2022 Vol. 43, No. 6
OCT6 inhibits differentiation of porcine-induced pluripotent stem cells through MAPK and PI3K signaling regulation
2022, 43(6): 911-922. doi: 10.24272/j.issn.2095-8137.2022.220
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As a transcription factor of the Pit-Oct-Unc (POU) domain family, octamer-binding transcription factor 6 (OCT6) participates in various aspects of stem cell development and differentiation. At present, however, its role in porcine-induced pluripotent stem cells (piPSCs) remains unclear. Here, we explored the function of OCT6 in piPSCs. We found that piPSCs overexpressing OCT6 maintained colony morphology and pluripotency under differentiation conditions, with a similar gene expression pattern to that of non-differentiated piPSCs. Functional analysis revealed that OCT6 attenuated the adverse effects of extracellular signal-regulated kinase (ERK) signaling pathway inhibition on piPSC pluripotency by activating phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling activity. Our research sheds new light on the mechanism by which OCT6 promotes PSC maintenance.
2022, 43(6): 923-926. doi: 10.24272/j.issn.2095-8137.2022.338
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2022, 43(6): 927-930. doi: 10.24272/j.issn.2095-8137.2022.155
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2022, 43(6): 931-934. doi: 10.24272/j.issn.2095-8137.2022.189
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2022, 43(6): 945-948. doi: 10.24272/j.issn.2095-8137.2022.339
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A chromosome minimalist view of genome regulation and evolution based on mouse chromosome engineering
2022, 43(6): 949-951. doi: 10.24272/j.issn.2095-8137.2022.386
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Pseudomonas plecoglossicida is the pathogen responsible for visceral white spot disease in large yellow croaker (Larimichthys crocea) and orange-spotted grouper (Epinephelus coioides). Previously, RNA sequencing showed that P. plecoglossicida flgK gene expression was significantly up-regulated in orange-spotted grouper spleens during infection. To explore the role of flgK in P. plecoglossicida pathogenicity, RNA interference (RNAi) was performed to silence the P. plecoglossicida flgK gene, and the mutant (flgK-RNAi strain) with the best silencing efficiency (89.40%) was chosen for further study. Results showed that flgK gene silencing significantly attenuated P. plecoglossicida motility, adhesion, and biofilm formation. Compared to those fish infected with the wild-type strain of P. plecoglossicida, orange-spotted grouper infected with the flgK-RNAi strain showed a 55% increase in the survival rate and a one-day delay in time of first death, with fewer pathogens in the spleen and fewer white spots on the spleen surface. RNAi of flgK significantly affected the transcriptome and metabolome of the spleen in infected orange-spotted grouper. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the C-type lectin receptor signaling pathway was the most significantly changed immune-related pathway and the mitogen-activated protein kinase (MAPK) signaling pathway was related to multiple immune-related pathways. Furthermore, arginine biosynthesis and glycerophospholipid metabolism were the most significantly changed metabolism-related pathways. These findings suggest that flgK is a virulence gene of P. plecoglossicida. Furthermore, flgK appears to be involved in the regulation of motility, adhesion, and biofilm formation in P. plecoglossicida, as well as in the regulation of inflammatory and immune responses of orange-spotted grouper to P. plecoglossicida infection.
Antiviral effects of natural small molecules on aquatic rhabdovirus by interfering with early viral replication
2022, 43(6): 966-976. doi: 10.24272/j.issn.2095-8137.2022.234
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Spring viremia of carp virus (SVCV) is globally widespread and poses a serious threat to aquatic ecology and aquaculture due to its broad host range. To develop effective agents to control SVCV infection, we selected 16 naturally active small molecules to assess their anti-SVCV activity. Notably, dihydroartemisinin (DHA) (100 µmol/L) and (S, S)-(+)-tetrandrine (TET) (16 µmol/L) exhibited high antiviral effects in epithelioma papulosum cyprinid (EPC) cells, with inhibitory rates of 70.11% and 73.54%, respectively. The possible antiviral mechanisms were determined as follows: 1. Pre-incubation with DHA and TET decreased viral particle infectivity in fish cells, suggesting that horizontal transmission of SVCV in the aquatic environment was disrupted; 2. Although neither had an effect on viral adhesion, TET (but not DHA) interfered with SVCV entry into host cells (>80%), suggesting that TET may have an antiviral function in early viral replication. For in vivo study, both agents enhanced the survival rate of SVCV-infected zebrafish by 53.3%, significantly decreased viral load, and modulated the expression of antiviral-related genes, indicating that DHA and TET may stimulate the host innate immune response to prevent viral infection. Overall, our findings indicated that DHA and TET had positive effects on suppressing SVCV infection by affecting early-stage viral replication, thus holding great potential as immunostimulants to reduce the risk of aquatic rhabdovirus disease outbreaks.
2022, 43(6): 977-988. doi: 10.24272/j.issn.2095-8137.2022.246
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Previous studies have identified multiple viruses in dead or severely diseased pangolins, but descriptions of the virome in healthy pangolins are lacking. This poses a greater risk of cross-species transmission due to poor preventive awareness and frequent interactions with breeders. In this study, we investigated the viral composition of 34 pangolins with no signs of disease at the time of sampling and characterized a large number of arthropod-associated viruses belonging to 11 families and vertebrate viruses belonging to eight families, including those with pathogenic potential in humans and animals. Several important vertebrate viruses were identified in the pangolins, including parvovirus, pestivirus, and picobirnavirus. The picobirnavirus was clustered with human and grey teal picobirnaviruses. Viruses with cross-species transmission ability were also identified, including circovirus, rotavirus, and astrovirus. Our study revealed that pangolins are frequently exposed to arthropod-associated viruses in the wild and can carry many vertebrate viruses under natural conditions. This study provides important insights into the virome of pangolins, underscoring the importance of monitoring potential pathogens in healthy pangolins to prevent outbreaks of infectious diseases in domesticated animals and humans.
Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway
2022, 43(6): 989-1004. doi: 10.24272/j.issn.2095-8137.2022.278
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Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.
2022, 43(6): 1005-1008. doi: 10.24272/j.issn.2095-8137.2022.244
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Unveiling the functional and evolutionary landscape of RNA editing in chicken using genomics and transcriptomics
2022, 43(6): 1011-1022. doi: 10.24272/j.issn.2095-8137.2022.331
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The evolutionary and functional features of RNA editing are well studied in mammals, cephalopods, and insects, but not in birds. Here, we integrated transcriptomic and whole-genomic analyses to exhaustively characterize the expansive repertoire of adenosine-to-inosine (A-to-I) RNA editing sites (RESs) in the chicken. In addition, we investigated the evolutionary status of the chicken editome as a potential mechanism of domestication. We detected the lowest editing level in the liver of chickens, compared to muscles in humans, and found higher editing activity and specificity in the brain than in non-neural tissues, consistent with the brain’s functional complexity. To a certain extent, specific editing activity may account for the specific functions of tissues. Our results also revealed that sequences critical to RES secondary structures remained conserved within avian evolution. Furthermore, the RNA editome was shaped by purifying selection during chicken domestication and most RESs may have served as a selection pool for a few functional RESs involved in chicken domestication, including evolution of nervous and immune systems. Regulation of RNA editing in chickens by adenosine deaminase acting on RNA (ADAR) enzymes may be affected by non-ADAR factors whose expression levels changed widely after ADAR knockdown. Collectively, we provide comprehensive lists of candidate RESs and non-ADAR-editing regulators in the chicken, thus contributing to our current understanding of the functions and evolution of RNA editing in animals.
2022, 43(6): 1023-1025. doi: 10.24272/j.issn.2095-8137.2022.427
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2022, 43(6): 1026-1040. doi: 10.24272/j.issn.2095-8137.2022.289
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Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease (AD) have been made and multifarious novel therapeutic approaches have been developed, AD remains an incurable disease. Evidence shows that AD neuropathology occurs decades before clinical presentation. AD is divided into three stages: preclinical stage, mild cognitive impairment (MCI), and AD dementia. In the natural world, some animals, such as non-human primates (NHPs) and canines, can develop spontaneous AD-like dementia. However, most animals do not develop AD. With the development of transgenic techniques, both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods. Most AD research focuses on early-onset familial AD (FAD) because FAD is associated with specific genetic mutations. However, there are no well-established late-onset sporadic AD (SAD) animal models because SAD is not directly linked to any genetic mutation, and multiple environmental factors are involved. Moreover, the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages. This review summarizes the common models used to study AD, from yeast to NHP models, and discusses the different applications, evaluation methods, and challenges related to AD animal models, as well as prospects for the evolution of future studies.
Single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection
2022, 43(6): 1041-1062. doi: 10.24272/j.issn.2095-8137.2022.443
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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs. However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000 single-nucleus transcriptomes of the lung, liver, kidney, and cerebral cortex in rhesus macaques (Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multi-organ dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019 (COVID-19). Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway, which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy (an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection, which may facilitate the development of therapeutic interventions for COVID-19.