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Whole-genome sequencing identifies novel genes for autism in Chinese trios. 全基因组测序发现中国三胞胎中的自闭症新基因
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-07 DOI: 10.1007/s11427-023-2564-8
Suhua Chang, Jia Jia Liu, Yilu Zhao, Tao Pang, Xiangyu Zheng, Zhirui Song, Anyi Zhang, Xuping Gao, Lingxue Luo, Yanqing Guo, Jing Liu, Li Yang, Lin Lu

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (P<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (SCN2A, NF1, SHANK3, CHD8 etc.), several high confidence genes were highlighted by a series of functional analyses, including CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1, and MRPL12, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of de novo variants found in patient was significantly associated with the parents' ages at the birth of the child, and gender with trend. We also identified small de novo structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.

自闭症谱系障碍(ASD)是一种神经发育障碍,具有高度遗传性和异质性。要充分了解其遗传学,需要进行全基因组测序(WGS),但在中国人群中利用 WGS 数据进行的 ASD 研究非常有限。在本研究中,我们对 334 人进行了 WGS 研究,其中包括 112 名 ASD 患者及其非 ASD 父母。我们在 85 个病例中发现了 146 个编码区的从头变异和 60 个编码区的遗传变异。通过将这些变异与关联模型相结合,我们发现了 33 个潜在的风险基因(P
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引用次数: 0
RpL38 modulates germ cell differentiation by controlling Bam expression in Drosophila testis. RpL38通过控制果蝇睾丸中Bam的表达调节生殖细胞分化
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s11427-024-2646-3
Yang Fang, Fengchao Zhang, Fangzhen Zhao, Jiajia Wang, Xinkai Cheng, Fei Ye, Jiayu He, Long Zhao, Ying Su

Switching from mitotic spermatogonia to meiotic spermatocytes is critical to producing haploid sperms during male germ cell differentiation. However, the underlying mechanisms of this switch remain largely unexplored. In Drosophila melanogaster, the gene RpL38 encodes the ribosomal protein L38, one component of the 60S subunit of ribosomes. We found that its depletion in spermatogonia severely diminished the production of mature sperms and thus led to the infertility of male flies. By examining the germ cell differentiation in testes, we found that RpL38-knockdown blocked the transition from spermatogonia to spermatocytes and accumulated spermatogonia in the testis. To understand the intrinsic reason for this blockage, we conducted proteomic analysis for these spermatogonia populations. Differing from the control spermatogonia, the accumulated spermatogonia in RpL38-knockdown testes already expressed many spermatocyte markers but lacked many meiosis-related proteins, suggesting that spermatogonia need to prepare some important proteins for meiosis to complete their switch into spermatocytes. Mechanistically, we found that the expression of bag of marbles (bam), a crucial determinant in the transition from spermatogonia to spermatocytes, was inhibited at both the mRNA and protein levels upon RpL38 depletion. We also confirmed that the bam loss phenocopied RpL38 RNAi in the testis phenotype and transcriptomic profiling. Strikingly, overexpressing bam was able to fully rescue the testis abnormality and infertility of RpL38-knockdown flies, indicating that bam is the key effector downstream of RpL38 to regulate spermatogonia differentiation. Overall, our data suggested that germ cells start to prepare meiosis-related proteins as early as the spermatogonial stage, and RpL38 in spermatogonia is required to regulate their transition toward spermatocytes in a bam-dependent manner, providing new knowledge for our understanding of the transition process from spermatogonia to spermatocytes in Drosophila spermatogenesis.

在雄性生殖细胞分化过程中,从有丝分裂精原细胞到减数分裂精母细胞的转换是产生单倍体精子的关键。然而,这种转换的内在机制在很大程度上仍未得到探索。在黑腹果蝇中,RpL38 基因编码核糖体蛋白 L38,它是核糖体 60S 亚基的一个组成部分。我们发现,精原细胞中该基因的缺失会严重减少成熟精子的产生,从而导致雄蝇不育。通过研究睾丸中生殖细胞的分化,我们发现 RpL38 的敲除阻断了精原细胞向精母细胞的转变,并在睾丸中积累了精原细胞。为了了解这种阻滞的内在原因,我们对这些精原细胞群进行了蛋白质组分析。与对照组精原细胞不同,RpL38敲除后的睾丸中积累的精原细胞已经表达了许多精母细胞标志物,但却缺乏许多减数分裂相关蛋白,这表明精原细胞需要为减数分裂准备一些重要蛋白才能完成向精母细胞的转变。从机理上讲,我们发现精原细胞向精母细胞转变过程中的一个重要决定因素--弹珠袋(bam)的表达在RpL38缺失后的mRNA和蛋白水平上都受到了抑制。我们还证实,在睾丸表型和转录组图谱分析中,bam缺失与RpL38 RNAi表型相同。令人震惊的是,过表达bam能够完全挽救RpL38敲除蝇的睾丸异常和不育,这表明bam是RpL38下游调控精原细胞分化的关键效应物。总之,我们的数据表明,生殖细胞早在精原细胞阶段就开始准备减数分裂相关蛋白,而精原细胞中的RpL38需要以依赖bam的方式调控精原细胞向精母细胞的转变,这为我们了解果蝇精子发生过程中精原细胞向精母细胞的转变过程提供了新的知识。
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引用次数: 0
MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy. 间充质干细胞介导的线粒体转移可恢复勒伯遗传性视神经病变神经祖细胞的线粒体 DNA 和功能。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-08 DOI: 10.1007/s11427-024-2647-8
Rui Wang, Feixiang Bao, Manjiao Lu, Xiaoyun Jia, Jiahui Xiao, Yi Wu, Qingjiong Zhang, Xingguo Liu

Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.

勒伯遗传性视神经病变(LHON)是一种与线粒体 DNA(mtDNA)突变有关的线粒体疾病,会使人衰弱。遗憾的是,由于线粒体替代方面的挑战,LHON 患者的现有治疗方案非常有限。在我们的研究中,我们将LHON尿液细胞重编程为诱导多能干细胞(iPSCs),并将其分化为神经祖细胞(NPCs)和神经元,用于疾病建模。我们的研究发现,LHON神经元的mtDNA突变水平明显较高,线粒体功能降低,证实了疾病的表型。然而,通过将 LHON iPSC 衍生的 NPC 与间充质干细胞(MSCs)共培养,我们观察到 LHON 神经元的突变 mtDNA 得到了明显的挽救,线粒体代谢功能也得到了显著改善。这些研究结果表明,与间充质干细胞共同培养可以增强 LHON 神经元的线粒体功能,即使在它们分化成神经元之后也是如此。这一发现有望成为LHON患者的一种潜在治疗策略。
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引用次数: 0
Huangjing is not only a good medicine but also an affordable healthy diet. 黄精不仅是一味良药,也是一种经济实惠的健康饮食。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-27 DOI: 10.1007/s11427-024-2713-1
Donghong Chen, Dun Si, Jingjing Liu, Jinping Si
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引用次数: 0
Unveiling the evolutionary dynamics of microRNA-targeted plant laccase genes. 揭示微RNA靶向植物漆酶基因的进化动态。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-22 DOI: 10.1007/s11427-024-2678-1
Rui-Rui He, Meng-Qi Lei, Yan-Zhao Feng, Jiao Xue, Yu-Chan Zhang, Yue-Qin Chen, Yang Yu
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引用次数: 0
Multi-omics analysis reveals the genetic and environmental factors in shaping the gut resistome of a keystone rodent species. 多组学分析揭示了形成一种关键啮齿动物肠道抗性组的遗传和环境因素。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-30 DOI: 10.1007/s11427-024-2679-3
Guoliang Li, Dong Zhu, Chaoyuan Cheng, Haiyan Chu, Fuwen Wei, Zhibin Zhang

Understanding the emergence and spread of antibiotic resistance genes (ARGs) in wildlife is critical for the health of humans and animals from a "One Health" perspective. The gut microbiota serve as a reservoir for ARGs; however, it remains poorly understood how environmental and host genetic factors influence ARGs by affecting the gut microbiota. To elucidate this, we analyzed whole-genome resequencing data from 79 individuals of Brandt's vole in two geographic locations with different antibiotics usage, together with metabolomic data and shotgun sequencing data. A high diversity of ARGs (851 subtypes) was observed in vole's gut, with a large variation in ARG composition between individuals from Xilingol and Hulunbuir in China. The diversity and composition of ARGs were strongly correlated with variations in gut microbiota community structure. Genome-wide association studies revealed that 803 loci were significantly associated (P<5.05×10-9) with 31 bacterial species, and bipartite networks identified 906 bacterial species-ARGs associations. Structural equation modeling analysis showed that host genetic factors, air temperature, and presence of pollutants (Bisphenol A) significantly affected gut microbiota community structure, which eventually regulated the diversity of ARGs. The present study advances our understanding of the complex host-environment interactions that underlie the spread of ARGs in the natural environments.

从 "一体健康 "的角度来看,了解野生动物抗生素耐药基因(ARGs)的出现和传播对人类和动物的健康至关重要。肠道微生物群是 ARGs 的储存库;然而,人们对环境和宿主遗传因素如何通过影响肠道微生物群来影响 ARGs 仍然知之甚少。为了弄清这个问题,我们分析了两个使用不同抗生素的地区的79只布氏田鼠的全基因组重测序数据,以及代谢组数据和枪式测序数据。在布氏田鼠肠道中观察到 ARGs 的高度多样性(851 个亚型),来自中国锡林郭勒和呼伦贝尔的布氏田鼠个体之间 ARGs 的组成差异很大。ARGs的多样性和组成与肠道微生物群落结构的变化密切相关。全基因组关联研究发现,803个基因位点与31种细菌有显著关联(P-9),双方位网络发现906种细菌与ARGs有关联。结构方程建模分析表明,宿主遗传因素、气温和污染物(双酚 A)的存在对肠道微生物群落结构有明显影响,最终调节了 ARGs 的多样性。本研究加深了我们对宿主与环境之间复杂的相互作用的理解,这种相互作用是 ARGs 在自然环境中传播的基础。
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引用次数: 0
Nanowire-mediated miRNA delivery. 纳米线介导的 miRNA 递送。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-22 DOI: 10.1007/s11427-024-2641-y
Yuan Wang, Bing Chen
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引用次数: 0
Role of macrophages in aortic dissection pathogenesis: insights from preclinical studies to translational prospective. 巨噬细胞在主动脉夹层发病机制中的作用:从临床前研究到转化前瞻的见解。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1007/s11427-024-2693-5
Shiyi Li, Weiguo Fu, Lixin Wang

Aortic dissection is a critical vascular disease that is characterized by a high mortality rate and inflammation significantly influences its onset and progression. Recent studies highlight the integral role of macrophages, key players in the immune system, in the pathological landscape of aortic dissection. These cells are involved in crucial processes, such as the remodeling of the extracellular matrix, immunocyte infiltration, and phenotypic switching of smooth muscle cells, which are essential for the structural integrity and functional dynamics of the aortic wall. Despite these insights, the specific contributions of macrophages to the development and progression of aortic dissection remains unclear. This review explores the pathogenesis of aortic dissection with a focus on macrophages and describes their origins, phenotypic variations, and potential roles based on the most recent research findings. Furthermore, we discuss key molecules related to macrophages during aortic dissection, their interactions with other cellular components within the aorta, and the implications of these interactions for future therapeutic strategies. This comprehensive analysis aimed to improve our understanding of macrophages in aortic dissection and promote the development of targeted interventions.

主动脉夹层是一种严重的血管疾病,其特点是死亡率高,而炎症对其发病和发展有重大影响。最近的研究突出表明,巨噬细胞是免疫系统的关键角色,在主动脉夹层的病理过程中发挥着不可或缺的作用。这些细胞参与了细胞外基质的重塑、免疫细胞的浸润和平滑肌细胞的表型转换等关键过程,对主动脉壁的结构完整性和功能动态至关重要。尽管有了这些认识,但巨噬细胞对主动脉夹层发生和发展的具体作用仍不清楚。本综述以巨噬细胞为重点探讨了主动脉夹层的发病机制,并根据最新研究成果描述了巨噬细胞的起源、表型变化和潜在作用。此外,我们还讨论了主动脉夹层期间与巨噬细胞有关的关键分子、它们与主动脉内其他细胞成分的相互作用以及这些相互作用对未来治疗策略的影响。这项综合分析旨在增进我们对主动脉夹层中巨噬细胞的了解,促进有针对性的干预措施的开发。
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引用次数: 0
NAP-seq: unveiling the hidden world of noncapped RNAs. NAP-seq:揭开非封顶 RNA 隐藏世界的神秘面纱。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-06-11 DOI: 10.1007/s11427-024-2623-5
Liang Liang, Yuanchao Xue
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引用次数: 0
Shifts in reproductive strategies in the evolutionary trajectory of plant lineages. 植物品系进化过程中生殖策略的转变。
IF 8 2区 生物学 Q1 BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-22 DOI: 10.1007/s11427-024-2597-9
Xin-Jian Zhang, Xian-Han Huang, Jacob B Landis, Quan-Sheng Fu, Jun-Tong Chen, Peng-Rui Luo, Li-Juan Li, Heng-Yi Lu, Hang Sun, Tao Deng

Understanding the maintenance and shift in reproductive strategies is a fundamental question in evolutionary research. Although many efforts have been made to compare different reproductive strategies, the association between reproductive strategies and lineage divergence is largely unknown. To explore the impact of different reproductive strategies on lineage divergence, we investigated the evolution of clonality in Saxifraga sect. Irregulares+Heterisia. By integrating several lines of evidence, we found that the loss of clonality in Irregulares+Heterisia was associated with a progressive increase in diversification rate and intraspecific morphological diversity but with a reduction in species distribution range. Our findings provide insights into the ecological and evolutionary effects of different reproductive strategies, suggesting the necessity of integrating clonality into ecological and evolutional research.

了解生殖策略的维持和转变是进化研究中的一个基本问题。尽管人们已经做了很多努力来比较不同的繁殖策略,但繁殖策略与世系分化之间的关系在很大程度上还是未知的。为了探索不同繁殖策略对世系分化的影响,我们研究了 Saxifraga sect.Irregulares+Heterisia的克隆进化。通过整合多种证据,我们发现Irregulares+Heterisia中克隆性的丧失与物种多样化率和种内形态多样性的逐渐增加有关,但与物种分布范围的缩小有关。我们的发现为不同繁殖策略对生态和进化的影响提供了见解,表明有必要将克隆性纳入生态和进化研究。
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引用次数: 0
期刊
Science China Life Sciences
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