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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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>.
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.
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.
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.
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.
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.