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Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.
PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase that phosphorylates Parkin and other proteins, plays a crucial role in mitophagy and protection against neurodegeneration. Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson’s disease. However, there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration. Additionally, PINK1 knockout pigs (Sus scrofa) do not appear to exhibit neurodegeneration. In our recent work involving non-human primates, we found that PINK1 is selectively expressed in primate brains, while absent in rodent brains. To extend this to other species, we used multiple antibodies to examine the expression of PINK1 in pig tissues. In contrast to tissues from cynomolgus monkeys (Macaca fascicularis), our data did not convincingly demonstrate detectable PINK1 expression in pig tissues. Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation, as observed in cultured monkey cells. A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain. Consistently, PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD. These findings provide new evidence that PINK1 expression is specific to primates, underscoring the importance of non-human primates in investigating PINK1 function and pathology related to PINK1 deficiency.
Animal models are extensively used in all aspects of biomedical research, with substantial contributions to our understanding of diseases, the development of pharmaceuticals, and the exploration of gene functions. The field of genome modification in rabbits has progressed slowly. However, recent advancements, particularly in CRISPR/Cas9-related technologies, have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases, including cardiovascular disorders, immunodeficiencies, aging-related ailments, neurological diseases, and ophthalmic pathologies. These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice. This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine, underscoring their impact and future potential in translational medicine.
Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.
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In eukaryotic organisms, the most common internal modification of messenger RNA (mRNA) is N6-methyladenosine (m6A). This modification can be dynamically and reversibly controlled by specific enzymes known as m6A writers and erasers. The fat-mass and obesity-associated protein (FTO) catalyzes RNA demethylation and plays a critical role in various physiological and pathological processes. Our research identified dynamic alterations in both m6A and FTO during the assembly of primordial follicles, with an inverse relationship observed for m6A levels and nuclear-localized FTO expression. Application of Fto small interfering RNA (siRNA) altered the expression of genes related to cell proliferation, hormone regulation, and cell chemotaxis, and affected RNA alternative splicing. Overexpression of the full-length Fto gene led to changes in m6A levels, alternative splicing of Cdk5, cell proliferation, cell cycle progression, and proportion of primordial follicles. Conversely, overexpression of Fto lacking a nuclear localization signal (NLS) did not significantly alter m6A levels or primordial follicle assembly. These findings suggest that FTO, localized in the nucleus but not in the cytoplasm, regulates RNA m6A demethylation and plays a role in cell proliferation, cell cycle progression, and primordial follicle assembly. These results highlight the potential of m6A and its eraser FTO as possible biomarkers and therapeutic targets.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.385
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Iron-sulfur (Fe-S) clusters are essential cofactors of proteins involved in various biological systems, such as electron transport, biosynthetic reactions, DNA repair and gene expression regulation and so on. Iron-sulfur cluster assembly protein IscA1 or MagR was found in mitochondria of most eukaryotes. MagR is a highly conserved A-type iron and iron-sulfur cluster binding protein, with two types of iron-sulfur clusters, [2Fe-2S] and [3Fe-4S], each conferring distinct magnetic properties. It forms a rod-like polymer structure in complex with photoreceptive cryptochrome (Cry) and serve as a putative magnetoreceptor to retrieve geomagnetic information in animal navigation. The N-terminal sequences of MagR are divergent in different species, however, the specific function is unknown. Here, in this study we find that the N-terminal sequences of pigeon MagR which was assumed as the mitochondrial targeting signal (MTS) were not cleaved after entry into the mitochondria but instead affected the binding efficiency of iron-sulfur clusters and irons. Moreover, the MagR/Cry complex formation was also dependent on N-terminal region of MagR. Thus, the N-terminal sequences play more important functional roles than mitochondrial targeting in pigeon MagR. These results further extended our understanding about the function of MagR and may provide new insights into the origin of magnetoreception from evolutional view.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.410
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Acetaminophen (APAP) is the most commonly used mild analgesic and antipyretic drug worldwide. Its overdoses account for 46% of all acute liver failures in the USA and 40–70% in Europe. However, the only approved pharmacological treatment is the antioxidant N-acetylcysteine (NAC), but it does not work well with advanced liver injury or administrates at later stage. Here, we found that a moderate intensity static magnetic field (SMF) treatment can reduce the mice death rate of high-dose APAP from 40% to 0%, and it works at both earlier liver injury stage and the later liver recovery stage. At the early liver injury stage, SMF can effectively decrease APAP-induced oxidative stress, reduce free radical levels and liver damage. Multiple oxidative stress markers were all reduced, while the antioxidant glutathione (GSH) level was increased by SMF. At the later liver recovery stage, the vertically downward SMF can increase the DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF can significantly reduce the high-dose APAP-induced liver damage and increase liver recovery, even at 24 hours after APAP overdose, when NAC alone does not work well anymore. Therefore, our study provides a non-invasive nonpharmaceutical physical tool that has dual roles in the injury and repair stages after APAP overdose. It can work as an alternative or combinational strategy with NAC to prevent or minimize liver damage induced by APAP, and maybe other toxin overdose as well.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.371
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Osteoporosis is a prevalent metabolic skeletal disease. While drug therapy is essential to prevent bone loss in osteoporosis patients, current treatments have limitations including side effects and high costs, necessitating the development of more efficient and safer targeted therapies. Utilizing a zebrafish larvae osteoporosis model, we explored the metabolite spermine’s influence on bone homeostasis. We found that spermine presented a dual action in osteoporotic zebrafish larvae: fostering bone formation and curtailing bone resorption. Moreover, spermine exhibited excellent biosafety while mitigating prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine also showcased protective attributes for the nervous systems of both zebrafish embryos and larvae. From the molecular level, we identified Rac1 as pivotal in mediating spermine’s anti-osteoporosis effects and P53 potentially worked downstream from Rac1. Furthermore, our experiments in mice models reinforced these findings, indicating that spermine not only ameliorates osteoporosis but also promotes bone formation and mineralization in healthy conditions, suggesting its strong potential as a bone-strengthening agent. This study underscores spermine’s beneficial role in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine emerge as promising candidates for new anti-osteoporosis drug development and as daily used bone-fortifying agents.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.324
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Lipid metabolism is closely associated with testosterone, which is known to affect body fat composition and muscle mass in males. However, the mechanism by which testosterone acts on lipid metabolism is not fully clear yet, especially in teleosts. In this study, we firstly observed that cyp17a1-/- zebrafish (Danio rerio) exhibited excessive visceral adipose tissue (VAT), lipid content and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The result of Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) demonstrated that chromatin accessibility of DNL genes were increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase (scd) and fatty acid synthase (fasn). Androgen receptor element (ARE) motif in the androgen signaling pathway was significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor (ar)-/- zebrafish and wild-type (WT) zebrafish administrated with Ar antagonist Flutamide exhibited excessive visceral adipose tissue, lipid content and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The Ar agonist, BMS-564929, diminished the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a (acaca), fasn and scd expression. Mechanistically, the rescuing effect of testosterone on cyp17a1-/- fish in terms of the the phenotypes mentioned above was abolished when ar was additionally depleted. Collectively, our findings revealed that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, which expand the understanding of the relationship between testosterone and lipid metabolism in teleosts.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.320
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The gut microbiota plays a crucial role in interacting with the host's physiological system and providing essential ecosystem services. It is known that diet can affect the composition of the gut microbiota, while the gut microbiota can also help the host adapt to specific dietary habits. As a facultative scavenger urban bird, the carrion crow (Corvus corone) is one of the hosts of high-abundance pathogen due to its facultative scavenging behavior. However, carrion crows rarely get sick, which is related to their unique physiological adaptation ability. The role of the gut microbiota in this process remains incompletely understood. In this study, we performed a comparative analysis using 16S rRNA amplicon sequencing technology, analyzing the colonic contents of carrion crows and 16 other bird species with different diets in Beijing, China. Our findings revealed that the predominant gut microbiota of the carrion crow primarily comprises Proteobacteria (75.51%) and Firmicutes (22.37%). We observed significant differences in the relative abundance of Enterococcus faecalis between groups, suggesting that Enterococcus faecalis may serve as a biomarker for carrion crows' facultative scavenging behavior. Subsequently, we isolated Enterococcus faecalis derived from carrion crows and conducted transplantation experiments in model mice to confirm the protective effects of this bacterial community against Salmonella infection. The results demonstrated that Enterococcus faecalis can downregulated the expression of pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6, prevented the colonization of Salmonella, and regulated the composition of gut microbiota in mice, thereby modulating the host's immune regulatory capacity. Finally, we demonstrated that the Enterococcus faecalis plays an immunoregulatory and anti-pathogen role in carrion crows during scavenging behavior, providing a typical case of how the gut microbiota can protect diet-specialized hosts.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.322
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Understanding the variations in gene expression between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques and crab-eating macaques serve as crucial nonhuman primate biomedical models with different phenotypes, but the large-scale of comparative transcriptome research between these two species has yet to be fully elucidated. Here, we conduct systematic comparisons utilizing newly sequenced RNA-seq data from 84 samples (41 Mfa samples and 43 Mmu samples) encompassing 14 common tissues. Our findings reveal that a small fraction of genes (~3.7%) show differential expression between the two macaque species, while ~36.5% of genes show tissue-specific expression in both macaques. We also compare gene expression between macaques and humans and ~22.6 % of the orthologous genes show differential expression in at least 2 tissues. Moreover, ~19.41% of genes overlapped with macaque-specific structural variants are more likely to show differential expression between humans and macaques. Of these, FAM220A shows elevated gene expression in humans compared to macaques because of lineage-specific duplication. In summary, our study presents a large-scale analysis of the transcriptomes within macaque species and between macaques and humans. These insights into gene expression variations will enhance the biomedical utility of macaque models and contributing to the broader realm of primate genomic studies.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.336
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Coilia nasus, a migratory fish species naturally inhabiting in the middle and lower reaches of the Yangtze River and offshore China, has high culturing potential and economic value. However, significant variation in the gonadal development rate among female individuals leads to inconsistent ovarian maturation times at the population level, so as to prolong reproductive period, and ovarian pre-maturity also limits fish growth rate. Here, we combined genome-wide association analysis (GWAS) and comparative transcriptome analysis to explore the potential associated SNPs and candidate genes associated with population-asynchronous ovarian development in C. nasus. Genotyping of female population was performed by whole-genome re-sequencing, resulting in the identification of 2,120,695 high-quality SNPs. Thirty-nine SNPs were proved to have suggestive association with ovarian development. A significant SNP peak was obtained on LG21 containing 30 suggestive associated SNPs, and cpne5a gene was identified as the causal gene of the peak. Therefore, single-marker association analysis and haplotype association analysis were performed based on cpne5a, and 4 genetic markers (p < 0.05) and 7 haplotypes (r2 > 0.9) significantly associated with the phenotype were obtained. The comparative transcriptome analysis based on the precocious maturing (PM) and normally maturing (NM) individuals screened out 29 and 426 overlapping differentially expressed genes (DEGs) between different body-size individuals in the brain and ovary, respectively. Combining the results of GWAS and transcriptome analysis, we identified genes and pathways related to HPG axis hormone secretion, extracellular matrix, angiogenesis and gap junctions were involved in population-asynchronous ovarian development. The results of the study provide a basis for in-depth understanding of the molecular mechanism of fish ovarian development, and may facilitate the genetic breeding of population-synchronous ovarian development strains of C. nasus in the future.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.311
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The genus Silurus is an important group of catfish species unevenly distributed in Eurasian freshwaters. Including economically important and endangered species, it has attracted the attention of biologists involved in separate subdisciplines. However, the lack of phylogenetic framework leaves unresolved the mechanisms behind the accumulation of a substantial portion of the genus diversity in East Asia. Herein, we combined 89 newly generated and 20 previously published mitogenomes from 13 morphological species to reconstruct phylogenetic relationships, biogeographic history, and estimate species diversity of the genus Silurus. Phylogenetic reconstructions yielded eight clades supported by both Maximum Likelihood and Bayesian Inference. Sequence-based species delimitation analyses yielded multiple Molecular Operational Taxonomic Units in several taxa including Silurus asotus complex (four) and S. microdorsalis (two), suggesting that species diversity is underestimated in the genus Silurus. A reconstructed time-calibrated tree of Silurus species provides an age estimate of the Most Recent Common Ancestor approximately 37.61 million years ago (Ma), and splits among clades within the genus occurred between 11.56 Ma and 29.44 Ma, and among MOTUs within species between 3.71 Ma and 11.56 Ma. Biogeographic reconstructions support China and Korean peninsula as the most likely ancestral area and several dispersal events to Europe and Central and Western Asia are inferred between 21.78 Ma and 26.67 Ma and multiple dispersal events to Japan are inferred between 2.51 Ma and 18.42 Ma. The Eocene–Oligocene extinction event, onset and intensification of the monsoon system, glacial cycles and associated sea-level fluctuations appeared to be important driving forces in the genus.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.309
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Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model for multiple sclerosis (MS), mimics its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post immunization, DPI) and the chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. The dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the mouse hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, while dendritic spine density was reduced only in the DG subregion during the chronic phase. Further, mRNA levels of proinflammatory cytokines (Il1β, Tnfα, and Ifnγ) and glial cell markers (Gfap and Cd68), were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase of EAE. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Additionally, primary cultures of hippocampal neurons showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.306
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The Chinese tree shrew (Tupaia belangeri chinensis) is from a mammalian order (Scandentia) related to primates. Its nervous, immune, and metabolic systems are similar to those of primates, including humans, making it widely used as a promising experimental model in biomedical research, such as cancer, infectious, metabolic, and mental diseases models. Herein, we used meta-transcriptomic sequencing to analyze plasma, oral and anal swab samples from 105 apparently healthy tree shrew individuals to identify potential zoonotic viruses. Eight mammalian viruses with complete genomes were identified, belonging to six viral families: Flaviviridae, Hepeviridae, Parvovirinae, Picornaviridae, Sedoreoviridae, and Spinareoviridae. We reported, for the first time, a rotavirus in tree shrews. Of particular note were three viruses – hepacivirus1, parvovirus, and picornavirus – that exhibited low genetic similarity (<70%) with previously reported viruses at the scale of whole genome and so were novel. Three other viruses – hepacivirus 2, hepatovirus A and hepevirus – exhibited high similarity (>94%) to known viruses. Phylogenetic analyses also revealed that the rotavirus and mammalian orthoreovirus identified in this study might be novel reassortants. These findings provided insights into the wide virus spectrum in captive Chinese tree shrews. The potential for the cross-species transmission of these viruses from tree shrews to other animals clearly warrants further investigation.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.302
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General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine in the medial prefrontal cortex and the primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from the perspective of neurotransmitters. We discovered that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine in the cortex increased during propofol-induced loss of consciousness. The dopamine concentration did not change following the hypnotic dose of propofol; however, the concentration increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Moreover, in the non-anesthesia groups, the neurotransmitter dynamic networks were not synchronized; however, in the anesthetic groups, the neurotransmitter dynamic networks were highly synchronized. These data revealed that neurotransmitter dynamics network synchronization may cause anesthetic-induced loss of consciousness.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.293
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Autotetraploid Carassius auratus (4nRR, 4n = 200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2n = 100, RR). Our study demonstrated that chromatophores and pigment changes were direct causes of 4nRR skin coloration and its variation (red coloration in RCC, brownish-yellow coloration in 4nRR). To further explore the molecular mechanisms underlying coloration formation and variation in 4nRR, we performed transcriptome profiling and molecular functional verification in RCC and 4nRR. Our result revealed that scarb1, associated with carotenoid metabolism, underwent significant downregulation in 4nRR. And then, efficiently editing this candidate pigmented gene provided clear evidence that scarb1 plays a significant role in RCC coloration. Subsequently, in 4nRR, we identified four divergent scarb1 homeologs: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting a predominant biased and allele-specific expression in the skin. Remarkably, after the precise editing of both original and duplicated scarb1 homeologs and/or alleles, 4nRR individuals, whether singly or multiply mutated, displayed a transition from brownish-yellow skin to a cyan-grey phenotype. Concurrently, the proportional areas of the cyan-grey regions displayed a gene-dose correlation. These findings illustrate the subfunctionalization of duplicated scarb1, with all scarb1 genes synergistically and equally contributing to the pigmentation of 4nRR. This is the first report concerning the functional differentiation of duplicated homeologs in autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.287
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Mutations in mitochondrial DNA (mtDNA) are maternally inherited and may cause severe disorders. Mitochondrial replacement therapy has been a promising option to prevent the transmission of mtDNA diseases, which include spindle transfer, polar body transfer and pronuclear transfer. The pronuclear transfer has been used for generating mitochondrial replaced mouse individuals and human embryos. In contrast, none of the primate individuals have been generated through pronuclear transfer. In this study, we successfully generated four healthy cynomolgus monkeys (Macaca fascicularis) using female pronuclear transfer, all of which have survived for more than two years and showed small amounts of mtDNA carryover (3.8%-6.7%), as well as relatively stable mtDNA heteroplasmy dynamics during development. Our non-human primate model demonstrates that pronuclear transfer has great potential to reduce the risk of inherited mtDNA disease, which provides a useful preclinical research model for human mitochondrial replacement therapy.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.280
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The Chinese tree shrew has emerged as a promising model for investigating adrenal steroid synthesis, but it is unclear whether the same cells produce the steroid hormones and whether its production is regulated in the same way in the human and tree shrews. Here, we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing, spatial transcriptome analysis, mass spectrometry, and immunohistochemistry. We compared the transcriptomes of various adrenal cell types across tree shrews, humans, Macaca fascicularis, and mice. Tree shrew adrenal glands were found to express many of the same key enzymes for steroid synthesis as humans, including CYP11B2, CYP11B1, CYB5A, and CHGA. We confirmed through biochemical analysis that tree shrew adrenal glands produce aldosterone, cortisol, and dehydroepiandrosterone but not dehydroepiandrosterone sulfate. We were able to correlate genes in adrenal cell types in tree shrew with genetic risk factors for polycystic ovary syndrome, primary aldosteronism, hypertension, and related disorders in humans based on genome-wide association studies. Our work suggests that the adrenal glands of Chinese tree shrews may be closely related cell populations and functionally similar to the human adrenal gland. Our comprehensive results, which are publicly available at https://treeshrewdb.streamlit.app, should help guide the development of this animal model of adrenal gland disorders.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.232
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The Amur tiger (Panthera tigris altaica) and Amur leopard (P. pardus orientalis) are two sympatric but competitive apex predators coexisting in the forests of Northeast Asia. They are both highly endangered animals on the planet, and their conservation is of great symbolic significance. Here we assembled a haplotype-resolved and chromosome-scale genome of a wild Amur leopard, and make a comparative genomic analysis with the same level Amur tiger genome. Comprehensive comparative genomic analysis identified several genes and pathways that potentially underlie adaptations to cold endurance, vision, hearing, smell, bone formation, and development. These adaptations likely facilitate the survival of Amur tigers and leopards as large predators in the cold northern environment. We also found genomic signatures related to these characteristics in Amur tigers than in Amur leopards, partly explaining the possible genomic basis for their coexistence and competition. Our findings improve our understanding of how Amur tigers and leopards co-adapt, and provide valuable genome-wide genetic information for further conservation of these two most endangered big cats.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.315
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A growing number of studies have identified that repeated exposure to Sevoflurane during development leads to long-term social abnormalities and cognitive impairment. Davunetide is an activity fragment of activity dependent neuroprotective protein (ADNP), which was coupled to social and cognitive protection. Whether Davunetide could attenuate the social deficits after sevoflurane exposure and the underlying developmental mechanisms are poorly understood. In this study, ribosome and proteome profiles were conducted to investigate the molecular basis in neonatal mice with sevoflurane-induced social deficits. We investigated the neuropathological basis through techniques such as Golgi staining, morphological analysis, Western blot, electrophysiology technology, and behavior analysis. Results showed that ADNP was significantly downregulated after Sevoflurane exposure during development. After adulthood, neurons in ACC of sevoflurane exhibited decrease in number of dendrites, total dendrite length and spine density. The expression of Homer, PSD95, synaptophsin and vglut2 were significantly reduced in sevoflurane group. Patch-clamp recording showed that frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were reduced. Importantly, davunetide significantly alleviated Sevoflurane induced synaptic defect, social behavior and cognitive impairment. Mechanistic analysis revealed that loss of ADNP caused Ca2+ activity dysregulation via Wnt/β-catenin signaling, leading to decreased the expression of synaptic proteins. Wnt suppression was all restored in davunetide-treated group. Taken together, we identified ADNP as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. Our data provide an insight into the social abnormalities and cognitive damage induced by sevoflurane exposure in neonatal mice and its underlying regulatory mechanism.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.308
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Dormancy is a fascinating survival technique that enables organisms to adapt to their environment and can be classified as either hibernation or aestivation, depending on the season. Organisms that are in a state of dormancy can display remarkable stress resistance, enabling them to survive in extreme environments. However, the question of how organisms adapt to their environment in their respective dormant states and how the two types of dormancy relate to each other and differ from each other still deserves further exploration. We selected Perccottus glenii and Protopterus annectens as the primary subjects to study hibernation and aestivation respectively. We analyzed them histologically and collected multiple organ transcriptome data from both species. The functional enrichment results reveal that dormancy entails a comprehensive alteration coordinated by multiple organs. Additionally, the differences between the two dormant species (regarding coping mechanisms to deal with extreme temperatures) were considerable. We also discovered noteworthy similarities in the expression patterns of genes linked to energy metabolism, neural activity, and biosynthesis during both dormant periods, indicating a correlation between hibernation and aestivation. To comprehend the connection between the two dormant species, we scrutinised the gene homology of various other distantly related species in dormant states from public databases. We discovered that almost half of the directly homologous genes showing significant differential expression during dormancy displayed a consistent expression trend. These genes, which exhibit similar expression patterns, mainly regulate metabolism during dormancy, and maintaining the biologically dormant state requires cell number and neural activity. This suggests that the similarity between hibernation and aestivation is due to convergent evolution. In conclusion, our study enhances the comprehension of the dormancy phenomenon and offers new insights into the molecular mechanisms behind vertebrate dormancy.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.286
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Drug addiction is a complex and chronic disease that affects the brain and behavior, leading to an inability to control the use of substances. It is characterized by compulsive drug-seeking, drug use, and a strong desire to use the substance, as well as the development of tolerance and withdrawal. Microglia, a type of glial cell in the central nervous system (CNS), play a crucial role in maintaining the health and function of the CNS. Accumulating evidence indicates that microglia play an important role in the progression of drug addiction. From a neuroimmunopharmacological perspective, herein we discuss the role and underlying mechanisms of microglia and potential therapeutic strategies by targeting microglia for drug addiction, and the limitations of the research on microglia in drug addiction.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.270
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The leopard coral grouper (<i>Plectropomus leopardus</i>) is a species of significant economic importance. While artificial cultivation of <i>P. leopardus</i> has thrived in recent decades, the advancement of selective breeding has been impeded by the absence of comprehensive population genome data. In this study, we identified over 8.73 million single nucleotide polymorphisms (SNPs) through whole-genome resequencing of 326 individuals spanning six distinct groups. Furthermore, we categorized 226 individuals with high-coverage sequencing (depth ≥ 14×) into eight clusters based on their genetic profiles and phylogenetic relationships. Notably, four of these clusters exhibited pronounced genetic differentiation compared with the other populations. To identify potentially advantageous loci for <i>P. leopardus</i>, we examined genomic regions exhibiting selective sweeps by analyzing the nucleotide diversity (<i>θπ</i>) and fixation index (<i>F<sub>st</sub></i>) in these four clusters. Moreover, by leveraging these high-coverage re-sequencing data, we successfully constructed the first haplotype reference panel specific to <i>P. leopardus</i>. This achievement holds promise for enabling high-quality, cost-effective imputation methods. Additionally, we used low-coverage sequencing data in conjunction with imputation for a genome-wide association study to identify candidate SNP loci and genes associated with growth traits. A significant concentration of these genes was observed on chromosome 17, which is primarily involved in skeletal muscle and embryonic development and cell proliferation. Notably, our investigation of growth-related SNPs across the eight clusters revealed that cluster 5 harbored the most promising candidate SNPs for genetic selective breeding efforts. These findings provide a robust toolkit and valuable insights into the management of germplasm resources and genome-driven breeding initiatives targeting <i>P. leopardus</i>.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.231
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Hereditary hearing loss (HHL) is a genetic disorder that impairs auditory function, and it can seriously affect the quality of human life and lead to major economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Recently, pigs have been widely used as valuable large model animals in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology and electrophysiological characteristics, as well as the recent progress in establishing distinct genetically modified porcine models of hearing loss. Additionally, we present the prospects, obstacles and recommendations in using pig models for HHL research. This review should provide insights and perspectives for the future research of porcine models for HHL.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.222
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Animal body size variation is of particular interest in evolutionary biology, but the genetic basis remains largely unknown. Previous studies have shown the presence of two parallel evolutionary genetic clusters within the fish genus Epinephelus, which showed evident divergence in body size, providing an excellent opportunity to investigate the genetic basis of body size variation in vertebrates. Herein, we performed phylo-transcriptomic methods and reconstructed the phylogeny of 13 epinephelids originated from the South China Sea. Two genetic clades with estimated divergence time of ~ 15.4 MYA (million years ago), were identified to correlate with large and small body size, respectively. A total of 180 rapidly evolving genes (REGs) and two positively selected genes (PSGs) were identified between the two groups. Functional enrichment analyses on these candidate genes revealed distinctly different enrichment categories between the two groups. These pathways or genes may play important roles in body size variation in groupers through complex regulatory networks. Based on the results of this study, we speculate that the ancestors of the two divergent groups of groupers may have adapted to different environments through habitat selection, leading to genetic variations in metabolic patterns, organ development, and lifespan, which finally resulted in the divergence of body size between two locally adapted populations. These findings provide important insights into the genetic mechanisms underlying body size variation in groupers and species differentiation.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.205
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The placenta plays a crucial role in the successful reproduction of mammals. Ruminant animals possess a semi-invasive placenta characterized by a highly vascularized structure and formed by maternal endometrial caruncles and fetal placental cotyledons. This specialized placenta is essential for fetal development until full term. The cow placenta consists of at least two trophoblast cell populations, including uninucleate (UNC) and binucleate (BNC) cells. However, the current inability to describe the transcriptomic dynamics of the placental natural environment has resulted in a poor understanding of the molecular and cellular interactions between trophoblast cells and niches, as well as of the molecular mechanisms controlling trophoblast differentiation and functionalization. To fill in this knowledge gap, we employed Stereo-seq, a spatial transcriptomics technique, to generate a map capturing the spatial gene expression patterns at near single-cell resolution in the cow placenta on 90 and 130 days of gestation, and attained high-resolution, spatially resolved gene expression profiles of cow placenta. Based on clustering and cell marker gene expression, key transcription factors, including YBX1 and NPAS2, were revealed to regulate the heterogeneity of trophoblast cell subpopulations. Cell communication and trajectory analysis provided a framework for understanding cell-cell interactions and the differentiation of trophoblasts into BNCs in the microenvironment of the cow placenta. Differential analysis of cell trajectories identified a set of genes involved in regulation of trophoblast differentiation. Additionally, we identified spatial modules and co-variant genes that play critical roles in shaping specific tissue structures. Together, this foundational information contributes to the discovery of important biological pathways underlying the development and function of the cow placenta.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.199
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Huntington's disease (HD) is an inherited neurodegenerative disorder for which there is currently no effective treatment available. Thus, it is imperative to establish appropriate disease models to delve deeply into the comprehensive progression of the disease. The genetic cause of HD is the abnormal expansion of CAG repeats in the huntingtin (HTT) gene, which leads to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat becomes misfolded and aggregates in the brain, causing selective loss of neurons in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders, including HD, and identifying potential therapeutic targets. Given the considerable species differences between rodents and large animals, large animal models of HD have been established to investigate the HD pathogenesis. These should facilitate the discovery of novel therapeutic targets, effective drug delivery, and improve treatment outcomes. We have previously explored the advantages of utilizing large animal models, particularly pigs, in other review articles. Since then, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. The current review aims to provide a more comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. In this review, we also explore the utilization of large animal models in Huntington's disease (HD) research, specifically focusing on sheep, non-human primates, and pigs. Our objective is to provide valuable insights into the application of these large animal models for investigating and treating neurodegenerative disorders.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.255
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As social animals, Indo-Pacific humpback dolphins have community differentiation, but the external-internal influencing factors and spatiotemporal dynamics are not well known. Thus, we monitored the social structure variation in an endangered Indo-Pacific humpback dolphin population in Xiamen Bay, China, during two periods, namely, 2007–2010 and 2017–2019, and analyzed the influence of habitat use and individual composition. In both periods, the population showed highly similar social differentiation, and the individuals were divided into two main clusters and a small cluster. The two main clusters occupied the east and west waters but the core distribution area of the east cluster moved further eastward during 2007–2010 and 2017–2019, and the distribution shift did not change the temporal stability of the social structure or inter-association of the east cluster. The 16 identical individuals in the two periods (accounting for 51.6% and 43.2%, respectively) seemed to constitute the basic framework of the social structure and could be the main reason for the stable social structure over the past decade. However, these individuals likely played a more critical role in maintaining the social network structure in 2007–2010 than that in 2017–2019. These results suggested that the internal factors of the dominant individuals’ composition contributed more to building the social network than the external factor of habitat use change. Based on the findings, different protective measures have been proposed for two main clusters respectively.
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Changes in protein abundance and reversible protein phosphorylation (RPP) play important roles in regulating hypometabolism but have never been documented in overwintering frogs at high altitudes. To test the hypothesis that protein abundance and phosphorylation change in response to winter hibernation, we conducted a comprehensive and quantitative proteomic and phosphoproteomic analysis of the liver of the Xizang plateau frog, Nanorana parkeri, living on the Qinghai-Xizang Plateau. In total, 5170 proteins and 5695 phosphorylation sites in 1938 proteins were quantified. Based on proteomic analysis, 674 differentially expressed proteins (438 up-regulated, 236 down-regulated) were screened in hibernating N. parkeri versus summer individuals. Functional enrichment analysis revealed that higher expressed proteins in winter were significantly enriched in immune-related signaling pathways, whereas lower expressed proteins were mainly involved in metabolic processes. A total of 4251 modified sites (4147 up-regulated, 104 down-regulated) belonging to 1638 phosphoproteins (1555 up-regulated, 83 down-regulated) were significantly changed in the liver. During hibernation, RPP regulated a diverse array of proteins involved in multiple functions, including metabolic enzymatic activity, ion transport, protein turnover, signal transduction, and alternative splicing. These changes contribute to enhancing protection, suppressing energy-consuming processes, and inducing metabolic depression. Moreover, the activities of phosphofructokinase, glutamate dehydrogenase, and ATPase were all significantly lower in winter compared to summer. In conclusion, our results support the hypothesis and demonstrate the importance of RPP as a regulatory mechanism when animals transition into a hypometabolic state.
Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal. However, whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown. In the present study, we discovered that the Nile tilapia (Oreochromis niloticus) encodes key components of the LAT signalosome, namely, LAT, ITK, GRB2, VAV1, SLP-76, GADS, and PLC-γ1. These components are evolutionarily conserved, and CD3ε mAb-induced T-cell activation markedly increased their expression. Additionally, at least ITK, GRB2, and VAV1 were found to interact with LAT for signalosome formation. Downstream of the first signal, the NF-κB, MAPK/ERK, and PI3K-AKT pathways were activated upon CD3ε mAb stimulation. Furthermore, treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal. Combined CD3ε and CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1, c-Fos, IL-2, CD122, and CD44 expression, thereby signifying T-cell activation. Moreover, rather than relying on the first or co-stimulatory signal alone, both signals were required for T-cell proliferation. Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses. These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response, providing a novel perspective for understanding the evolution of the adaptive immune system.
Long non-coding RNAs (lncRNAs) function as key modulators in mammalian immunity, particularly due to their involvement in lncRNA-mediated competitive endogenous RNA (ceRNA) crosstalk. Despite their recognized significance in mammals, research on lncRNAs in lower vertebrates remains limited. In the present study, we characterized the first immune-related lncRNA (pol-lnc78) in the teleost Japanese flounder (Paralichthys olivaceus). Results indicated that pol-lnc78 acted as a ceRNA for pol-miR-n199-3p to target the sterile alpha and armadillo motif-containing protein (SARM), the fifth discovered member of the Toll/interleukin 1 (IL-1) receptor (TIR) adaptor family. This ceRNA network regulated the antibacterial responses of flounder via the Toll-like receptor (TLR) signaling pathway. Specifically, SARM acted as a negative regulator and exacerbated bacterial infection by inhibiting the expression of inflammatory cytokines IL-1β and tumor necrosis factor-α (TNF-α). Pol-miR-n199-3p reduced SARM expression by specifically interacting with the 3’ untranslated region (UTR), thereby promoting SARM-dependent inflammatory cytokine expression and protecting the host against bacterial dissemination. Furthermore, pol-lnc78 sponged pol-miR-n199-3p to ameliorate the inhibition of SARM expression. During infection, the negative regulators pol-lnc78 and SARM were significantly down-regulated, while pol-miR-n199-3p was significantly up-regulated, thus favoring host antibacterial defense. These findings provide novel insights into the mechanisms underlying fish immunity and open new horizons to better understand ceRNA crosstalk in lower vertebrates.
The dynamics of animal social structures are heavily influenced by environmental patterns of competition and cooperation. In folivorous colobine primates, prevailing theories suggest that larger group sizes should be favored in rainforests with a year-round abundance of food, thereby reducing feeding competition. Yet, paradoxically, larger groups are frequently found in high-altitude or high-latitude montane ecosystems characterized by a seasonal scarcity of leaves. This contradiction is posited to arise from cooperative benefits in heterogeneous environments. To investigate this hypothesis, we carried out a six-year field study on two neighboring groups of golden snub-nosed monkey (Rhinopithecus roxellana), a species representing the northernmost distribution of colobine primates. Results showed that the groups adjusted their movement and habitat selection in response to fluctuating climates and spatiotemporal variability of resources, indicative of a dynamic foraging strategy. Notably, during the cold, resource-scarce conditions in winter, the large group occupied food-rich habitats but did not exhibit significantly longer daily travel distances than the smaller neighboring group. Subsequently, we compiled an eco-behavioral dataset of 52 colobine species to explore their evolutionary trajectories. Analysis of this dataset suggested that the increase in group size may have evolved via home range expansion in response to the cold and heterogeneous climates found at higher altitudes or latitudes. Hence, we developed a multi-benefits framework to interpret the formation of larger groups by integrating environmental heterogeneity. In cold and diverse environments, even smaller groups require larger home ranges to meet their dynamic survival needs. The spatiotemporal distribution of high-quality resources within these expanded home ranges facilitates more frequent interactions between groups, thereby encouraging social aggregation into larger groups. This process enhances the benefits of collaborative actions and reproductive opportunities, while simultaneously optimizing travel costs through a dynamic foraging strategy.
The gastrointestinal tract is essential for food digestion, nutrient absorption, waste elimination, and microbial defense. Single-cell transcriptome profiling of the intestinal tract has greatly enriched our understanding of cellular diversity, functional heterogeneity, and their importance in intestinal tract development and disease. Although such profiling has been extensively conducted in humans and mice, the single-cell gene expression landscape of the pig cecum remains unexplored. Here, single-cell RNA sequencing was performed on 45 572 cells obtained from seven cecal samples in pigs at four different developmental stages (days (D) 30, 42, 150, and 730). Analysis revealed 12 major cell types and 38 subtypes, as well as their distinctive genes, transcription factors, and regulons, many of which were conserved in humans. An increase in the relative proportions of CD8+ T and Granzyme A (low expression) natural killer T cells (GZMAlow NKT) cells and a decrease in the relative proportions of epithelial stem cells, Tregs, RHEX+ T cells, and plasmacytoid dendritic cells (pDCs) were noted across the developmental stages. Moreover, the post-weaning period exhibited an up-regulation in mitochondrial genes, COX2 and ND2, as well as genes involved in immune activation in multiple cell types. Cell-cell crosstalk analysis indicated that IBP6+ fibroblasts were the main signal senders at D30, whereas IBP6 fibroblasts assumed this role at the other stages. NKT cells established interactions with epithelial cells and IBP6+ fibroblasts in the D730 cecum through mediation of GZMA-F2RL1/F2RL2 pairs. This study provides valuable insights into cellular heterogeneity and function in the pig cecum at different development stages.
Birds exhibit extraordinary mobility and remarkable navigational skills, obtaining guidance cues from the Earth’s magnetic field for orientation and long-distance movement. Bird species also show tremendous diversity in navigation strategies, with considerable differences even within the same taxa and among individuals from the same population. The highly conserved iron and iron-sulfur cluster binding magnetoreceptor (MagR) protein is suggested to enable animals, including birds, to detect the geomagnetic field and navigate accordingly. Notably, MagR is also implicated in other functions, such as electron transfer and biogenesis of iron-sulfur clusters, raising the question of whether variability exists in its biochemical and biophysical features among species, particularly birds. In the current study, we conducted a comparative analysis of MagR from two different bird species, including the migratory European robin and the homing pigeon. Sequence alignment revealed an extremely high degree of similarity between the MagRs of these species, with only three sequence variations. Nevertheless, two of these variations underpinned significant differences in metal binding capacity, oligomeric state, and magnetic properties. These findings offer compelling evidence for the marked differences in MagR between the two avian species, potentially explaining how a highly conserved protein can mediate such diverse functions.
Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein (LBP), but the underlying epigenetic mechanisms remain understudied. Herein, LBP-/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP-/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP-/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein β (C/EBPβ) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene SCD as potential regulators and therapeutic targets.
The gut microbiome interacts with the host to maintain body homeostasis, with gut microbial dysbiosis implicated in many diseases. However, the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear. This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation. We conducted succinylome analysis of hippocampal proteins in germ-free (GF) and specific pathogen-free (SPF) mice and metagenomic analysis of feces from SPF mice. These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice. Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins, including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice. We constructed a panoramic map of gut microbiota-regulated succinylation, acetylation, and phosphorylation, and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways. Pearson correlation analysis indicated that 13 taxa, predominantly belonging to the Bacteroidetes phylum, were correlated with the biological functions of post-translational modifications. Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways. This study highlights the hippocampal physiological changes induced by the absence of gut microbiota, and proteomic quantification of succinylation, phosphorylation, and acetylation, contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.
Parkinson’s disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog (Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP+)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP+-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.
Geographical background and dispersal ability may strongly influence assemblage dissimilarity; however, these aspects have generally been overlooked in previous large-scale beta diversity studies. Here, we examined whether the patterns and drivers of taxonomic beta diversity (TBD) and phylogenetic beta diversity (PBD) of breeding birds in China vary across (1) regions on both sides of the Hu Line, which demarcates China’s topographical, climatic, economic, and social patterns, and (2) species with different dispersal ability. TBD and PBD were calculated and partitioned into turnover and nestedness components using a moving window approach. Variables representing climate, habitat heterogeneity, and habitat quality were employed to evaluate the effects of environmental filtering. Spatial distance was considered to assess the impact of dispersal limitation. Variance partitioning analysis was applied to assess the relative roles of these variables. In general, the values of TBD and PBD were high in mountainous areas and were largely determined by environmental filtering. However, different dominant environmental filters on either side of the Hu Line led to divergent beta diversity patterns. Specifically, climate-driven species turnover and habitat heterogeneity-related species nestedness dominated the regions east and west of the line, respectively. Additionally, bird species with stronger dispersal ability were more susceptible to environmental filtering, resulting in more homogeneous assemblages. Our results indicated that regions with distinctive geographical backgrounds may present different ecological factors that lead to divergent assemblage dissimilarity patterns, and dispersal ability determines the response of assemblages to these ecological factors. Identifying a single universal explanation for the observed pattern without considering these aspects may lead to simplistic or incomplete conclusions. Consequently, a comprehensive understanding of large-scale beta diversity patterns and effective planning of conservation strategies necessitate the consideration of both geographical background and species dispersal ability.
Regulatory sequences and transposable elements (TEs) account for a large proportion of the genomic sequences of species; however, their roles in gene transcription, especially tissue-specific expression, remain largely unknown. Pigs serve as an excellent animal model for studying genomic sequence biology due to the extensive diversity among their wild and domesticated populations. Here, we conducted an integrated analysis using H3K27ac ChIP-seq, H3K4me3 ChIP-seq, and RNA-seq data from 10 different tissues of seven fetuses and eight closely related adult pigs. We aimed to annotate the regulatory elements and TEs to elucidate their associations with histone modifications and mRNA expression across different tissues and developmental stages. Based on correlation analysis between mRNA expression and H3K27ac and H3K4me3 peak activity, results indicated that H3K27ac exhibited stronger associations with gene expression than H3K4me3. Furthermore, 1.45% of TEs overlapped with either the H3K27ac or H3K4me3 peaks, with the majority displaying tissue-specific activity. Notably, a TE subfamily (LTR4C_SS), containing binding motifs for SIX1 and SIX4, showed specific enrichment in the H3K27ac peaks of the adult and fetal ovaries. RNA-seq analysis also revealed widespread expression of TEs in the exons or promoters of genes, including 4 688 TE-containing transcripts with distinct development stage-specific and tissue-specific expression. Of note, 1 967 TE-containing transcripts were enriched in the testes. We identified a long terminal repeat (LTR), MLT1F1, acting as a testis-specific alternative promoter in SRPK2 (a cell cycle-related protein kinase) in our pig dataset. This element was also conserved in humans and mice, suggesting either an ancient integration of TEs in genes specifically expressed in the testes or parallel evolutionary patterns. Collectively, our findings demonstrate that TEs are deeply embedded in the genome and exhibit important tissue-specific biological functions, particularly in the reproductive organs.
We examined the global biogeography of the Scytodes thoracica group of spitting spiders based on 23 years of sampling at the species level (61 species in the thoracica group and 84 species of Scytodes) using DNA data from six loci. Our results indicated that the thoracica group initially dispersed from Southeast Asia to East Africa between 46.5 and 33.0 million years ago, and dispersal events intensified between Southeast/South Asia and East/South Africa from the early to late Miocene. The timing of these events indicates that Asian-African faunal exchange of the thoracica group was driven by the Indian monsoon, and the pattern of dispersal suggests that colonialization took root when the Indian monsoon shifted from a North-South direction to an East-West direction from the middle Eocene.
The insect mitogenome is typically a compact circular molecule with highly conserved gene contents. Nonetheless, mitogenome structural variations have been reported in specific taxa, and gene rearrangements, usually the tRNAs, occur in different lineages. Because synapomorphies of mitogenome organizations can provide information for phylogenetic inferences, comparative analyses of mitogenomes have been given increasing attention. However, most studies use a very few species to represent the whole genus, tribe, family, or even order, overlooking potential variations at lower taxonomic levels, which might lead to some incorrect inferences. To provide new insights into mitogenome organizations and their implications for phylogenetic inference, this study conducted comparative analyses for mitogenomes of three social bee tribes (Meliponini, Bombini, and Apini) based on the phylogenetic framework with denser taxonomic sampling at the species and population levels. Comparative analyses revealed that mitogenomes of Apini and Bombini are the typical type, while those of Meliponini show diverse variations in mitogenome sizes and organizations. Large inverted repeats (IRs) cause significant gene rearrangements of protein coding genes (PCGs) and rRNAs in Indo-Malay/Australian stingless bee species. Molecular evolution analyses showed that the lineage with IRs have lower dN/dS ratios for PCGs than lineages without IRs, indicating potential effects of IRs on the evolution of mitochondrial genes. The finding of IRs and different patterns of gene rearrangements suggested that Meliponini is a hotspot in mitogenome evolution. Unlike conserved PCGs and rRNAs whose rearrangements were found only in the mentioned lineages within Meliponini, tRNA rearrangements are common across all three tribes of social bees, and are significant even at the species level, indicating that comprehensive sampling is needed to fully understand the patterns of tRNA rearrangements, and their implications for phylogenetic inference.
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (22:6n-3, DHA), play crucial roles in the reproductive health of vertebrates, including humans. Nevertheless, the underlying mechanism related to this phenomenon remains largely unknown. In this study, we employed two zebrafish genetic models, i.e., elovl2-/- mutant as an endogenous DHA-deficient model and fat1 (omega-3 desaturase encoding gene) transgenic zebrafish as an endogenous DHA-rich model, to investigate the effects of DHA on oocyte maturation and quality. Results show that the elovl2-/- mutants had much lower fecundity and poorer oocyte quality than the wild-type controls, while the fat1 zebrafish had higher fecundity and better oocyte quality than wild-type controls. DHA deficiency in elovl2-/- embryos led to defects in egg activation, poor microtubule stability, and reduced pregnenolone levels. Further study revealed that DHA promoted pregnenolone synthesis by enhancing transcription of cyp11a1, which encodes the cholesterol side-chain cleavage enzyme, thereby stabilizing microtubule assembly during oogenesis. In turn, the hypothalamic-pituitary-gonadal axis was enhanced by DHA. In conclusion, using two unique genetic models, our findings demonstrate that endogenously synthesized DHA promotes oocyte maturation and quality by promoting pregnenolone production via transcriptional regulation of cyp11a1.
Monitoring the prevalence of antimicrobial resistance genes (ARGs) is vital for addressing the global crisis of antibiotic-resistant bacterial infections. Despite its importance, the characterization of ARGs and microbiome structures, as well as the identification of indicators for routine ARG monitoring in pig farms, are still lacking, particularly concerning variations in antimicrobial exposure in different countries or regions. Here, metagenomics and random forest machine learning were used to elucidate the ARG profiles, microbiome structures, and ARG contamination indicators in pig manure under different antimicrobial pressures between China and Europe. Results showed that Chinese pigs exposed to high-level antimicrobials exhibited higher total and plasmid-mediated ARG abundances compared to those in European pigs (P<0.05). ANT(6)-Ib, APH(3')-IIIa, and tet(40) were identified as shared core ARGs between the two pig populations. Furthermore, the core ARGs identified in pig populations were correlated with those found in human populations within the same geographical regions. Lactobacillus and Prevotella were identified as the dominant genera in the core microbiomes of Chinese and European pigs, respectively. Forty ARG markers and 43 biomarkers were able to differentiate between the Chinese and European pig manure samples with accuracies of 100% and 98.7%, respectively. Indicators for assessing ARG contamination in Chinese and European pigs also achieved high accuracy (r=0.72–0.88). Escherichia flexneri in both Chinese and European pig populations carried between 21 and 37 ARGs. The results of this study emphasize the importance of global collaboration in reducing antimicrobial resistance risk and provide validated indicators for evaluating the risk of ARG contamination in pig farms.
Glycogen serves as the principal energy reserve for metabolic processes in aquatic shellfish and substantially contributes to the flavor and quality of oysters. The Jinjiang oyster (Crassostrea ariakensis) is an economically and ecologically important species in China. In the present study, RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) were performed to investigate gene expression and chromatin accessibility variations in oysters with different glycogen contents. Analysis identified 9 483 differentially expressed genes (DEGs) and 7 215 genes with significantly differential chromatin accessibility (DCAGs) were obtained, with an overlap of 2 600 genes between them. Notably, a significant proportion of these genes were enriched in pathways related to glycogen metabolism, including “Glycogen metabolic process” and “Starch and sucrose metabolism”. In addition, genome-wide association study (GWAS) identified 526 single nucleotide polymorphism (SNP) loci associated with glycogen content. These loci corresponded to 241 genes, 63 of which were categorized as both DEGs and DCAGs. This study enriches basic research data and provides insights into the molecular mechanisms underlying the regulation of glycogen metabolism in C. ariakensis.
A total of 10 specimens of Alcyonacea corals were collected at depths ranging from 905 m to 1 633 m by the manned submersible Shenhai Yongshi during two cruises in the South China Sea (SCS). Based on mitochondrial genomic characteristics, morphological examination, and sclerite scanning electron microscopy, the samples were categorized into four suborders (Calcaxonia, Holaxonia, Scleraxonia, and Stolonifera), and identified as 9 possible new cold-water coral species. Assessments of GC-skew dissimilarity, phylogenetic distance, and average nucleotide identity (ANI) revealed a slow evolutionary rate for the octocoral mitochondrial sequences. The nonsynonymous (Ka) to synonymous (Ks) substitution ratio (Ka/Ks) suggested that the 14 protein-coding genes (PCGs) were under purifying selection, likely due to specific deep-sea environmental pressures. Correlation analysis of the median Ka/Ks values of five gene families and environmental factors indicated that the genes encoding cytochrome b (cyt b) and DNA mismatch repair protein (mutS) may be influenced by environmental factors in the context of deep-sea species formation. This study highlights the slow evolutionary pace and adaptive mechanisms of deep-sea corals.
Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.
PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase that phosphorylates Parkin and other proteins, plays a crucial role in mitophagy and protection against neurodegeneration. Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson’s disease. However, there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration. Additionally, PINK1 knockout pigs (Sus scrofa) do not appear to exhibit neurodegeneration. In our recent work involving non-human primates, we found that PINK1 is selectively expressed in primate brains, while absent in rodent brains. To extend this to other species, we used multiple antibodies to examine the expression of PINK1 in pig tissues. In contrast to tissues from cynomolgus monkeys (Macaca fascicularis), our data did not convincingly demonstrate detectable PINK1 expression in pig tissues. Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation, as observed in cultured monkey cells. A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain. Consistently, PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD. These findings provide new evidence that PINK1 expression is specific to primates, underscoring the importance of non-human primates in investigating PINK1 function and pathology related to PINK1 deficiency.
Animal models are extensively used in all aspects of biomedical research, with substantial contributions to our understanding of diseases, the development of pharmaceuticals, and the exploration of gene functions. The field of genome modification in rabbits has progressed slowly. However, recent advancements, particularly in CRISPR/Cas9-related technologies, have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases, including cardiovascular disorders, immunodeficiencies, aging-related ailments, neurological diseases, and ophthalmic pathologies. These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice. This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine, underscoring their impact and future potential in translational medicine.
Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

Vol 44, No 6 (18 November 2023)

Indexed by SCI-E

2022 影响因子 4.9

2/176 Zoology (Q1)

2023 Journal Citation Reports®

中科院期刊分区动物学一区

双月刊, 始于 1980

主编: Yong-Gang Yao

ISSN 2095-8137

CN 53-1229/Q

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