence of genotype × environment interactions across multiple seasons. Seven to ten major QTLs were identified for each trait with many being adjacent or overlapping for different trait pairs. A fivefold cross-validation of the model indicated prediction accuracies of 0.46-0.62. GP results based on any two-season phenotypes were strongly correlated with phenotypic means of a pooled analysis of three-season experiments (r = 0.83-0.92). When used for selection of improvement in lint, seed and oil yields, GP captured 40-100% of individuals with comparable lint yields of those selected based on the three-season phenotypic results. Thus, this quantitative genomics-enabled approach can not only decipher the genomic variation underlying lint, seed and seed oil traits and their interrelations, but can provide predictions for their simultaneous improvement. We discuss future breeding strategies in cotton that will enhance the entire value of the crop, not just its fibre.

M1 macrophage-derived exosomes inhibit cardiomyocyte proliferation through delivering miR-155.

BACKGROUND: M1 macrophages are closely associated with cardiac injury after myocardial infarction (MI). Increasing evidence shows that exosomes play a key role in pathophysiological regulation after MI, but the role of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration remains unclear. In this study, we explored the impact of M1 macrophage-derived exosomes on cardiomyocytes regeneration in vitro and in vivo. METHODS: M0 macrophages were induced to differentiate into M1 macrophages with GM-CSF (50 ng/mL) and IFN-γ (20 ng/mL). Then M1-Exos were isolated and co-incubated with cardiomyocytes. Cardiomyocyte proliferation was detected by pH3 or ki67 staining. Quantitative real-time PCR (qPCR) was used to test the level of miR-155 in macrophages, macrophage-derived exosomes and exosome-treated cardiomyocytes. MI model was constructed and LV-miR-155 was injected around the infarct area, the proliferation of cardiomyocytes was counted by pH3 or ki67 staining. The downstream gene and pathway of miR-155 were predicted and verified by dual-luciferase reporter gene assay, qPCR and immunoblotting analysis. IL-6 (50 ng/mL) was added to cardiomyocytes transfected with miR-155 mimics, and the proliferation of cardiomyocytes was calculated by immunofluorescence. The protein expressions of IL-6R, p-JAK2 and p-STAT3 were detected by Western blot. RESULTS: The results showed that M1-Exos suppressed cardiomyocytes proliferation. Meanwhile, miR-155 was highly expressed in M1-Exos and transferred to cardiomyocytes. miR-155 inhibited the proliferation of cardiomyocytes and antagonized the pro-proliferation effect of interleukin 6 (IL-6). Furthermore, miR-155 targeted gene IL-6 receptor (IL-6R) and inhibited the Janus kinase 2(JAK)/Signal transducer and activator of transcription (STAT3) signaling pathway. CONCLUSION: M1-Exos inhibited cardiomyocyte proliferation by delivering miR-155 and inhibiting the IL-6R/JAK/STAT3 signaling pathway. This study provided new insight and potential treatment strategy for the regulation of myocardial regeneration and cardiac repair by macrophages.

Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau.

BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

GhWRKY41 forms a positive feedback regulation loop and increases cotton defence response against Verticillium dahliae by regulating phenylpropanoid metabolism.

Despite the established significance of WRKY proteins and phenylpropanoid metabolism in plant immunity, how WRKY proteins modulate aspects of the phenylpropanoid pathway remains undetermined. To understand better the role of WRKY proteins in plant defence, we identified a cotton (Gossypium hirsutum) protein, GhWRKY41, that is, universally and rapidly induced in three disease-resistant cotton cultivars following inoculation with the plant pathogenic fungus, Verticillium dahliae. We show that overexpression of GhWRKY41 in transgenic cotton and Arabidopsis enhances resistance to V. dahliae, while knock-down increases cotton more susceptibility to the fungus. GhWRKY41 physically interacts with itself and directly activates its own transcription. A genome-wide chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), in combination with RNA sequencing (RNA-seq) analyses, revealed that 43.1% of GhWRKY41-binding genes were up-regulated in cotton upon inoculation with V. dahliae, including several phenylpropanoid metabolism master switches, receptor kinases, and disease resistance-related proteins. We also show that GhWRKY41 homodimer directly activates the expression of GhC4H and Gh4CL, thereby modulating the accumulation of lignin and flavonoids. This finding expands our understanding of WRKY-WRKY protein interactions and provides important insights into the regulation of the phenylpropanoid pathway in plant immune responses by a WRKY protein.

Identification of two novel rice S genes through combination of association and transcription analyses with gene-editing technology.

Traditional rice blast resistance breeding largely depends on utilizing typical resistance (R) genes. However, the lack of durable R genes has prompted rice breeders to find new resistance resources. Susceptibility (S) genes are potential new targets for resistance genetic engineering using genome-editing technologies, but identifying them is still challenging. Here, through the integration of genome-wide association study (GWAS) and transcriptional analysis, we identified two genes, RNG1 and RNG3, whose polymorphisms in 3'-untranslated regions (3'-UTR) affected their expression variations. These polymorphisms could serve as molecular markers to identify rice blast-resistant accessions. Editing the 3'-UTRs using CRISPR/Cas9 technology affected the expression levels of two genes, which were positively associated with rice blast susceptibility. Knocking out either RNG1 or RNG3 in rice enhanced the rice blast and bacterial blight resistance, without impacting critical agronomic traits. RNG1 and RNG3 have two major genotypes in diverse rice germplasms. The frequency of the resistance genotype of these two genes significantly increased from landrace rice to modern cultivars. The obvious selective sweep flanking RNG3 suggested it has been artificially selected in modern rice breeding. These results provide new targets for S gene identification and open avenues for developing novel rice blast-resistant materials.

Enhancement for phonon-mediated superconductivity up to 37 K in few-hydrogen metal-bonded layered magnesium hydride under atmospheric pressure.

The discovery of superconductivity in layered MgB2 has renewed interest in the search for high-temperature conventional superconductors, leading to the synthesis of numerous hydrogen-dominated materials with high critical temperatures (Tc) under high pressures. However, achieving a high-Tc superconductor under ambient pressure remains a challenging goal. In this study, we propose a novel approach to realize a high-temperature superconductor under ambient pressure by introducing a hexagonal H monolayer into the hexagonal close-packed magnesium lattice, resulting in a new and stable few-hydrogen metal-bonded layered magnesium hydride (Mg4)2H1. This compound exhibits superior ductility compared to multi-hydrogen, cuprate, and iron-based superconductors due to its metallic bonding. Our unconventional strategy diverges from the conventional design principles used in hydrogen-dominated covalent high-temperature superconductors. Using anisotropic Migdal-Eliashberg equations, we demonstrate that the stable (Mg4)2H1 compound is a typical phonon-mediated superconductor, characterized by strong electron-phonon coupling and an excellent Tc of 37 K under ambient conditions, comparable to that of MgB2. Our findings not only present a new pathway for exploring high-temperature superconductors but also provide valuable insights for future experimental synthesis endeavors.

Association of Globodera rostochiensis (Nematoda) with Stunted and Chlorotic Potato Plants in Yunnan and Sichuan Provinces in China.

On a global basis, potato cyst nematodes (Globodera spp. Skarbilovich 1959 [Behrens 1975]) are one of the most serious soilborne pathogens in potato (Solanum tuberosum L.) production. In 2019 to 2020, 188 soil samples were taken from rhizosphere soil associated with the roots of stunted and chlorotic potato plants in the main potato-growing areas of Yunnan and Sichuan Provinces of China. Globodera rostochiensis Wollenweber 1923 (Skarbilovich 1959) was recovered from 112 of the samples. Nematode identification was as confirmed by morphometric, light microscopy, electron microscopy, and molecular methodologies. Population densities of G. rostochiensis ranged from 47.0 to 69.0 eggs/g of soil. A BLASTn homology search program was used to compare the sequences of populations of G. rostrochienses from Yunnan and Sichuan Provinces with populations of other Heteroderinae spp. and populations of G. rostochiensis from other nations. Although potato has been grown in China for at least 400 years and the nation produces more potato than any other country, potato cyst nematodes were not reported in China until 2022.

USP10 exacerbates neointima formation by stabilizing Skp2 protein in vascular smooth muscle cells.

The underlying mechanism of neointima formation remains unclear. Ubiquitin-specific peptidase 10 (USP10) is a deubiquitinase that plays a major role in cancer development and progression. However, the function of USP10 in arterial restenosis is unknown. Herein, USP10 expression was detected in mouse arteries and increased after carotid ligation. The inhibition of USP10 exhibited thinner neointima in the model of mouse carotid ligation. In vitro data showed that USP10 deficiency reduced proliferation and migration of rat thoracic aorta smooth muscle cells (A7r5) and human aortic smooth muscle cells (HASMCs). Mechanically, USP10 can bind to Skp2 and stabilize its protein level by removing polyubiquitin on Skp2 in the cytoplasm. The overexpression of Skp2 abrogated cell cycle arrest induced by USP10 inhibition. Overall, the current study demonstrated that USP10 is involved in vascular remodeling by directly promoting VSMC proliferation and migration via stabilization of Skp2 protein expression.

Genomic prediction of cotton fibre quality and yield traits using Bayesian regression methods.

Genomic selection or genomic prediction (GP) has increasingly become an important molecular breeding technology for crop improvement. GP aims to utilise genome-wide marker data to predict genomic breeding value for traits of economic importance. Though GP studies have been widely conducted in various crop species such as wheat and maize, its application in cotton, an essential renewable textile fibre crop, is still significantly underdeveloped. We aim to develop a new GP-based breeding system that can improve the efficiency of our cotton breeding program. This article presents a GP study on cotton fibre quality and yield traits using 1385 breeding lines from the Commonwealth Scientific and Industrial Research Organisation (CSIRO, Australia) cotton breeding program which were genotyped using a high-density SNP chip that generated 12,296 informative SNPs. The aim of this study was twofold: (1) to identify the models and data sources (i.e. genomic and pedigree) that produce the highest prediction accuracies; and (2) to assess the effectiveness of GP as a selection tool in the CSIRO cotton breeding program. The prediction analyses were conducted under various scenarios using different Bayesian predictive models. Results highlighted that the model combining genomic and pedigree information resulted in the best cross validated prediction accuracies: 0.76 for fibre length, 0.65 for fibre strength, and 0.64 for lint yield. Overall, this work represents the largest scale genomic selection studies based on cotton breeding trial data. Prediction accuracies reported in our study indicate the potential of GP as a breeding tool for cotton. The study highlighted the importance of incorporating pedigree and environmental factors in GP models to optimise the prediction performance.

The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction.

PURPOSE: Inflammation associated endothelial cell (EC) dysfunction is key to atherosclerotic disease. Recent studies have demonstrated a protective role of amitriptyline in cardiomyocytes induced by hypoxia/reoxygenation. However, the mechanism by which amitriptyline regulates the inflammatory reaction in ECs remains unknown. Thus, the aim of this study was to investigate whether amitriptyline protects against inflammation in TNF-α-treated ECs. METHODS: HUVECs were incubated with amitriptyline (2.5 µM) or TNF-α (20 ng/ml) for 24 h. EdU, tube formation, transwell, DHE fluorescence staining, and monocyte adhesion assays were performed to investigate endothelial function. Thoracic aortas were isolated from mice, and vascular tone was measured with a wire myograph system. The levels of ICAM-1, VCAM-1, MCP-1, phosphorylated MAPK and NF-κB were detected using western blotting. RESULTS: Amitriptyline increased the phosphorylation of nitric oxide synthase (eNOS) and the release of NO. Amitriptyline significantly inhibited TNF-α-induced increases in ASMase activity and the release of ceramide and downregulated TNF-α-induced expression of proinflammatory proteins, including ICAM-1, VCAM-1, and MCP-1 in ECs, as well as the secretion of sICAM-1 and sVCAM-1. TNF-α treatment obviously increased monocyte adhesion and ROS production and impaired HUVEC proliferation, migration and tube formation, while amitriptyline rescued proliferation, migration, and tube formation and decreased monocyte adhesion and ROS production. Additionally, we demonstrated that amitriptyline suppressed TNF-α-induced MAPK phosphorylation as well as the activity of NF-κB in HUVECs. The results showed that the relaxation response of aortic rings to acetylcholine in the WT-TNF-α group was much lower than that in the WT group, and the sensitivity of aortic rings to acetylcholine in the WT-TNF-α group and WT-AMI-TNF-α group was significantly higher than that in the WT-TNF-α group. CONCLUSION: These results suggest that amitriptyline reduces endothelial inflammation, consequently improving vascular endothelial function. Thus, the identification of amitriptyline as a potential strategy to improve endothelial function is important for preventing vascular diseases.

High hydrogen production in the InSe/MoSi2N4 van der Waals heterostructure for overall water splitting.

Very recently, the septuple-atomic-layer MoSi2N4 has been successfully synthesized by a chemical vapor deposition method. However, pristine MoSi2N4 exhibits some shortcomings, including poor visible-light harvesting capability and a low separation rate of photo-excited electron-hole pairs, when it is applied in water splitting to produce hydrogen. Fortunately, we find that MoSi2N4 can be considered as a good co-catalyst to be stacked with InSe forming an efficient heterostructure photocatalyst. Here, the electronic and photocatalytic properties of the two-dimensional (2D) InSe/MoSi2N4 heterostructure have been systematically investigated by density functional theory for the first time. The results demonstrate that 2D InSe/MoSi2N4 has a type-II band alignment with a favourable direct bandgap of 1.61 eV and exhibits suitable band edge positions for overall water splitting. Particularly, 2D InSe/MoSi2N4 has high electron mobility (104 cm2 V-1 s-1) and shows a noticeable optical absorption coefficient (105 cm-1) in the visible-light region of the solar spectrum. These brilliant properties declare that 2D InSe/MoSi2N4 is a potential photocatalyst for overall water splitting.

Opposite Beet Cyst Nematode Infection Phenotypes of Transgenic Arabidopsis Between Overexpressing GmSNAP18 and AtSNAP2 and Between Overexpressing GmSHMT08 and AtSHMT4.

The rhg1-a GmSNAP18 (an α-SNAP) and Rhg4 GmSHMT08 are two major cloned genes conferring soybean cyst nematode resistance in Peking-type soybeans, but the application of α-SNAPs and SHMTs in cyst nematode management remains elusive. In this study, GmSNAP18 and GmSHMT08, together with their orthologs in Arabidopsis, AtSNAP2 (an α-SNAP) and AtSHMT4, were individually transformed into Arabidopsis Col-0 to generate the transgenic lines, and the growth of transgenic plants, beet cyst nematode (BCN) infection phenotypes, and AtSNAP2, AtSHMT4, and AtPR1 expression patterns were analyzed using Arabidopsis-BCN compatible interaction system, in addition with protein-protein interaction assay. Pulldown and BiFC assays revealed that GmSNAP18 and GmSHMT08 interacted with AtSHMT4 and AtSNAP2, respectively. Plant root growth was not impacted by overexpression of GmSNAP18 and AtSNAP2. However, overexpression of GmSHMT08 and AtSHMT4 both increased plant height, additionally, overexpression of GmSHMT08 decreased rosette leaf size. Overexpression of GmSNAP18 and GmSHMT08 both suppressed AtPR1 expression and significantly enhanced BCN susceptibility, while overexpression of AtSNAP2 and AtSHMT4 both substantially boosted AtPR1 expression and remarkably enhanced BCN resistance, in transgenic Arabidopsis. Overexpression of GmSNAP18 reduced, while overexpression of AtSNAP2 unaltered AtSHMT4 expression. Overexpression of GmSHMT08 and AtSHMT4 both suppressed AtSNAP2 expression in transgenic Arabidopsis. Thus, different expression patterns of AtPR1 and AtSHMT4 are likely associated with opposite BCN infection phenotypes of Arabidopsis between overexpressing GmSNAP18 and AtSNAP2, and between overexpressing GmSHMT08 and AtSHMT4; and boosted AtPR1 expression are required for enhanced BCN resistance in Arabidopsis. All these results establish a basis for extension of α-SNAPs and SHMTs in cyst nematode management.

Breeding a Soybean Cultivar Heinong 531 with Peking-Type Cyst Nematode Resistance, Enhanced Yield, and High Seed-Oil Contents.

Soybean cyst nematode (SCN) is a destructive threat to soybean production. It is economically important to develop a new SCN-resistant soybean cultivar with high yield and other good agronomic traits. In this study, a yellow-seed-coated and yellow-hilum-pigmented cultivar Heinong 531 belonging to maturity group I was developed by a pedigree breeding method through a test-cross between a female parental SCN-resistant soybean cultivar Pengdou 158 and a male parental line F1 (high-yield but SCN-susceptible Hefeng 55 × SCN-resistant Kangxian 12). Heinong 531 was evaluated for SCN resistance in both SCN-infested field and autoclaved soil inoculated with hatched second-stage juveniles of SCN HG Type 0. The results indicated that SCN development at all stages in Heinong 531 was suppressed and the female index was only 1.6 to 5.6%. Heinong 531 as well as Pengdou 158 and Kangxian 12 were identified as carrying the Peking-type resistance with both rhg1-a GmSNAP18 and Rhg4 GmSHMT08 genes. In the 2-year regional trials, the average yield of Heinong 531 reached 2805.0 kg/ha, and the 1-year production trial demonstrated an average yield of 2,751.5 kg/ha with yield increase of >12.0% when compared with the local cultivars. The average seed-fat (oil) contents of Heinong 531 reached up to 22.3%. The Peking-type SCN-resistant Heilong 531 with enhanced yield and high seed-oil contents was released in China in June 2021 with the certified number of 'Heishendou 20210004'. These agronomic traits make Heinong 531 a good prospect in a wide attempt to control SCN in the main soybean-producing areas of Northeast China.

Ubiquitin-specific protease 2 regulates Ang â ¡-induced cardiac fibroblasts activation by up-regulating cyclin D1 and stabilizing ß-catenin in vitro.

Cardiac fibrosis, featuring abnormally elevated extracellular matrix accumulation, decreases tissue compliance, impairs cardiac function and accelerates heart failure. Mounting evidence suggests that the ubiquitin proteasome pathway is involved in cardiac fibrosis. In the present study, ubiquitin-specific protease 2 (USP2) was identified as a novel therapeutic target in cardiac fibrosis. Indeed, USP2 expression was increased in angiotensin II-induced primary cardiac fibroblasts (CFs) from neonatal rats. In addition, USP2 inhibition suppressed CFs proliferation, collagen synthesis and cell cycle progression. Furthermore, USP2 interacted with ß-catenin, thereby regulating its deubiquitination and stabilization in CFs. To sum up, these findings revealed that USP2 has a therapeutic potential for the treatment of cardiac fibrosis.

Prostaglandin E receptor subtype 4 protects against diabetic cardiomyopathy by modulating cardiac fatty acid metabolism via FOXO1/CD36 signalling.

BACKGROUND: Cardiac fatty acid metabolism is essential for maintaining normal cardiac function at baseline and in response to various disease stress, like diabetes. EP4 is widely expressed in cardiomyocytes and has been demonstrated to play a role in cardio function. However, its function in regulating cardiac fatty acid metabolism is remained unknown. METHODS: Mice were fed with standard chow or high-fat for eight weeks. The effects of EP4 deficiency on cardiac function, cardiomyocytes hypertrophy and myocardial fibrosis were studied. The possible regulatory mechanisms were further investigated. RESULTS: EP4-/- mice exhibited concentric hypertrophy and myocardial fibrosis with cardiac energy deprivation due to reduction of fatty acid uptake and inhibition of ATP generation mediated by FOXO1/CD36 signalling. Moreover, pharmacologically activated EP4 alleviated impaired fatty acid transport and insufficient ATP generation in cardiomyocytes. CONCLUSION: EP4 tightly coordinates the rates of cardiac fatty acid uptake and ATP generation via FOXO1/CD36 signalling axis. Our study provides evidences for the link between EP4 and cardiac fatty acid transport and further pointed out that EP4 could be a potential target for modulating fatty acid metabolism and curbing cardiac tissue-specific impairment of function following diabetes.

Combining targeted metabolite analyses and transcriptomics to reveal the specific chemical composition and associated genes in the incompatible soybean variety PI437654 infected with soybean cyst nematode HG1.2.3.5.7.

BACKGROUND: Soybean cyst nematode, Heterodera glycines, is one of the most devastating pathogens of soybean and causes severe annual yield losses worldwide. Different soybean varieties exhibit different responses to H. glycines infection at various levels, such as the genomic, transcriptional, proteomic and metabolomic levels. However, there have not yet been any reports of the differential responses of incompatible and compatible soybean varieties infected with H. glycines based on combined metabolomic and transcriptomic analyses. RESULTS: In this study, the incompatible soybean variety PI437654 and three compatible soybean varieties, Williams 82, Zhonghuang 13 and Hefeng 47, were used to clarify the differences in metabolites and transcriptomics before and after the infection with HG1.2.3.5.7. A local metabolite-calibrated database was used to identify potentially differential metabolites, and the differences in metabolites and metabolic pathways were compared between the incompatible and compatible soybean varieties after inoculation with HG1.2.3.5.7. In total, 37 differential metabolites and 20 KEGG metabolic pathways were identified, which were divided into three categories: metabolites/pathways overlapped in the incompatible and compatible soybeans, and metabolites/pathways specific to either the incompatible or compatible soybean varieties. Twelve differential metabolites were found to be involved in predicted KEGG metabolite pathways. Moreover, 14 specific differential metabolites (such as significantly up-regulated nicotine and down-regulated D-aspartic acid) and their associated KEGG pathways (such as the tropane, piperidine and pyridine alkaloid biosynthesis, alanine, aspartate and glutamate metabolism, sphingolipid metabolism and arginine biosynthesis) were significantly altered and abundantly enriched in the incompatible soybean variety PI437654, and likely played pivotal roles in defending against HG1.2.3.5.7 infection. Three key metabolites (N-acetyltranexamic acid, nicotine and D,L-tryptophan) found to be significantly up-regulated in the incompatible soybean variety PI437654 infected by HG1.2.3.5.7 were classified into two types and used for combined analyses with the transcriptomic expression profiling. Associated genes were predicted, along with the likely corresponding biological processes, cellular components, molecular functions and pathways. CONCLUSIONS: Our results not only identified potential novel metabolites and associated genes involved in the incompatible response of PI437654 to soybean cyst nematode HG1.2.3.5.7, but also provided new insights into the interactions between soybeans and soybean cyst nematodes.

LncRNA-Gm9795 promotes inflammation in non-alcoholic steatohepatitis via NF-[Formula: see text]B/JNK pathway by endoplasmic reticulum stress.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a key stage in leading development of non-alcoholic simple fatty liver (NAFL) into cirrhosis and even liver cancer. This study aimed at exploring the lncRNAs expression profile in NASH and the biological function of a novel LncRNA-gm9795. METHODS: Microarray analysis was performed to compare the expression profiles of lncRNAs in the liver of NASH, NAFLD and normal mice (5 mice for each group). Methionine-choline-deficient Medium (MCD) with Lipopolysaccharide (LPS) or palmitic acid (PA)were used to built NASH cell models. The role and mechanism of LncRNA-gm9795 in NASH were explored by knocking down or over-expressing its expression. RESULTS: A total of 381 lncRNAs were found to be not only highly expressed in NAFLD, but also is going to go even higher in NASH. A novel LncRNA-gm9795 was significantly highly expressed in liver tissues of NASH animal models and NASH cell models. By staining with Nile red, we found that gm9795 did not affect the fat accumulation of NASH. However, gm9795 in NASH cell models significantly promoted the expression of TNF [Formula: see text], IL-6, IL-1[Formula: see text], the important inflammatory mediators in NASH. At the same time, we found that gm9795 upregulated the key molecules in endoplasmic reticulum stress (ERS), while NF-[Formula: see text]B/JNK pathways were also activated. When ERS activator Thapsigargin (TG) was introduced in cells with Ggm9757 si-RNA, NF-[Formula: see text]B and JNK pathways were activated. Conversely, ERS inhibitor Tauroursodeoxycholic acid (TUDCA) inhibited NF-kB and JNK pathways in cells with gm9795 overexpression plasmid. CONCLUSION: LncRNA-gm9795 promotes inflammatory response in NASH through NF-kB and JNK pathways by ERS, which might provide theoretical basis for revealing the pathogenesis of NASH and discovering new therapeutic targets.