摘要: Selective regulation of gene expression across distinct brain regions is crucial for establishing and maintaining subdivision identities. DNA methylation, a key regulator of gene transcription, modulates transcriptional activity through the conversion of 5-methylcytosine(5mC) to 5-hydroxymethylcytosine(5hmC). While DNA methylation is hypothesized to play an essential role in shaping brain identity by influencing gene expression patterns, its direct contribution, especially in primates, remains largely unexplored. This study examined DNA methylation landscapes and transcriptional profiles across four brain regions, including the cortex, cerebellum, striatum, and hippocampus, using samples from 12 rhesus monkeys.The cerebellum exhibited distinct epigenetic and transcriptional signatures, with differentially methylated regions(DMRs) significantly enriched in metabolic pathways. Notably, genes harboring clustered differentially hydroxymethylated regions(DhMRs) overlapped with those implicated in schizophrenia. Moreover, 5mC located1 kb upstream of the ATG start codon was correlated with gene expression and exhibited region-specific associations with 5hmC. These findings provide insights into the coordinated regulation of cerebellum-specific 5mC and5hmC, highlighting their potential roles in defining cerebellar identity and contributing to neuropsychiatric diseases.

摘要: The domesticated silkworm(Bombyx mori) has evolved a highly efficient nitrogen utilization system to support silk production. The silk glands play a pleiotropic role in sequestering nitrogen resources for silk synthesis,mitigating aminoacidemia by assimilating free amino acids,and reallocating nitrogen during metamorphosis through programmed cell death. However, the specific functions of nitrogen metabolism-related genes in this process remain unclear. Using CRISPR/Cas9-based gene editing,mutations were generated in glutamine synthetase(GS),glutamate synthetase(GOGAT), asparagine synthetase(AS), glutamate dehydrogenase(GDH) and glutamate oxaloacetate transaminase 1(GOT1). Disruption of GS,GOGAT, and AS consistently reduced silkworm cocoon and pupal weight and significantly down-regulated silk protein gene transcription, whereas GOT1 mutation had no such effect. GOGAT mutants exhibited abnormally enlarged silk glands, whereas GS and AS mutants showed delayed programmed cell death in the silk glands. In contrast, GOT1 mutants displayed normal silk gland morphology but were consistently smaller. Disruption of GS, GOGAT, and AS led to more extensive transcriptional changes, including altered expression of transcription factors in the silk glands, compared with GOT1 mutants.Both GS and GOGAT mutants exhibited up-regulation of AS and GDH, while only GOGAT mutants displayed elevated AS enzymatic activity, suggesting that GOGAT may compete with AS for glutamine in the silk glands to support silk protein synthesis. AS mutants showed significantly elevated GOT activity and up-regulation of several metabolic pathways, indicating that AS may functionally interact with GOT in regulating both silk gland development and programmed cell death during metamorphosis.

摘要: Cichlid fishes are a textbook example for adaptive radiations, since they diversified into several hundred highly specialized species in each of three great East African lakes. Even scale-eating, an extremely specialized feeding mode, evolved independently multiple times in these radiations and in Lake Tanganyika alone, six endemic scale-eating species occupy this extremely specialized ecological niche. Perissodus microlepis went a step further, by evolving bilaterally asymmetrical heads with an intra-specific polymorphism where left-and rightheaded morphs predominantly scrape scales from the opposite sides of their prey. While the bilateral asymmetry of scale-eating cichlids has been known, exactly which craniofacial features explain the laterality of the heads remained unclear. Here we aimed, by utilizing microcomputed tomography(μCT), to resolve this issue of how bilateral symmetry in the skeletal structure is broken in scale-eating Perissodus. Our 3D geometric morphometrics analysis clearly separated and identified the two groups of either left-or right-headed fish. In addition, we observed consistent asymmetric volume changes in the premaxilla,maxilla, and mandible of the craniofacial structures, where left-headed fish have larger jaw elements on the right side,and vice versa. The bimodality implies that the effect sizes of environmental factors might be minor while genetics might be responsible to a larger extent for the asymmetry observed in their head morphology. High-speed video analyses of attacks by asymmetrical morphotypes revealed that they utilize their asymmetrical mouth protrusion, as well as lateralized behavior, to re-orientate the gape towards the preferred side of their prey fish to more efficiently scrape scales.

摘要: In Chinese culture,the dragon symbolizes faith,strength,courage,and an air of mystery.In 2024,guided by this auspicious emblem and supported by authors,readers,reviewers,and editorial board members,Zoological Research(ZR) has successfully completed its annual publishing objectives,achieved significant progress,and secured continued national funding support through its selection for China's Science and Technology Journal Excellence Action Plan (phaseⅡ).As we enter the year of the snake,a symbol of wisdom,renewal,transformation,and growth,we take this opportunity to reflect on past achievements and express our sincere appreciation to all contributors.

摘要: DNA2, a multifunctional enzyme with structure-specific nuclease, 5'-to-3' helicase, and DNA-dependent ATPase activities, plays a pivotal role in the cellular response to DNA damage. However, its involvement in cerebral ischemia/reperfusion(I/R) injury remains to be elucidated.This study investigated the involvement of DNA2 in cerebral I/R injury using conditional knockout(cKO) mice(Nestin-Cre) subjected to middle cerebral artery occlusion(MCAO), an established model of cerebral I/R. Results demonstrated a gradual up-regulation of DNA2 expression,peaking at 72 h post-MCAO. Notably, DNA2 cKO mice exhibited more pronounced brain injury, neurological deficits, and neuronal apoptosis within the penumbra following MCAO. Additionally, DNA2 expression was elevated in an oxygen-glucose deprivation/reoxygenation(OGD/R) cell culture model, and DNA2 knockdown(KD)exacerbated neuronal apoptosis and oxidative stress.Transcriptome analysis of ischemic penumbra tissues via RNA sequencing revealed significant down-regulation of Homer1 in DNA2 cKO mice. Furthermore, in vitro experiments demonstrated that overexpression of Homer1a ameliorated DNA2 KD-induced neuronal apoptosis. Collectively, these findings demonstrate that DNA2 deficiency exacerbates cerebral I/R injury through the down-regulation of Homer1a, highlighting a novel regulatory axis in ischemic neuroprotection.

摘要: Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-β plaques, neurofibrillary tangles, and reactive astrogliosis. Developing effective diagnostic,preventative, and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease. Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally, these models are limited in their ability to elucidate the interplay among amyloid-β plaques,neurofibrillary tangles, and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation. In this study, we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice) designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms. Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection, these mice exhibited pronounced astrogliosis, substantial amyloid-β plaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss, elevated astrocytic GABA levels, and significant spatial memory deficits. Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis. These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-β plaque and neurofibrillary tangle-associated pathology. The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.

摘要: Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however, its abnormal accumulation is also implicated in various neurological disorders. The olfactory bulb(OB), an early target in neurodegenerative diseases, acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles. This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate(FAC). Olfactory function was assessed through olfactory discrimination tests, while iron levels in OB tissues, cerebrospinal fluid(CSF), and serum were quantified using inductively coupled plasma mass spectrometry(ICP-MS), immunohistochemical staining,and iron assays. Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis. Results showed that intranasal FAC administration impaired olfactory function,accompanied by iron deposition in the olfactory mucosa and OB, as well as damage to olfactory sensory neurons.Notably, these effects occurred without elevations in CSF or serum iron levels. OB iron accumulation activated multiple immune cells, including microglia and astrocytes,but did not trigger ferroptosis. Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity, with an abundance of neuroglia and neurons. Among neurons, GABAergic neurons were the most prevalent, followed by glutamatergic and dopaminergic neurons, while cholinergic and serotonergic neurons were sparsely distributed. Under iron-stressed conditions, oligodendrocytes, dopaminergic neurons, and glutamatergic neurons exhibited significant damage, while GABAergic neurons remained unaffected.These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress,offering novel insights into the loss of specific cell types in the OB during iron dysregulation.

摘要: Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD), supporting the “body-first” hypothesis. However,there remains a notable absence of PD-specific animal models induced by inflammatory cytokines. This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1, identified in our previous research. The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models. Based on these findings, 2-month-old C57BL/6J mice were intravenously administered CXCL1(20 ng/kg/day) for 2 weeks(5 days per week), successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model.These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling. The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1. Linoleic acid, a PPAR-γ activator, significantly mitigated MPTPand CXCL1-induced toxicity and reduced serum CXCL1levels. In addition, the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks, offering an efficient platform for studying inflammation-driven processes in PD. The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.

摘要: Increasing evidence implicates disruptions in testicular fatty acid metabolism as a contributing factor in nonobstructive azoospermia(NOA), a severe form of male infertility. However, the precise mechanisms linking fatty acid metabolism to NOA pathogenesis have not yet been fully elucidated. Multi-omics analyses, including microarray analysis, single-cell RNA sequencing(scRNA-seq), and metabolomics, were utilized to investigate disruptions in fatty acid metabolism associated with NOA using data from public databases. Results identified ACSL6, ACSBG2, and OLAH as key genes linked to fatty acid metabolism dysregulation, suggesting their potential causative roles in NOA. A marked reduction in omega-3 polyunsaturated fatty acids, especially docosahexaenoic acid(DHA), was observed, potentially contributing to the pathological process of NOA. Sertoli cells in NOA patients exhibited apparent fatty acid metabolic dysfunction, with PPARG identified as a key transcription factor(TF) regulating this process. Functional analyses demonstrated that PPARG is crucial for maintaining blood-testis barrier(BTB) integrity and promoting spermatogenesis via regulation of fatty acid metabolism. These findings reveal the pivotal role of fatty acid metabolism in NOA and identify PPARG as a potential therapeutic target.

摘要: Severe combined immunodeficiency disease(SCID),characterized by profound immune system dysfunction,can lead to life-threatening infections and death. Animal models play a pivotal role in elucidating biological processes and advancing therapeutic strategies. Recent advances in gene-editing technologies, including zincfinger nucleases(ZFNs), transcription activator-like effector nucleases(TALENs), CRISPR/Cas9, and base editing, have significantly enhanced the generation of SCID models. These models have not only deepened our understanding of disease pathophysiology but have also driven progress in cancer therapy, stem cell transplantation, organ transplantation, and infectious diseasemanagement.Thisreviewprovidesa comprehensive overview of current SCID models generated using novel gene-editing approaches,highlighting their potential applications in translational medicine and their role in advancing biomedical research.