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当前状态:  doi: 10.24272/j.issn.2095-8137.2023.390
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Most of the described Mesozoic ants belong to stem groups that existed only during the Cretaceous. The earliest crown ants have hitherto been known from the Turonian (Late Cretaceous, ca. 94–90Ma) deposits of the USA, Kazakhstan, and Botswana. However, the discovery of an alate male in Kachin amber from the earliest Cenomanian (ca. 99Ma), representing a new genus and species, <i>Antiquiformica alata</i>, revises the narrative on ant diversification. <i>Antiquiformica</i> is clearly differentiated from all known males of stem ants in the distinctly geniculate antenna with an elongate scape, extending far beyond the occipital margin of the head and half the length of the funiculus, and in the partly reduced forewing venation. Furthermore, the combination of a one-segmented waist with a well-developed node, an elongate scape extending beyond the occipital margin, and reduced forewing venation, in particular, the completely reduced crossveins m-cu and rs-m and absence of closed cells rm and mcu, demonstrates that the fossil belongs to the extant subfamily Formicinae. The result of Fourier Transform Infrared Spectroscopy (FTIR) indicates that the piece of amber containing <i>A. alata</i> originated from the mines of Kachin, Myanmar. The new fossil significantly revises our understanding of the early evolution of Formicinae. The discovery of <i>Antiquiformica</i> in Cenomanian amber indicates that the subfamily Formicinae arose at least by the start of the Late Cretaceous, while crown ants certainly arose earlier, in the earliest Cretaceous or even in the Late Jurassic, although paleontological evidence is lacking to support the latter hypothesis.
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当前状态:  doi: 10.24272/j.issn.2095-8137.2024.028
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Iridovirus has become a great threat to global aquaculture due to its high mortality, while the molecular events in virus pathogenesis are not well elucidated. Here, the multi-omics approach was performed with Singapore grouper iridovirus (SGIV)-infected groupers, and the roles of key metabolites were investigated. SGIV induced obvious histopathological damage and changes of metabolic enzymes in liver. Besides, SGIV significantly decreased the contents of lipid droplets, triglycerides, cholesterol, and lipoprotein. Metabolome analysis showed that that the differentially metabolites were enriched in 19 pathways, and lipid metabolites, including glycerophosphates and alpha-linolenic acid (ALA) were down-regulated, which is consistent with the disturbed lipid homeostasis in liver. Combining with transcriptomic and metabolomic data, the top enriched pathways were related to cell growth and death, nucleotide, carbohydrate, amino acid, and lipid metabolisms, supporting the conclusion that SGIV infection induced liver metabolic reprogramming. Integrative transcriptomic and proteomic analysis indicated that SGIV infection activated the crucial molecular events in phagosome-immune depression-metabolism dysregulation-necrosis signaling cascade. Of note, integrative multi-omics analysis demonstrated that metabolites ALA and linoleic acid (LA) were consumed, while L-glutamic acid (GA) was accumulated, accompanied by the alteration of immune, inflammation, and cell death related genes. Further experimental data showed that ALA, but not GA suppressed SGIV replication by activating host antioxidant and anti-inflammatory effects. Together, our findings for the first time provide a comprehensive resource to understand the landscape of host response dynamics during fish iridovirus infection, and highlight the antiviral roles of ALA in the prevention and treatment for iridovirus diseases.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.369
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As an ectotherm, fish are highly susceptible to changes in temperature, which can have a significant impact on their reproductive cycles. In this study, we examined the fertility and histological characteristics of zebrafish (Danio rerio) ovaries exposed to a temperature gradient from the species' thermopreferendum temperature of 27°C to low temperatures of 22°C, 20°C, and 13°C for two weeks. Comparative analyses of metabolomics (six biological replicates for each temperature) and transcriptomics (four biological replicates for each temperature) were conducted under the four distinct temperature conditions. We found low temperatures inhibited the development of oocyte and from which identified differential metabolites involved in steroid hormone production, antioxidant function, and catabolism of lipid and protein. The disrupted reproductive hormones, increased proteolysis and lipid degradation greatly halted oocyte development and egg maturation. More interestingly, we found a significant increase in bile acids content in the ovary of the cold treated fish, and proved the bile acids constitute a significant contributing factor to ovarian failure. Our findings offer valuable insights into the mechanisms governing the response of fish reproduction to cold stress.
当前状态:  doi: 10.24272/j.issn.2095-8137.2024.010
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The cellular heterogeneity of spermatogenic cells is determined by the complex differentiation process of spermatogenesis. However, effectively revealing the overall regulatory mechanism of mammalian spermatogenic cell development and differentiation via traditional methods is difficult. With the development of technology, the emergence of single-cell transcriptome sequencing technology has partially solved this problem. Many single-cell sequencing protocols have been reported. Here, we describe the principles of 10X Genomics technology and summarize the methods for downstream analysis of single-cell transcriptome sequencing data. We explore the mechanisms of single-cell transcriptome sequencing technology in revealing the heterogeneity of testicular ecological niche cells, the establishment and imbalance of testicular immune homeostasis during the process of human spermatogenesis, the process of abnormal spermatogenesis in humans, and, ultimately, the molecular evolution of mammalian spermatogenesis.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.407
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Substance Use Disorders (SUDs) present complex central nervous system pathologies that significantly impact global health, social, and economic wellbeing. Current pharmacological therapies for SUDs face limitations, prompting the exploration of vaccine-based immunotherapy as an alternative. This Perspective outlines the mechanisms and benefits of SUD vaccines, discussing key design concepts essential for efficacy and specificity. Traditional protein carrier-based vaccines have limitations, which we address through a proposed biomimetic hapten-carrier-adjuvant integrated molecular vaccine strategy. This novel approach utilizes polymers as carriers for hapten conjugation, offering advantages over traditional carriers, including tunable physical and chemical properties, reduced immunogenicity, biocompatibility, and safety. The strategy emphasizes the spatial organization of haptens, adjuvants, and B cell targeting peptides, and their self-assembly into virus-like nanoparticles for targeted delivery. The potential of these versatile polymer carriers for developing polyvalent vaccines against SUDs is also highlighted.
当前状态:  doi: 10.24272/j.issn.2095-8137.2023.323
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Mild traumatic brain injury (mTBI) induced posttraumatic headache (PTH) is a pressing public health concern that continues to be a leading cause of disability worldwide. PTH is often accompanied by neurological disorders, however, the exact underlying mechanism remains largely unknown. Identifying the potential biomarkers may prompt diagnosis and develop effective treatments for mTBI induced PTH. Here, a mouse model of mTBI-induced PTH was established, and a series of technologies were employed to investigate the effects on cerebral structure and functions during the short-term recovery periods. Results indicated that mTBI induced PTH exhibited balance deficits during early stage of post injury. The metabolic kinetics studies revealed that variations in neurotransmitters were most prominent in the regions of cerebellum (CE), temporal lobe/cortex, and hippocampus in the early stages of PTH. Additionally, variations of functional activities and connectivity were further detected in the brain in the early stage of PTH, particularly in CE and temporal cortex. These findings suggested that CE and temporal cortex play central roles in the investigation of the mechanism of PTH. Moreover, the results suggested that GABA and glutamate might serve as potential diagnostic or prognostic biomarkers for PTH. Future studies should investigate the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, and these two regions can be utilized as the targets for the non-invasive stimulation treatment technologies in the future clinical treatment.
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.2095-8137.2023.320
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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.2095-8137.2023.336
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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.2095-8137.2023.302
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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.2095-8137.2023.280
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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.2095-8137.2023.315
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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.2095-8137.2023.286
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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.2095-8137.2023.205
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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.
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Special Column on Large Animal Model
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.
Huntington’s disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin (HTT) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.
Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models 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 recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models.
Mutations in mitochondrial DNA (mtDNA) are maternally inherited and have the potential to cause severe disorders. Mitochondrial replacement therapies, including spindle, polar body, and pronuclear transfers, are promising strategies for preventing the hereditary transmission of mtDNA diseases. While pronuclear transfer has been used to generate mitochondrial replacement mouse models and human embryos, its application in non-human primates has not been previously reported. In this study, we successfully generated four healthy cynomolgus monkeys (Macaca fascicularis) via female pronuclear transfer. These individuals all survived for more than two years and exhibited minimal mtDNA carryover (3.8%–6.7%), as well as relatively stable mtDNA heteroplasmy dynamics during development. The successful establishment of this non-human primate model highlights the considerable potential of pronuclear transfer in reducing the risk of inherited mtDNA diseases and provides a valuable preclinical research model for advancing mitochondrial replacement therapies in humans.
Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques (Macaca mulatta, MMU) and crab-eating macaques (M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from 84 samples (41 MFA samples and 43 MMU samples) encompassing 14 common tissues. Our findings revealed a small fraction of genes (3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover, 19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary, this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.
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 with evident divergence in body size, providing an excellent opportunity to investigate the genetic basis of body size variation in vertebrates. Herein, we performed phylotranscriptomic analysis and reconstructed the phylogeny of 13 epinephelids originating from the South China Sea. Two genetic clades with an estimated divergence time of approximately 15.4 million years ago were correlated with large and small body size, respectively. A total of 180 rapidly evolving genes and two positively selected genes were identified between the two groups. Functional enrichment analyses of these candidate genes revealed distinct enrichment categories between the two groups. These pathways and genes may play important roles in body size variation in groupers through complex regulatory networks. Based on our results, 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, resulting in body size divergence between the two locally adapted populations. These findings provide important insights into the genetic mechanisms underlying body size variation in groupers and species differentiation.
The leopard coral grouper (Plectropomus leopardus) is a species of significant economic importance. Although artificial cultivation of P. leopardus has thrived in recent decades, the advancement of selective breeding has been hindered by the lack of comprehensive population genomic 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 P. leopardus, we examined genomic regions exhibiting selective sweeps by analyzing the nucleotide diversity (θπ) and fixation index (FST) in these four clusters. Using these high-coverage resequencing data, we successfully constructed the first haplotype reference panel specific to P. leopardus. This achievement holds promise for enabling high-quality, cost-effective imputation methods. Additionally, we combined low-coverage sequencing data with imputation techniques for a genome-wide association study, aiming 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 detailed investigation of growth-related SNPs across the eight clusters revealed that cluster 5 harbored the most promising candidate SNPs, showing potential 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 P. leopardus.
Dormancy represents a fascinating adaptive strategy for organisms to survive in unforgiving environments. After a period of dormancy, organisms often exhibit exceptional resilience. This period is typically divided into hibernation and aestivation based on seasonal patterns. However, the mechanisms by which organisms adapt to their environments during dormancy, as well as the potential relationships between different states of dormancy, deserve further exploration. Here, we selected Perccottus glenii and Protopterus annectens as the primary subjects to study hibernation and aestivation, respectively. Based on histological and transcriptomic analysis of multiple organs, we discovered that dormancy involved a coordinated functional response across organs. Enrichment analyses revealed noteworthy disparities between the two dormant species in their responses to extreme temperatures. Notably, similarities in gene expression patterns pertaining to energy metabolism, neural activity, and biosynthesis were noted during hibernation, suggesting a potential correlation between hibernation and aestivation. To further explore the relationship between these two phenomena, we analyzed other dormancy-capable species using data from publicly available databases. This comparative analysis revealed that most orthologous genes involved in metabolism, cell proliferation, and neural function exhibited consistent expression patterns during dormancy, indicating that the observed similarity between hibernation and aestivation may be attributable to convergent evolution. In conclusion, this study enhances our comprehension of the dormancy phenomenon and offers new insights into the molecular mechanisms underpinning vertebrate dormancy.
Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males. However, the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood, especially in teleosts. In this study, 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 assay for transposase accessible chromatin with sequencing (ATAC-seq) results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase (scd) and fatty acid synthase (fasn). Androgen response element (ARE) motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor (ar)-/- and wild-type (WT) zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue, lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis enzymes. The Ar agonist BMS-564929 reduced the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a (acaca), fasn, and scd expression. Mechanistically, the rescue effect of testosterone on cyp17a1-/- fish in terms of phenotypes was abolished when ar was additionally depleted. Collectively, these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.
Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish (Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse (Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.
The autotetraploid Carassius auratus (4nRR, 4n=200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2n=100, RR). In the current study, we demonstrated that chromatophores and pigment changes directly caused the coloration and variation of 4nRR skin (red in RCC, brownish-yellow 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. Results revealed that scarb1, associated with carotenoid metabolism, underwent significant down-regulation in 4nRR. Efficient editing of this candidate pigment gene provided clear evidence of its significant role in RCC coloration. Subsequently, we identified four divergent scarb1 homeologs in 4nRR: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting biased and allele-specific expression in the skin. Remarkably, after precise editing of both the 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-gray phenotype. Concurrently, the proportional areas of the cyan-gray 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 an autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.
Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking 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 the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the 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, but only reduced in the DG subregion during the chronic phase. Furthermore, 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. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also 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.
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.
The Chinese tree shrew (Tupaia belangeri chinensis), a member of the mammalian order Scandentia, exhibits considerable similarities with primates, including humans, in aspects of its nervous, immune, and metabolic systems. These similarities have established the tree shrew as a promising experimental model for biomedical research on cancer, infectious diseases, metabolic disorders, and mental health conditions. Herein, we used meta-transcriptomic sequencing to analyze plasma, as well as oral and anal swab samples, from 105 healthy asymptomatic tree shrews to identify the presence of potential zoonotic viruses. In total, eight mammalian viruses with complete genomes were identified, belonging to six viral families, including Flaviviridae, Hepeviridae, Parvovirinae, Picornaviridae, Sedoreoviridae, and Spinareoviridae. Notably, the presence of rotavirus was recorded in tree shrews for the first time. Three viruses — hepacivirus 1, parvovirus, and picornavirus — exhibited low genetic similarity (<70%) with previously reported viruses at the whole-genome scale, indicating novelty. Conversely, three other viruses — hepacivirus 2, hepatovirus A and hepevirus — exhibited high similarity (>94%) to known viral strains. Phylogenetic analyses also revealed that the rotavirus and mammalian orthoreovirus identified in this study may be novel reassortants. These findings provide insights into the diverse viral spectrum present in captive Chinese tree shrews, highlighting the necessity for further research into their potential for cross-species transmission.
As highly social animals, Indo-Pacific humpback dolphins (Sousa chinensis) exhibit community differentiation. Nevertheless, our understanding of the external and internal factors influencing these dynamics, as well as their spatiotemporal variations, is still limited. In the present study, variations in the social structure of an endangered Indo-Pacific humpback dolphin population in Xiamen Bay, China, were monitored over two distinct periods (2007–2010 and 2017–2019) to analyze the effects of habitat utilization and the composition of individuals within the population. In both periods, the population demonstrated a strikingly similar pattern of social differentiation, characterized by the division of individuals into two main clusters and one small cluster. Spatially, the two primary clusters occupied the eastern and western waters, respectively, although the core distribution area of the eastern cluster shifted further eastward between the two periods. Despite this distribution shift, the temporal stability of the social structure and inter-associations within the eastern cluster remained unaffected. A subset of 16 individuals observed in both periods, comprising 51.6% and 43.2% of the population in each respective period, emerged as a foundational element of the social structure and may be responsible for sustaining social structure stability, especially during the 2007–2010 period. These observations suggest that the composition of dominant individuals, an internal factor, had a more substantial influence on the formation of the social network than changes in habitat use, an external factor. Consequently, the study proposes distinct conservation measures tailored to each of the two main clusters.

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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