来源于诱导多能干细胞衍生的间充质干细胞的细胞外囊泡可通过调节ILK-PI3K/AKT通路减轻化疗诱导的小鼠卵巢损伤
化疗是导致育龄期妇女生育力下降的重要原因，可使卵巢组织中的卵泡数量严重下降，从而引起内分泌紊乱、生殖功能障碍或原发性卵巢功能不全（POI）。最近的研究表明，间充质干细胞分泌的细胞外囊泡在许多退行性疾病中都可以发挥治疗作用。该研究发现，移植来自人类诱导多能干细胞衍生的间充质干细胞（iPSC-MSCs）的细胞外囊泡（EVs），可明显减轻化疗引起的POI小鼠模型的卵巢损伤，恢复卵巢卵泡数量，改善颗粒细胞增殖，并抑制化疗引起的小鼠颗粒细胞、体外培养的卵巢和POI小鼠卵巢中的凋亡。进一步的研究发现，iPSC-MSC-EVs的处理可以激活ILK-PI3K/AKT通路的上调，逆转了化疗引起的ILK-PI3K/AKT通路的下调，进而抑制了细胞的凋亡，加速细胞周期和促进细胞增殖。iPSC-MSC-EVs富含miRNAs，体外实验的结果表明，iPSC-MSC-EVs可能是通过转移靶向ILK通路基因的功能性miRNAs发挥作用。总的来说，该研究为改善女性化疗患者的卵巢损伤和提高POI患者的卵巢功能的治疗方法提供了一个新思路，并初步阐明了iPSC-MSC-EVs减轻化疗引起的卵巢损伤的基本分子机制。
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通过梯度下降算法分解用于小鼠腰骶脊髓运动测绘的光遗传运动基元力场
产生对生存至关重要的多样化运动行为是所有动物的中枢神经系统（CNS）面临的挑战。在运动执行期间，CNS执行复杂的计算以控制大量的神经肌肉骨骼元素。模块化运动神经控制理论提出脊髓中间神经元组织成离散的模块，这些模块可以由运动神经系统线性组合以产生各种行为模式。这些模块过去被表证为刺激诱发力场，力场包括肢体端点在肢体工作区不同位置产生的肌肉等长收缩力量。在该文中，我们询问由不同脊髓刺激引起的力场是否确实代表了运动控制的最基本单元，或者每个力场本身是有限数量的更基本的运动模块的组合。为了探索更基本的模块，我们用光遗传学刺激了有完整CNS及脊髓化的 Thy1-ChR2 转基因小鼠（n=21）的腰骶脊髓，从尽可能多的单一刺激位点（每只小鼠 20-70 个位点）以最低必要光度引发后肢端点力场。我们发现由此产生的各种力场无法通过仅几个聚类进行简单分类。我们使用梯度下降将力场进一步分解为它们的基本力场，其线性组合解释了力场的可变性。在小鼠中，我们确定了 4-5 个基本力场，它们沿着腰骶脊髓具有部分可定位但重叠的表征。基本力场的结构和脊髓分布方式使得从头端到尾端穿过腰骶脊髓的行波可能会产生摆动相到支撑相的后肢步态周期。这些基本力场可能代表更基本的运动神经控制子模块，而CNS可以灵活地合并这些子模块以生成用于构建不同行为的运动控制模块库。
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动物模型解析先天性心脏病的遗传特征
先天性心脏病是出生缺陷致死的主要原因之一，发病率约占新生儿的1%。虽然数百个基因鉴定出来与先天性心脏病遗传有关，但是先天性心脏病的遗传病因及发病机制仍知之甚少。这主要是由于先天性心脏病的可变的表现度和不完全外显造成的。该综述回顾了先天性心脏病的单基因遗传及寡基因遗传的证据，及新生突变，常见突变和遗传修饰因子的作用。为了进一步了解致病机制，我们使用跨物种的单细胞测序数据来揭示先天性心脏病基因在人类和小鼠胚胎心脏中的细胞表达特征。深入了解 CHD 的遗传病因可能有助于实施精准医学和产前诊断，从而促进早期干预以改善 CHD 患者的预后。
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病毒性脑炎研究进展：病毒传播、宿主免疫反应和实验动物模型
在过去的几个世纪，大流行性病毒感染导致多次公共卫生危机的爆发。在所有的病毒感染中，嗜神经性病毒感染累及脑膜和脑实质的病毒性脑炎，因其较高的死亡率和致残率而受到越来越多的关注。明确常见嗜神经病毒的感染途径和宿主免疫反应机制对于减少病毒传播和提高抗病毒治疗效果至关重要。该文从嗜神经病毒的种类及在人体的传播途径、宿主免疫反应的研究进展以及病毒性脑炎研究常用的实验动物模型等三大方面进行了系统性的梳理和总结。该综述有助于深入了解嗜神经病毒感染的致病和人体免疫反应机制的最新进展，并为如何应对大流行感染提供有价值的科学依据和展望。
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在演化框架下界定蜜蜂亚种以制定合理的保护策略
对东方蜜蜂Apis cerana Fabricius, 1793的保护迫在眉睫，但仍缺乏切实可行的行动方案。这种广域分布的昆虫同时具有趋同和趋异适应的特征，很大程度上造成了形态表型特征的混淆和亚种分类地位的混乱。模糊的亚种界限危及到蜜蜂保护的基础，如果我们无法明确目标和优先级，就无法保护它们。在该研究中，我们调查了来自东方蜜蜂亚洲大陆支系主要种群的362头工蜂的基因组单碱基核苷酸变异，以解析进化历史是如何塑造其种群结构的。研究基于核基因组 SNPs 初步划分了八个亚种级别的遗传单元，其中七个边缘单元均表现出独立的单系性，并与广域分布的中部单元之间存在显著的遗传分化。同时，我们证明：包括体型大小等性状在内的大部分经典蜜蜂形态特征，都与所属生境的气候特征存在密切关联。此类特征并不能反映种群间真实的演化关系，故不适用于亚种的界定。相反，翅脉特征表现出对环境的相对独立性，并支持了核基因组数据所界定的亚种划分。线粒体系统发生分析进一步表明，目前的亚种结构是共同祖先种群经历多次独立分化的结果。根据该研究的发现，我们提出了使用演化独立性、有效形态特征和地理隔离作为亚种划分证据的方法。我们正式定义和描述了东方蜜蜂亚洲大陆支系的八个亚种。阐明东方蜜蜂的演化历史和亚种定义，有助于为广域和局域性分布的蜜蜂遗传单元提供定制化的保护策略，并指导蜂群引种和繁育。
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单细胞转录组图谱揭示四氯化碳诱导进行性肝纤维化中的阶段特异性应答
慢性肝损伤会带来进行性肝纤维化，并最终导致肝硬化，而肝硬化在全球范围内的发病率和死亡率一直居高不下。目前临床上依然缺乏有效治疗肝纤维化的方法，尤其是针对晚期患者。这一现状部分来自于我们对肝脏细胞的异质性以及不同纤维化阶段细胞特异性反应的认知还很有限。为了揭示哺乳动物肝纤维化过程中的多细胞调控网络，我们利用四氯化碳诱导的小鼠肝纤维化模型，构建了包含不同纤维化阶段、囊括所有主要肝脏细胞类型的总计49 919细胞核的单细胞核转录组图谱。整合数据分析首先区分出肝细胞、肝星状细胞和内皮细胞对损伤的相继反应，我们进一步重建了纤维化过程中的细胞间相互作用和基因调控网络。这些分析揭示了一系列以往被忽略的众多方面的变化细节，包括肝细胞增殖能力的耗竭、中心周围肝细胞代谢功能紊乱、肝星状细胞激活后的凋亡清除失调、促纤维化信号的累积以及从抗血管生成向促血管生成的转变。因此，我们的数据为深入理解肝纤维化进程中的分子基础提供了重要参考。
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2023, 44(4): 675-677.
doi: 10.24272/j.issn.2095-8137.2022.484
2023, 44(4): 678-692.
doi: 10.24272/j.issn.2095-8137.2022.354
The stress response is essential for animal self-defense and survival. However, species may exhibit stress response variation depending on their specific environmental and selection pressures. Blind cavefish dwell in cave environments, which differ markedly in stressors and resource availability compared to surface aquatic environments. However, whether blind cavefish exhibit differences in stress response as an adaptation to their cave environments remains unclear. Here, we investigated differences in stress response in six closely related Triplophysa species, including three blind cavefish (T. longibarbata, T. jiarongensis, and T. rosa) and three normal-sighted river fish (T. nasobarbatula, T. dongsaiensis, and T. bleekeri). Results showed that blind cavefish exhibited a range of distinct behavioral responses compared to sighted river fish, including greater levels of activity, shorter duration of freezing, absence of erratic movements or thrashing behavior, and opposite behavioral trends over time. Furthermore, the cavefish species demonstrated attenuated increases in metabolic rate in response to stressors related to novel environments. Cave-dwelling T. rosa also exhibited lower basal hypothalamic-pituitary-inter-renal (HPI) axis-related gene expression levels and stress hormone concentrations compared to river-dwelling T. bleekeri. These results suggest that blind cavefish may have lost their behavioral stress response, potentially mediated by a reduction in basal activity of the HPI axis, thus enabling the conservation of energy by reducing unnecessary expenditure in energy-limited caves.
2023, 44(4): 693-697.
doi: 10.24272/j.issn.2095-8137.2022.266
2023, 44(4): 698-700.
doi: 10.24272/j.issn.2095-8137.2022.164
The sizes of Astyanax mexicanus blind cavefish populations of North-East Mexico are demographic parameters of great importance for investigating a variety of ecological, evolutionary, and conservation issues. However, few estimates have been obtained. For these mobile animals living in an environment difficult to explore as a whole, methods based on capture-mark-recapture are appropriate, but their feasibility and interpretation of results depend on several assumptions that must be carefully examined. Here, we provide evidence that minimally invasive genetic identification from captures at different time intervals (three days and three years) can give insights into cavefish population size dynamics as well as other important demographic parameters of interest. We also provide tools to calibrate sampling and genotyping efforts necessary to reach a given level of precision. Our results suggest that the El Pachón cave population is currently very small, of an order of magnitude of a few hundreds of individuals, and is distributed in a relatively isolated area. The probable decline in population size in the El Pachón cave since the last census in 1971 raises serious conservation issues.
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doi: 10.24272/j.issn.2095-8137.2023.029
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We describe a new species of Nanohyla from the Song Hinh Protected Forest in Phu Yen Province, southern Vietnam, based on an integrative taxonomic approach. The new species represents a divergent lineage (16S rRNA gene uncorrected P-distance>5.3%), which clearly differs from any other Nanohyla species based on a series of morphological characters, most notably the presence of white spots on the top of its head. Morphologically, Nanohyla albopunctata sp. nov. is characterized by small body size (male SVL 18.2–20.2 mm); moderately slender body habitus; rounded snout; distinct tympanum; rounded canthus rostralis; loreal region slightly concave; skin on dorsum tubercular, ventral surfaces smooth; mid-vertebral skin ridge and dorsomedial stripe absent; superciliary tubercles absent; supratympanic fold indistinct; finger I reduced, less than half of finger II in length; II–IV fingers bearing discs with weak terminal grooves; two distinct palmar tubercles; two metatarsal tubercles; hindlimbs long, tibiotarsal articulation of adpressed limb reaching well beyond snout; fingers free of webbing; toe webbing formula: I 1–2 II 1–2 III 1–2 IV 1½–1 V; dorsum varying from dark gray to yellowish-gray, with darker "teddy-bear"-shaped brown marking; posterior surfaces of thighs and cloacal region with several brown stripes; chin, chest, and belly with gray mottling. We also report on the male advertisement call of the new species, characterized by a series of rattling sounds, consisting of 2–6 calls lasting 0.63 s, with 1–3 initial pulses and 5–9 successive pulses at a dominant frequency of ca. 3.02 kHz. To date, Nanohyla albopunctata sp. nov. is known only from the monsoon lowland tropical forest at the foothills of the Ca Mountain Range in Phu Yen Province of southern Vietnam at elevations of 200–400 m a.s.l., uncommon for the generally mountain-restricted Nanohyla genus. Our discovery brings the total number of Nanohyla species to 10, seven of which occur in Vietnam. We preliminary suggest the new species be considered as Data Deficient (DD) following the IUCN Red List categories.
We describe a new species of Nanohyla from the Song Hinh Protected Forest in Phu Yen Province, southern Vietnam, based on an integrative taxonomic approach. The new species represents a divergent lineage (16S rRNA gene uncorrected P-distance>5.3%), which clearly differs from any other Nanohyla species based on a series of morphological characters, most notably the presence of white spots on the top of its head. Morphologically, Nanohyla albopunctata sp. nov. is characterized by small body size (male SVL 18.2–20.2 mm); moderately slender body habitus; rounded snout; distinct tympanum; rounded canthus rostralis; loreal region slightly concave; skin on dorsum tubercular, ventral surfaces smooth; mid-vertebral skin ridge and dorsomedial stripe absent; superciliary tubercles absent; supratympanic fold indistinct; finger I reduced, less than half of finger II in length; II–IV fingers bearing discs with weak terminal grooves; two distinct palmar tubercles; two metatarsal tubercles; hindlimbs long, tibiotarsal articulation of adpressed limb reaching well beyond snout; fingers free of webbing; toe webbing formula: I 1–2 II 1–2 III 1–2 IV 1½–1 V; dorsum varying from dark gray to yellowish-gray, with darker "teddy-bear"-shaped brown marking; posterior surfaces of thighs and cloacal region with several brown stripes; chin, chest, and belly with gray mottling. We also report on the male advertisement call of the new species, characterized by a series of rattling sounds, consisting of 2–6 calls lasting 0.63 s, with 1–3 initial pulses and 5–9 successive pulses at a dominant frequency of ca. 3.02 kHz. To date, Nanohyla albopunctata sp. nov. is known only from the monsoon lowland tropical forest at the foothills of the Ca Mountain Range in Phu Yen Province of southern Vietnam at elevations of 200–400 m a.s.l., uncommon for the generally mountain-restricted Nanohyla genus. Our discovery brings the total number of Nanohyla species to 10, seven of which occur in Vietnam. We preliminary suggest the new species be considered as Data Deficient (DD) following the IUCN Red List categories.
2023, 44(3): 451-466.
doi: 10.24272/j.issn.2095-8137.2023.031
Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis, a major cause of morbidity and mortality worldwide. However, there are currently no effective anti-fibrotic therapies available, especially for late-stage patients, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific responses in different fibrosis stages. To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes, we generated a single-nucleus transcriptomic atlas encompassing 49 919 nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride (CCl4)-induced progressive liver fibrosis. Integrative analysis distinguished the sequential responses to injury of hepatocytes, hepatic stellate cells and endothelial cells. Moreover, we reconstructed the cell-cell interactions and gene regulatory networks implicated in these processes. These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions, dysfunction for clearance by apoptosis of activated hepatic stellate cells, accumulation of pro-fibrotic signals, and the switch from an anti-angiogenic to a pro-angiogenic program during CCl4-induced progressive liver fibrosis. Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.
2023, 44(3): 467-482.
doi: 10.24272/j.issn.2095-8137.2022.379
Chalcidoidea is one of the most biologically diverse groups among Hymenoptera. Members are characterized by extraordinary parasitic lifestyles and extensive host ranges, among which several species attack plants or serve as pollinators. However, higher-level chalcidoid relationships remain controversial. Here, we performed mitochondrial phylogenomic analyses for major clades (18 out of 25 families) of Chalcidoidea based on 139 mitochondrial genomes. The compositional heterogeneity and conflicting backbone relationships in Chalcidoidea were assessed using various datasets and tree inferences. Our phylogenetic results supported the monophyly of 16 families and polyphyly of Aphelinidae and Pteromalidae. Our preferred topology recovered the relationship (Mymaridae+(Signiphoridae+Leucospidae)+(Chalcididae+((Perilampidae+Eucharitidae)+ remaining Chalcidoidea)))). The monophyly of Agaonidae and Sycophaginae was rejected, while the gall-associated ((Megastigmidae+Ormyridae)+(Ormocerinae+Eurytomidae)) relationship was supported in most results. A six-gene inversion may be a synapomorphy for most families, whereas other derived gene orders may introduce confusion in phylogenetic signals at deeper nodes. Dating estimates suggested that Chalcidoidea arose near the Jurassic/Cretaceous boundary and that two dynamic shifts in diversification occurred during the evolution of Chalcidoidea. We hypothesized that the potential codiversification between chalcidoids and their hosts may be crucial for accelerating the diversification of Chalcidoidea. Ancestral state reconstruction analyses supported the hypothesis that gall-inducers were mainly derived from parasitoids of gall-inducers, while other gall-inducers were derived from phytophagous groups. Taken together, these findings advance our understanding of mitochondrial genome evolution in the major interfamilial phylogeny of Chalcidoidea.
2023, 44(3): 483-493.
doi: 10.24272/j.issn.2095-8137.2022.414
Despite the urgent need for conservation consideration, strategic action plans for the preservation of the Asian honeybee, Apis cerana Fabricius, 1793, remain lacking. Both the convergent and divergent adaptations of this widespread insect have led to confusing phenotypical traits and inconsistent infraspecific taxonomy. Unclear subspecies boundaries pose a significant challenge to honeybee conservation efforts, as it is difficult to effectively prioritize conservation targets without a clear understanding of subspecies identities. Here, we investigated genome variations in 362 worker bees representing almost all populations of mainland A. cerana to understand how evolution has shaped its population structure. Whole-genome single nucleotide polymorphisms (SNPs) based on nuclear sequences revealed eight putative subspecies, with all seven peripheral subspecies exhibiting mutually exclusive monophyly and distinct genetic divergence from the widespread central subspecies. Our results demonstrated that most classic morphological traits, including body size, were related to the climatic variables of the local habitats and did not reflect the true evolutionary history of the organism. Thus, such morphological traits were not suitable for subspecific delineation. Conversely, wing vein characters showed relative independence to the environment and supported the subspecies boundaries inferred from nuclear genomes. Mitochondrial phylogeny further indicated that the present subspecies structure was a result of multiple waves of population divergence from a common ancestor. Based on our findings, we propose that criteria for subspecies delineation should be based on evolutionary independence, trait distinction, and geographic isolation. We formally defined and described eight subspecies of mainland A. cerana. Elucidation of the evolutionary history and subspecies boundaries enables a customized conservation strategy for both widespread and endemic honeybee conservation units, guiding colony introduction and breeding.
2023, 44(3): 494-504.
doi: 10.24272/j.issn.2095-8137.2022.535
The coronavirus disease 2019 (COVID-19) pandemic has greatly damaged human society, but the origins and early transmission patterns of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen remain unclear. Here, we reconstructed the transmission networks of SARS-CoV-2 during the first three and six months since its first report based on ancestor-offspring relationships using BANAL-52-referenced mutations. We explored the position (i.e., root, middle, or tip) of early detected samples in the evolutionary tree of SARS-CoV-2. In total, 6 799 transmission chains and 1 766 transmission networks were reconstructed, with chain lengths ranging from 1–9 nodes. The root node samples of the 1 766 transmission networks were from 58 countries or regions and showed no common ancestor, indicating the occurrence of many independent or parallel transmissions of SARS-CoV-2 when first detected (i.e., all samples were located at the tip position of the evolutionary tree). No root node sample was found in any sample (n=31, all from the Chinese mainland) collected in the first 15 days from 24 December 2019. Results using six-month data or RaTG13-referenced mutation data were similar. The reconstruction method was verified using a simulation approach. Our results suggest that SARS-CoV-2 may have already been spreading independently worldwide before the outbreak of COVID-19 in Wuhan, China. Thus, a comprehensive global survey of human and animal samples is essential to explore the origins of SARS-CoV-2 and its natural reservoirs and hosts.
2023, 44(3): 505-521.
doi: 10.24272/j.issn.2095-8137.2022.440
Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1-Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.
2023, 44(3): 522-524.
doi: 10.24272/j.issn.2095-8137.2023.110
2023, 44(3): 525-542.
doi: 10.24272/j.issn.2095-8137.2023.025
Viral infections have led to many public health crises and pandemics in the last few centuries. Neurotropic virus infection-induced viral encephalitis (VE), especially the symptomatic inflammation of the meninges and brain parenchyma, has attracted growing attention due to its high mortality and disability rates. Understanding the infectious routes of neurotropic viruses and the mechanism underlying the host immune response is critical to reduce viral spread and improve antiviral therapy outcomes. In this review, we summarize the common categories of neurotropic viruses, viral transmission routes in the body, host immune responses, and experimental animal models used for VE study to gain a deeper understanding of recent progress in the pathogenic and immunological mechanisms under neurotropic viral infection. This review should provide valuable resources and perspectives on how to cope with pandemic infections.
2023, 44(3): 543-555.
doi: 10.24272/j.issn.2095-8137.2022.389
Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes (CD68, CD163, CD206, TMEM119, CSF3R, CX3CR1, TREM2, CD11b, CSF1R, and F4/80) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes (NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain.
2023, 44(3): 556-558.
doi: 10.24272/j.issn.2095-8137.2023.091
2023, 44(3): 559-576.
doi: 10.24272/j.issn.2095-8137.2022.406
Parkinson’s disease (PD) relates to defective mitochondrial quality control in the dopaminergic motor network. Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset, pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra (SNpc). In a reciprocal manner, LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation. Pharmacological intervention in these disease-modifying pathways may facilitate the development of novel PD therapeutics, despite the current lack of an established drug evaluation model. As such, we reviewed the feasibility of employing the versatile global Pink1 knockout (KO) rat model as a self-sufficient, spontaneous PD model for investigating both disease etiology and drug pharmacology. These rats retain clinical features encompassing basal mitophagic flux changes with PD progression. We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.
2023, 44(3): 577-590.
doi: 10.24272/j.issn.2095-8137.2022.463
Congenital heart disease (CHD) is observed in up to 1% of live births and is one of the leading causes of mortality from birth defects. While hundreds of genes have been implicated in the genetic etiology of CHD, their role in CHD pathogenesis is still poorly understood. This is largely a reflection of the sporadic nature of CHD, as well as its variable expressivity and incomplete penetrance. We reviewed the monogenic causes and evidence for oligogenic etiology of CHD, as well as the role of de novo mutations, common variants, and genetic modifiers. For further mechanistic insight, we leveraged single-cell data across species to investigate the cellular expression characteristics of genes implicated in CHD in developing human and mouse embryonic hearts. Understanding the genetic etiology of CHD may enable the application of precision medicine and prenatal diagnosis, thereby facilitating early intervention to improve outcomes for patients with CHD.
2023, 44(3): 591-603.
doi: 10.24272/j.issn.2095-8137.2022.487
Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation. Nonetheless, current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models, which are not transferable or reproducible in large animal models due to different factors such as: (i) complex and varied features of human ischemic cardiac disease (ICD), which are challenging to mimic in animal models, (ii) significant differences in surgical techniques applied, and (iii) differences in cardiovascular anatomy and physiology between small versus large animals. This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury (IRI), as well as the different methods used to induce and assess IRI, and the obstacles faced in using large animals for translational research in the settings of cardiac IR.
2023, 44(3): 604-619.
doi: 10.24272/j.issn.2095-8137.2022.276
Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system (CNS) of all animals. During movement execution, the CNS performs complex calculations to control a large number of neuromusculoskeletal elements. The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns. These modules have been previously represented as stimulus-evoked force fields (FFs) comprising isometric limb-endpoint forces across workspace locations. Here, we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules. To probe for potentially more elementary modules, we optogenetically stimulated the lumbosacral spinal cord of intact and spinalized Thy1-ChR2 transgenic mice (n=21), eliciting FFs from as many single stimulation loci as possible (20–70 loci per mouse) at minimally necessary power. We found that the resulting varieties of FFs defied simple categorization with just a few clusters. We used gradient descent to further decompose the FFs into their underlying basic force fields (BFFs), whose linear combination explained FF variability. Across mice, we identified 4–5 BFFs with partially localizable but overlapping representations along the spinal cord. The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral spinal cord may generate a swing-to-stance gait cycle. These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.
2023, 44(3): 620-635.
doi: 10.24272/j.issn.2095-8137.2022.340
Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma, causing endocrine disorder, reproductive dysfunction, and primary ovarian insufficiency (POI). Recent studies have suggested that extracellular vesicles (EVs) secreted from mesenchymal stem cells (MSCs) exert therapeutic effects in various degenerative diseases. In this study, transplantation of EVs from human induced pluripotent stem cell-derived MSCs (iPSC-MSC-EVs) resulted in significant restoration of ovarian follicle numbers, improved granulosa cell proliferation, and inhibition of apoptosis in chemotherapy-damaged granulosa cells, cultured ovaries, and in vivo ovaries in mice. Mechanistically, treatment with iPSC-MSC-EVs resulted in up-regulation of the integrin-linked kinase (ILK) -PI3K/AKT pathway, which is suppressed during chemotherapy, most likely through the transfer of regulatory microRNAs (miRNAs) targeting ILK pathway genes. This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.
2023, 44(3): 636-649.
doi: 10.24272/j.issn.2095-8137.2022.531
Telomeres are nucleoprotein structures located at the end of each chromosome, which function in terminal protection and genomic stability. Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo. As relatively long-lived mammals based on body size, bats display unique telomeric patterns, including the up-regulation of genes involved in alternative lengthening of telomeres (ALT), DNA repair, and DNA replication. At present, however, the relevant molecular mechanisms remain unclear. In this study, we performed cross-species comparison and identified EPAS1, a well-defined oxygen response gene, as a key telomeric protector in bat fibroblasts. Bat fibroblasts showed high expression of EPAS1, which enhanced the transcription of shelterin components TRF1 and TRF2, as well as DNA repair factor RAD50, conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion. Based on a human single-cell transcriptome atlas, we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation. Using in vitro-cultured human pulmonary endothelial cells, we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans. In addition, the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence. In conclusion, we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging, drawing insights from the longevity of bats.
2023, 44(3): 650-662.
doi: 10.24272/j.issn.2095-8137.2022.281
Hereditary spastic paraplegia (HSP) is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons. Due to the advancement of next-generation sequencing, more than 70 novel HSP disease-causing genes have been identified in the past decade. Despite this, our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor. One major challenge in studying HSP pathogenicity is selective neuronal vulnerability, characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations, despite the presence of germline disease-causing variants in every cell of the patient. Furthermore, disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration. In the current review, we explore the correlation between transcriptomic data and clinical manifestations, as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice, expression patterns of different genes in the brain during development, and single-cell transcriptomic data from related tissues. Furthermore, we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.
2023, 44(3): 663-674.
doi: 10.24272/j.issn.2095-8137.2022.418
The biological function of the novel zinc-finger SWIM domain-containing protein family (ZSWIM) during embryonic development remains elusive. Here, we conducted a genome-wide analysis to explore the evolutionary processes of the ZSWIM gene family members in mice, Xenopus tropicalis, zebrafish, and humans. We identified nine putative ZSWIM genes in the human and mouse genome, eight in the Xenopus genome, and five in the zebrafish genome. Based on multiple sequence alignment, three members, ZSWIM5, ZSWIM6, and ZSWIM8, demonstrated the highest homology across all four species. Using available RNA sequencing (RNA-seq) data, ZSWIM genes were found to be widely expressed across different tissues, with distinct tissue-specific properties. To identify the functions of the ZSWIM protein family during embryogenesis, we examined temporal and spatial expression patterns of zswim family genes in Xenopus embryos. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that each member had a distinct expression profile. Whole-mount in situ hybridization showed that both zswim1 and zswim3 were maternally expressed genes; zswim5 and zswim6 were expressed throughout embryogenesis and displayed dynamic expression in the brain, eyes, somite, and bronchial arch at the late tailbud stages; zswim7 was detected in the eye area; zswim8 showed a dynamic expression pattern during the tailbud stages, with expression detected in the brain, eyes, and somite; zswim9 was faintly expressed throughout embryonic development. This study provides a foundation for future research to delineate the functions of ZSWIM gene members.
2023, 44(3): 675-675.
The stress response is essential for animal self-defense and survival. However, species may exhibit stress response variation depending on their specific environmental and selection pressures. Blind cavefish dwell in cave environments, which differ markedly in stressors and resource availability compared to surface aquatic environments. However, whether blind cavefish exhibit differences in stress response as an adaptation to their cave environments remains unclear. Here, we investigated differences in stress response in six closely related Triplophysa species, including three blind cavefish (T. longibarbata, T. jiarongensis, and T. rosa) and three normal-sighted river fish (T. nasobarbatula, T. dongsaiensis, and T. bleekeri). Results showed that blind cavefish exhibited a range of distinct behavioral responses compared to sighted river fish, including greater levels of activity, shorter duration of freezing, absence of erratic movements or thrashing behavior, and opposite behavioral trends over time. Furthermore, the cavefish species demonstrated attenuated increases in metabolic rate in response to stressors related to novel environments. Cave-dwelling T. rosa also exhibited lower basal hypothalamic-pituitary-inter-renal (HPI) axis-related gene expression levels and stress hormone concentrations compared to river-dwelling T. bleekeri. These results suggest that blind cavefish may have lost their behavioral stress response, potentially mediated by a reduction in basal activity of the HPI axis, thus enabling the conservation of energy by reducing unnecessary expenditure in energy-limited caves.
The sizes of Astyanax mexicanus blind cavefish populations of North-East Mexico are demographic parameters of great importance for investigating a variety of ecological, evolutionary, and conservation issues. However, few estimates have been obtained. For these mobile animals living in an environment difficult to explore as a whole, methods based on capture-mark-recapture are appropriate, but their feasibility and interpretation of results depend on several assumptions that must be carefully examined. Here, we provide evidence that minimally invasive genetic identification from captures at different time intervals (three days and three years) can give insights into cavefish population size dynamics as well as other important demographic parameters of interest. We also provide tools to calibrate sampling and genotyping efforts necessary to reach a given level of precision. Our results suggest that the El Pachón cave population is currently very small, of an order of magnitude of a few hundreds of individuals, and is distributed in a relatively isolated area. The probable decline in population size in the El Pachón cave since the last census in 1971 raises serious conservation issues.
Vol 44, No 3 (18 May 2023)
Indexed by SCI-E
2021 影响因子 6.975
2/176 Zoology (Q1)
2022 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
期刊动态More >
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