Relationship between arginine methylation and vascular calcification.

In patients on maintenance hemodialysis (MHD), vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD), which is the primary cause of death in chronic kidney disease (CKD). The main component of VC in CKD is the vascular smooth muscle cells (VSMCs). VC is an ordered, dynamic activity. Under the stresses of oxidative stress and calcium-­phosphorus imbalance, VSMCs undergo osteogenic phenotypic transdifferentiation, which promotes the formation of VC. In addition to traditional epigenetics like RNA and DNA control, post-translational modifications have been discovered to be involved in the regulation of VC in recent years. It has been reported that the process of osteoblast differentiation is impacted by catalytic histone or non-histone arginine methylation. Its function in the osteogenic process is comparable to that of VC. Thus, we propose that arginine methylation regulates VC via many signaling pathways, including as NF-B, WNT, AKT/PI3K, TGF-/BMP/SMAD, and IL-6/STAT3. It might also regulate the VC-related calcification regulatory factors, oxidative stress, and endoplasmic reticulum stress. Consequently, we propose that arginine methylation regulates the calcification of the arteries and outline the regulatory mechanisms involved.

Contribution of elovl5a to Docosahexaenoic Acid (DHA) Synthesis at the Transcriptional Regulation Level in Common Carp, Cyprinus carpio.

Docosahexaenoic acid (DHA) is an essential nutrient for humans and plays a critical role in human development and health. Freshwater fish, such as the common carp (Cyprinus carpio), have a certain degree of DHA biosynthesis ability and could be a supplemental source of human DHA needs. The elongase of very-long-chain fatty acid 5 (Elovl5) is an important enzyme affecting polyunsaturated fatty acid (PUFA) biosynthesis. However, the function and regulatory mechanism of the elovl5 gene related to DHA synthesis in freshwater fish is not clear yet. Previous studies have found that there are two copies of the elovl5 gene, elovl5a and elovl5b, which have different functions. Our research group found significant DHA content differences among individuals in Yellow River carp (Cyprinus carpio var.), and four candidate genes were found to be related to DHA synthesis through screening. In this study, the expression level of elovl5a is decreased in the high-DHA group compared to the low-DHA group, which indicated the down-regulation of elovl5a in the DHA synthesis pathways of Yellow River carp. In addition, using a dual-luciferase reporter gene assay, we found that by targeting the 3'UTR region of elovl5a, miR-26a-5p could regulate DHA synthesis in common carp. After CRISPR/Cas9 disruption of elovl5a, the DHA content in the disrupted group was significantly higher than in the wildtype group; meanwhile, the expression level of elovl5a in the disrupted group was significantly reduced compared with the wildtype group. These results suggest that elovl5a may be down-regulating DHA synthesis in Yellow River carp. This study could provide useful information for future research on the genes and pathways that affect DHA synthesis.

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease.

Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An in vivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an in vitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with ß-glycerophosphate (ß-GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and ß-GP-induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α-SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The in vitro results also demonstrated that ß-GP-induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3-MA blocked HDAC2's protective effect on osteogenic differentiation in ß-GP-treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.

PRMT3 methylates HIF-1α to enhance the vascular calcification induced by chronic kidney disease.

BACKGROUND: Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD. METHODS: A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to ß-glycerophosphate (ß-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model. RESULTS: PRMT3 was upregulated in VSMCs of medial artery of CKD mice and ß-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the ß-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs. CONCLUSION: The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.

LMCD1 is involved in tubulointerstitial inflammation in the early phase of renal fibrosis by promoting NFATc1-mediated NLRP3 activation.

Prolonged renal inflammation contributes to fibrosis, which may eventually lead to irreversible chronic kidney disease. Our previous work demonstrated that LIM and cysteine-rich domain 1 (LMCD1) are associated with renal interstitial fibrosis in a 21-day unilateral ureteral obstruction (21UUO) mouse model. Interestingly, based on the gene expression omnibus database, we found that LMCD1 is enhanced in the mouse kidney as early as 5, 7, and 10 days following unilateral ureteral obstruction (UUO), suggesting that LMCD1 may exert its function in an earlier phase. To validate this conjecture, a 7UUO mouse model and a tumor necrosis factor-α (TNF-α)-stimulated HK-2 cell model were established, followed by injection of adenovirus vectors carrying short hairpin RNA targeting LMCD1. LMCD1 silencing ameliorated renal collagen deposition and reduced the expression of profibrotic factors in the 7UUO model. LMCD1 silencing alleviated tubulointerstitial inflammation by mitigating F4/80+ cell infiltration, monocyte chemoattractant protein-1 release and nuclear factor-κB activation. In addition, LMCD1 silencing suppressed NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and nuclear factor of activated T cells 1 (NFATc1) nuclear translocation. Consistent results were obtained in TNF-α-stimulated HK-2 cells in vitro. Mechanistically, the transcriptional coactivator LMCD1 cooperates with the transcription factor NFATc1 to increase NLRP3 expression. Collectively, these findings suggest that LMCD1 participates in tubulointerstitial inflammation via an LMCD1-NFATc1/NLRP3 mechanism. LMCD1 may therefore become a potential target for the control of renal inflammation and fibrosis.

Transcriptome Analysis Reveals Molecular Underpinnings of Common Carp (Cyprinus carpio) Under Hypoxia Stress.

As an essential environmental factor that affects the economic benefits of aquaculture, hypoxia is one of the urgent problems to be solved in the aquaculture fish breeding industry. Common carp (Cyprinus carpio) is a critical economic fish in China, and at present, there are many breeding strains of common carp with different character advantages in China, including Hebao red carp (C. carpio var wuyuanesis) and Songpu mirror carp (C. carpio var specularis). Even if the environmental adaptation of common carp is generally strong, the genetic background of hypoxia tolerance in different strains of common carp is unclear yet. This study tested the hypoxia tolerance of Songpu minor carp, Hebao red carp, and their hybrid F1 population by an acute hypoxia treatment. Muscle and liver tissues were used for transcriptome sequencing analysis to identify the key factors for hypoxia tolerance and explore the potential genetic mechanism for breeding high hypoxia tolerance in common carp. The comparative transcriptomic analysis revealed abundant hypoxia response-related genes and their differential regulation mechanism in these two tissues of different common carp strains under acute hypoxia, including immune response, cellular stress response, HIFs (hypoxia-inducible factors), MAP kinase, iron ion binding, and heme binding. Our findings will facilitate future investigation on the hypoxia response mechanism and provide a solid theoretical basis for breeding projects in common carp.

Bibliometric analysis of the global literature productivity of adult-onset Still's disease (2011-2020).

Adult-onset Still's disease is a nonfamilial, or sporadic, systemic autoinflammatory disorder accompanied by peak fever ≥ 39 °C, arthralgia or arthritis, skin rashes, leukocytosis (≥ 10,000 cells/mm3) with neutrophils ≥ 80%, and other clinical symptoms. This study aimed to analyze the quantity and quality of publications, and to exhibit the current global status and trend of adult-onset Still's disease research. Searched with the search term 'Adult onset Still disease' on the Web of Science for time limited to 2011-2020. Original articles and reviews were selected. A total of 537 articles were retrieved from 44 countries, of which 13 met the criteria of major active countries. High-income countries contributed 378 articles (70.39%). The number of articles annually increased significantly in the 10-year period (P < 0.001). China (n = 90, 16.76%), Japan (n = 79, 14.71%), Italy (n = 59, 10.99%), the United States (n = 52, 9.68%) and South Korea (n = 45, 8.38%) are the five most productive countries. Adjusted by population, Italy led the top list, followed by South Korea and Israel. According to gross domestic product analysis, Italy ranked first, followed by Portugal and Turkey. A significant correlation was detected between average citations and AAS (P = 0.002), MRC (P < 0.001). From 2011 to 2020, the number of global articles was increasing rapidly. Most papers came from high-income countries. The relationship between the bibliometric and altmetric analyses are basically consistent, therefore the two can prove/complement each other.

Suppression of LMCD1 ameliorates renal fibrosis by blocking the activation of ERK pathway.

Tubulointerstitial fibrosis is a common pathway of chronic kidney disease (CKD) and is closely related to the progression of CKD. LMCD1, acting as an intermediary, has been reported to play a role in cardiac fibrosis. However, its role in renal fibrosis is yet to be deciphered. Based on the GEO database, we found the expression of LMCD1 is increased in kidney tissues of CKD patients and in human proximal tubular epithelial (HK-2) cells treated with transforming growth factor-ß1 (TGF-ß1), suggesting that LMCD1 may be involved in tubulointerstitial fibrosis. Herein, we investigated the role of LMCD1 in mice with unilateral ureteral obstruction (UUO) and in TGF-ß1-stimulated HK-2 cells. In the UUO model, the expression of LMCD1 was upregulated. UUO-induced renal histopathological changes were mitigated by knockdown of LMCD1. LMCD1 silence alleviated renal interstitial fibrosis in UUO mice by decreasing the expression of TGF-ß1, fibronectin, collagen I, and collagen III. LMCD1 deficiency suppressed cell apoptosis in kidney to prevent UUO-triggered renal injury. Furthermore, LMCD1 deficiency blocked the activation of ERK signaling in UUO mice. In vitro, LMCD1 was upregulated in HK-2 cells after TGF-ß1 stimulation. LMCD1 silence abrogated TGF-ß1-mediated upregulation of fibrotic genes. Treatment of HK-2 cells with ERK-specific inhibitor SCH772984 and agonist TPA validated LMCD1 exerted its function via activating ERK signaling. Together, our findings suggest that inhibition of LMCD1 protects against renal interstitial fibrosis by impeding ERK activation.

Temporal coherency of mechanical stimuli modulates tactile form perception.

The human hand can detect both form and texture information of a contact surface. The detection of skin displacement (sustained stimulus) and changes in skin displacement (transient stimulus) are thought to be mediated in different tactile channels; however, tactile form perception may use both types of information. Here, we studied whether both the temporal frequency and the temporal coherency information of tactile stimuli encoded in sensory neurons could be used to recognize the form of contact surfaces. We used the fishbone tactile illusion (FTI), a known tactile phenomenon, as a probe for tactile form perception in humans. This illusion typically occurs with a surface geometry that has a smooth bar and coarse textures in its adjacent areas. When stroking the central bar back and forth with a fingertip, a human observer perceives a hollow surface geometry even though the bar is physically flat. We used a passive high-density pin matrix to extract only the vertical information of the contact surface, suppressing tangential displacement from surface rubbing. Participants in the psychological experiment reported indented surface geometry by tracing over the FTI textures with pin matrices of the different spatial densities (1.0 and 2.0 mm pin intervals). Human participants reported that the relative magnitude of perceived surface indentation steeply decreased when pins in the adjacent areas vibrated in synchrony. To address possible mechanisms for tactile form perception in the FTI, we developed a computational model of sensory neurons to estimate temporal patterns of action potentials from tactile receptive fields. Our computational data suggest that (1) the temporal asynchrony of sensory neuron responses is correlated with the relative magnitude of perceived surface indentation and (2) the spatiotemporal change of displacements in tactile stimuli are correlated with the asynchrony of simulated sensory neuron responses for the fishbone surface patterns. Based on these results, we propose that both the frequency and the asynchrony of temporal activity in sensory neurons could produce tactile form perception.

Carotid intima-media thickness in patients with hyperuricemia: a systematic review and meta-analysis.

OBJECTIVE: Despite the high incidence and mortality of cardiovascular events in hyperuricemia patients, the role of serum uric acid in cardiovascular diseases is still controversial. The aim of this meta-analysis was to explore the difference of carotid intima-media thickness in hyperuricemia and control groups. METHODS: We performed this meta-analysis by searching the PubMed, Cochrane Library, Embase and Web of Science databases up to July 2020. The 95% confidence intervals and standard mean differences were calculated to analyze the differences in carotid intima-media thickness in hyperuricemia groups and control groups. Sensitivity analysis, subgroup analysis and meta-regression were used to explore the sources of heterogeneity. Publication bias was evaluated by funnel plot and Begg's regression test. We used Stata 14.0 software to complete our analyses. RESULTS: A total of 8 articles were included. The results showed that there was a significant increase in carotid intima-media thickness in the hyperuricemia groups compared with the control groups [SMD = 0.264, 95% CI (0.161-0.366), P < 0.001]. Subgroup analyses showed that age, sample size, blood pressure and body mass index were not the source of heterogeneity. Meta-regression enrolled the method of CIMT measurement, location, age, smoking and diabetes mellitus as categorical variables, but none of these factors was found to be significant in the model. The Begg's test value (P = 0.174) was greater than 0.05, indicating there was no publication bias. CONCLUSION: The results showed that carotid intima-media thickness was increased in hyperuricemia patients compared with controls, which indicated that hyperuricemia patients may have a higher risk of cardiovascular diseases.

Does vitamin D improve symptomatic and structural outcomes in knee osteoarthritis? A systematic review and meta-analysis.

OBJECTIVE: To provide evidence on the effects of vitamin D supplementation on knee osteoarthritis (KOA) and new targets for clinical prevention and treatment of KOA. METHOD: The PubMed, Embase, Web of science, Wanfang, CNKI and SinoMed databases were retrieved to investigate the effects of vitamin D supplementation on patients with KOA. The search time was from databases establishment to 15 November 2020. RevMan5.3 software was used for meta-analysis. The results were expressed as standardized mean difference (SMD) with 95% confidence interval (CI) or weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: A total of 1599 patients with osteoarthritis of the knee were included in the study, which involved six articles. The results of the meta-analysis showed that vitamin D supplementation is statistically significant for WOMAC score (SMD = - 0.67, 95% CI - 1.23 to - 0.12) in patients with KOA, including WOMAC pain score (SMD = - 0.32, 95% CI - 0.63 to - 0.02), function score (SMD = - 0.34, 95% CI - 0.60 to - 0.08) and stiffness score (SMD = - 0.13, 95% CI - 0.26 to - 0.01). In subgroup analysis, vitamin D supplementation less than 2000 IU was statistically significant for the reduction of stiffness score (SMD = - 0.22, 95% CI - 0.40 to - 0.04). Vitamin D supplements can reduce synovial fluid volume progression in patients with KOA (SMD = - 0.20, 95% CI - 0.39 to - 0.02). There was no statistical significance in improving tibia cartilage volume (SMD = 0.12, 95% CI - 0.05 to 0.29), joint space width (SMD = - 0.10, 95% CI - 0.26 to 0.05) and bone marrow lesions (SMD = 0.03, 95% CI - 0.26 to 0.31). CONCLUSION: Vitamin D supplements can improve WOMAC pain and function in patients with KOA. But there is a lack of strong evidence that vitamin D supplementation can prevent structural progression in patients with KOA.

HDAC1 potentiates CD4 + T cell activation by inhibiting miR-124 and promoting IRF1 in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease leading to considerable morbidity worldwide, which can be developed from a breakdown in immunological tolerance, resulting in T cell hyperactivation. T cell hyperactivation has been implicated in the tissue damage associated with many diseases. Although many researchers have identified the involvement of T-cell receptor-associated signaling molecules in T-cell activation, the mechanisms underlying this process are yet to be elaborated. In the current study, we set out to reveal a novel transcriptional mechanism required for CD4 + T cell immunoactivity involved in SLE. First of all, miR-124 was experimentally determined to be under-expressed in peripheral blood samples of SLE patients relative to healthy individuals. We further isolated CD4 + T cells from the peripheral blood samples of SLE patients and healthy individuals, and found that miR-124 was poorly expressed in peripheral blood-derived CD4 + T cells of SLE patients. Subsequent experiments demonstrated that re-expression of miR-124 inhibited the immunoactivity of CD4 + T cells from SLE patients, which was achieved through the down-regulation of IRF1 since dual-luciferase reporter gene assay findings indicated that miR-124 could target IRF1. In addition, HDAC1 was found to be enriched at the miR-124 promoter resulting in inhibition of miR-124 expression, thereby promoting the immunoactivity of CD4 + T cells. In conclusion, we identify that as a stimulator of CD4 + T cell immunoactivity, HDAC1 may be implicated in the immunopathology of SLE. The study will open up new avenues to explore future immunotherapy strategies for SLE.

The risk of leukemia in patients with rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: The relationship between rheumatoid arthritis (RA) and the risk of leukemia was still controversial. This study aimed to assess the risk of leukemia in patients with rheumatoid arthritis by systematic review and meta-analysis. METHODS: Relevant studies were identified by searching PubMed, Embase, Cochrane Library, and SinoMed up to December 2019. Random effects model analysis was used to pool standardized incidence ratios (SIRs) and 95% confidence interval. RESULTS: A total of 15 relevant studies that met the criteria were included. Compared with the general population, patients with RA showed an increased risk of leukemia (SIR = 1.51, 95% CI: 1.34-1.70). The statistical heterogeneity was moderate with an I2 of 55.5%. In subgroup analysis, the source of heterogeneity may be due to differences in sample size. Publication bias was not found in the Begg funnel plot and the Egger test. CONCLUSION: Our findings suggested that the risk of leukemia in RA was increased compared with the general population. Key points • This is the first systematic review and meta-analysis to assess the risk of leukemia in RA. • Our study suggested that the risk of leukemia in RA was increased compared with the general population. • This study indicated that the risk of leukemia in RA was higher in non-Asian populations.

Top 100 Cited Articles on Osteoarthritis from 1990 to 2020.

Objectives: The purpose of this study was to identify and analyze the 100 top-cited articles in the field of osteoarthritis (OA) from 1990 to 2020. Methods: We used the Web of Science to retrieve the articles related to OA. Then we selected 100 target articles and manually collected their general information, including article title, author, year of publication, journal, type of article, and the number of citations. Results: The 100 top-cited articles were published in the period from 1990 to 2015. These articles have been cited 66,494 times in total, with the highest being 2382 times, the lowest being 433 times, the median number being 613, and a mean of 664.94 times. The 100 top-cited articles appeared in a total of 35 influential journals. The greatest number of articles in the top of 100 was published in Arthritis and Rheumatism. The authors of these articles came from 18 countries, led by the United States (n = 48), followed by the United Kingdom (n = 15). Among all the institutions, Boston University led the list with 10 articles. The most prevalent type of the study was review (n = 38) and clinical study (n = 38), followed by guideline (n = 12), basic science (n = 10) and other types. Conclusions: This study provided some insights on the literature development and citation of OA in the recent 30 years. Articles published in high-impact journals are more likely to be cited in the field of OA. As recent studies did not have enough time to accumulate the number of citations, the latest articles may not be included in the top 100 cited articles.

Silencing long non-coding RNA NEAT1 attenuates rheumatoid arthritis via the MAPK/ERK signalling pathway by downregulating microRNA-129 and microRNA-204.

The participation of long noncoding RNAs (lncRNAs) and microRNAs (miRs) in the progression of rheumatoid arthritis (RA) is a key area of investigation. The current study aimed to investigate the action of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in fibroblast-like synoviocyte (FLS) proliferation and synovitis in RA. A rat model of RA was established. LncRNA NEAT1 expression in the synovial tissues of patients with RA and FLSs from the RA rat model was determined using RT-qPCR. Next, dual luciferase reporter gene assay was applied to investigate the relationship between miR-129/204 and mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK). A putative binding relationship between miR-204 and lncRNA NEAT1 was evaluated by RIP assay, and miR-129 promoter methylation was determined using MSP. After the expression of lncRNA NEAT1, miR-129 or miR-204 was altered in FLSs, the extent of ERK1/2 phosphorylation was assessed. In addition, FLS synovitis and proliferation were determined by ELISA and EdU assay, respectively. In RA rats, lncRNA NEAT1 was silenced and miR-129/miR-204 was overexpressed to explore their roles in vivo. LncRNA NEAT1 was upregulated, while miR-129 and miR-204 were downregulated in RA synovial tissues and FLSs. MAPK1 was target gene of both miR-129 and miR-204. LncRNA NEAT1 bound to miR-204 and promoted miR-129 promoter methylation. Silencing lncRNA NEAT1 or overexpressing miR-129/miR-204 enhanced miR-129/miR-204 expression, but reduced the extent of ERK1/2 phosphorylation, proliferation of FLSs, and synovitis in RA. Collectively, silencing lncRNA NEAT1 promoted miR-129 and miR-204 to inhibit the MAPK/ERK signalling pathway, reducing FLS synovitis in RA.Abbreviations: ACR: American College of Rheumatology; ELISA: Enzyme-linked immunosorbent assay; ERK: extracellular signal-regulated kinase; FLS: fibroblast-like synoviocyte; GADPH: glyceraldehyde-3-phosphate dehydrogenase; HRP: horseradish peroxidase; IFA: Incomplete Freund's Adjuvant; lncRNAs: long noncoding RNAs; MSP: Methylation-specific PCR; NC: negative control; NEAT1: nuclear paraspeckle assembly transcript 1; OD: optical density; RA: rheumatoid arthritis; RIPA: Radio Immunoprecipitation Assay; RLU: relative light units; RT-qPCR: reverse transcription quantitative polymerase chain reaction; UTR: untranslated region.

Exosomal miRNA-486-5p derived from rheumatoid arthritis fibroblast-like synoviocytes induces osteoblast differentiation through the Tob1/BMP/Smad pathway.

The pathogenesis of rheumatoid arthritis (RA) is related to the inhibition of osteoblast differentiation. Exosomes secreted from RA fibroblast-like synoviocytes (RA-FLSs-exos) are associated with the pathogenesis of RA and microRNAs (miRNAs) being crucial for RA progression. Accordingly, the aim of the present study is to elucidate the effect of RA-FLS-derived exosomes on osteoblast differentiation and further identify exosomal cargos responsible for this effect. RA-FLSs were isolated from a RA patient and osteoblasts from the donor bone. Isolated RA-FLSs-exos were co-cultured with osteoblasts. Osteoblast differentiation was evaluated by ALP quantification assays, Alizarin Red S staining, and determining markers of osteoblast activity (Osx, OC, Col1a1 and Dlx2). Collagen induced arthritis (CIA)-induced mouse models were established. RA-FLSs-exo could be phagocytosed by osteoblasts. Elevating the expression of miR-486-5p in RA-FLSs-exo promoted osteoblast differentiation. miR-486-5p targeted Tob1 and activated the BMP/Smad signaling pathway in osteoblasts. In addition, RA-FLSs-exo containing miR-486-5p facilitated osteoblast differentiation by activating the BMP/Smad signaling pathway and repressing Tob1. Moreover, RA-FLSs-exo containing miR-486-5p alleviated the disease severity of RA by decreasing Tob1 expression in CIA-induced mice. To sum up, RA-FLSs-exo carrying miR-486-5p serve as a promoter for osteoblast differentiation in RA, ultimately highlighting a promising competitive new target for RA treatment.

A Drive to Driven Model of Mapping Intraspecific Interaction Networks.

Community ecology theory suggests that an individual's phenotype is determined by the phenotypes of its coexisting members to the extent at which this process can shape community evolution. Here, we develop a mapping theory to identify interaction quantitative trait loci (QTL) governing inter-individual dependence. We mathematically formulate the decision-making strategy of interacting individuals. We integrate these mathematical descriptors into a statistical procedure, enabling the joint characterization of how QTL drive the strengths of ecological interactions and how the genetic architecture of QTL is driven by ecological networks. In three fish full-sib mapping experiments, we identify a set of genome-wide QTL that control a range of societal behaviors, including mutualism, altruism, aggression, and antagonism, and find that these intraspecific interactions increase the genetic variation of body mass by about 50%. We showcase how the interaction QTL can be used as editors to reconstruct and engineer new social networks for ecological communities.

The allotetraploid origin and asymmetrical genome evolution of the common carp Cyprinus carpio.

Common carp (Cyprinus carpio) is an allotetraploid species derived from recent whole genome duplication and provides a model to study polyploid genome evolution in vertebrates. Here, we generate three chromosome-level reference genomes of C. carpio and compare to related diploid Cyprinid genomes. We identify a Barbinae lineage as potential diploid progenitor of C. carpio and then divide the allotetraploid genome into two subgenomes marked by a distinct genome similarity to the diploid progenitor. We estimate that the two diploid progenitors diverged around 23 Mya and merged around 12.4 Mya based on the divergence rates of homoeologous genes and transposable elements in two subgenomes. No extensive gene losses are observed in either subgenome. Instead, we find gene expression bias across surveyed tissues such that subgenome B is more dominant in homoeologous expression. CG methylation in promoter regions may play an important role in altering gene expression in allotetraploid C. carpio.

Patterns of Geographical and Potential Adaptive Divergence in the Genome of the Common Carp (Cyprinus carpio).

The common carp, Cyprinus carpio, is a cyprinid fish species cultured in Europe and Asia. It accounts for >70% of freshwater aquaculture production worldwide. We conducted a population genomics analysis on C. carpio using high-throughput SNP genotyping of 2,198 individuals from 14 populations worldwide to determine the genetic architecture of common carp populations and the genetic bases for environmental adaptation. Structure analyses including phylogeny and principal component analysis were also conducted, showing distinct geographical patterns in European and Asian populations. The linkage disequilibrium block average lengths of the 14 populations ranged from 3.94 kb to 36.67 kb. Genes within selective sweep regions were identified by genome scanning among the different populations, including gdf6a, bmpr1b, and opsin5. Gene Ontology and KEGG enrichment analyses revealed potential trait-related loci and genes associated with body shape, scaling patterns, and skin color. This population genomics analysis may provide valuable clues for future genome-assisted breeding of C. carpio.

Genomic, Transcriptomic, and Epigenomic Features Differentiate Genes That Are Relevant for Muscular Polyunsaturated Fatty Acids in the Common Carp.

Polyunsaturated fatty acids (PUFAs) are a set of important nutrients that mainly include arachidonic acid (ARA4), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and α-linolenic acid (ALA). Recently, fish-derived PUFAs have been associated with cardiovascular health, fetal development, and improvement of brain functions. Studies have shown that fish muscular tissues are rich in PUFAs, which are influenced by various factors, including genetic variations, regulatory profiles, and methylation status of desaturase genes during fatty acid desaturation and elongation processes. However, the genetic mechanism and the pathways involved in fatty acid metabolism in fishes remain unclear. The overall aim of this study was to assess differences in gene expression responses among fishes with different fatty acid levels. To achieve this goal, we conducted genome-wide association analysis (GWAS) using a 250K SNP array in a population of 203 samples of common carp (Cyprinus carpio) and identified nine SNPs and 15 genes associated with muscular PUFA content. Then, RNA-Seq and whole genome bisulfite sequencing (WGBS) of different groups with high and low EPA, DHA, ARA4, and ALA contents in muscle, liver and brain tissues were conducted, resulting in 6,750 differentially expressed genes and 5,631 genes with differentially methylated promoters. Gene ontology and KEGG pathway enrichment analyses of RNA-Seq and WGBS results identified enriched pathways for fatty acid metabolism, which included the adipocytokine signaling pathway, ARA4 and linoleic acid metabolism pathway, and insulin signaling pathway. Integrated analysis indicated significant correlations between gene expression and methylation status among groups with high and low PUFA contents in muscular tissues. Taken together, these multi-level results uncovered candidate genes and pathways that are associated with fatty acid metabolism and paved the way for further genomic selection and carp breeding for PUFA traits.