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m6A landscape is more pervasive when Trypanosoma brucei exits the cell cycle. 当布氏锥虫退出细胞周期时,m6A 的分布更为普遍。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-17 DOI: 10.1016/j.bj.2024.100728
Lúcia Serra, Sara Silva Pereira, Idálio J Viegas, Henrique Machado, Lara López-Escobar, Luisa M Figueiredo

N6-methyladenosine (m6A) is a mRNA modification with important roles in gene expression. In African trypanosomes, this post-transcriptional modification is detected in hundreds of transcripts and it affects the stability of the variant surface glycoprotein (VSG) transcript in the proliferating blood stream form. However, how the m6A landscape varies across the life cycle remains poorly defined. Using full-length, non-fragmented RNA, we immunoprecipitated and sequenced m6A-modified transcripts across three life cycle stages of Trypanosoma brucei - slender (proliferative), stumpy (quiescent), and procyclic forms (proliferative). We found that 1037 transcripts are methylated in at least one of these three life cycle stages. While 21% of methylated transcripts are common in the three stages of the life cycle, globally each stage has a distinct methylome. Interestingly, 47% of methylated transcripts are detected in the quiescent stumpy form only, suggesting a critical role for m6A when parasites exit the cell cycle and prepare for transmission by the Tsetse fly. In this stage, we found that a significant proportion of methylated transcripts encodes for proteins involved in RNA metabolism, which is consistent with their reduced transcription and translation. Moreover, we found that not all major surface proteins are regulated by m6A, as procyclins are not methylated, and that, within the VSG repertoire, not all VSG transcripts are demethylated upon parasite differentiation to procyclic form. This study reveals that the m6A regulatory landscape is specific to each life cycle stage, becoming more pervasive as T. brucei exits the cell cycle.

N6-甲基腺苷(m6A)是一种在基因表达中起重要作用的 mRNA 修饰。在非洲锥虫中,这种转录后修饰可在数百个转录本中检测到,而且会影响增殖血流形态中变异表面糖蛋白(VSG)转录本的稳定性。然而,m6A 在整个生命周期中的变化情况仍不十分明确。我们使用全长、非碎裂的 RNA,对布氏锥虫三个生命周期阶段--纤细型(增殖型)、粗壮型(静止型)和原环状型(增殖型)--的 m6A 修饰转录本进行了免疫沉淀和测序。我们发现,有 1037 个转录本在这三个生命周期阶段中至少有一个阶段被甲基化。虽然 21% 的甲基化转录本在生命周期的三个阶段中很常见,但总体而言,每个阶段都有一个独特的甲基化组。有趣的是,47%的甲基化转录本仅在静止期的残体中被检测到,这表明当寄生虫退出细胞周期并准备被采采蝇传播时,m6A 起着关键作用。在这一阶段,我们发现相当一部分甲基化转录本编码参与 RNA 代谢的蛋白质,这与它们的转录和翻译减少是一致的。此外,我们还发现并非所有主要的表面蛋白都受 m6A 的调控,因为原环蛋白并没有被甲基化,而且在 VSG 基因库中,并非所有的 VSG 转录本都会在寄生虫分化为原环形态时被去甲基化。这项研究揭示了 m6A 的调控格局是每个生命周期阶段所特有的,随着布氏原虫退出细胞周期而变得更加普遍。
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引用次数: 0
In vivo SPECT imaging of Tc-99m radiolabeled exosomes from human umbilical-cord derived mesenchymal stem cells in small animals 人脐带间充质干细胞Tc-99 m放射性标记外泌体在小动物体内的SPECT成像。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-16 DOI: 10.1016/j.bj.2024.100721

Extracellular vesicles derived from human umbilical cord-derived mesenchymal stem cells (UCMSC-EVs) have been postulated to have therapeutic potential for various diseases. However, the biodistribution and pharmacokinetics of these vesicles are still unclear. For a better understanding of the in vivo properties of UCMSC-EVs, in the present study, these vesicles were first radiolabeled with Technetium-99m (99mTc-UCMSC-EVs) and evaluated using in vivo single photon emission computed tomography (SPECT) imaging and biodistribution experiments. SPECT images demonstrated that the liver and spleen tissues mainly took up the 99mTc-UCMSC-EVs. The biodistribution study observed slight uptake in the thyroid and stomach, indicating that 99mTc-UCMSC-EVs was stable at 24 h in vivo. The pharmacokinetic analyses of the blood half-life demonstrated the quick distribution phase (0.85 ± 0.28 min) and elimination phase (25.22 ± 20.76 min) in mice. This study provides a convenient and efficient method for 99mTc-UCMSC-EVs preparation without disturbing their properties. In conclusion, the biodistribution, quick elimination, and suitable stability in vivo of 99mTc-UCMSC-EVs were quantified by the noninvasive imaging and pharmacokinetic analyses, which provides useful information for indication selection, dosage protocol design, and toxicity assessment in future applications.

从人脐带间充质干细胞(UCMSC-EVs)中提取的细胞外囊泡被认为具有治疗各种疾病的潜力。然而,这些囊泡的生物分布和药代动力学尚不清楚。为了更好地了解 UCMSC-EVs 的体内特性,本研究首先用锝-99m(99mTc-UCMSC-EVs)对这些囊泡进行了放射性标记,并使用体内单光子发射计算机断层扫描(SPECT)成像和生物分布实验对其进行了评估。SPECT 图像显示,肝脏和脾脏组织主要吸收了 99m锝-UCMSC-EVs。生物分布研究观察到甲状腺和胃有轻微摄取,表明 99mTc-UCMSC-EVs 在体内 24 小时内是稳定的。血液半衰期的药代动力学分析表明,99mTc-UCMSC-EVs 在小鼠体内的分布期(0.85 ± 0.28 分钟)和消除期(25.22 ± 20.76 分钟)均较快。该研究为制备 99mTc-UCMSC-EVs 提供了一种方便、高效且不会干扰其特性的方法。总之,该研究通过无创成像和药代动力学分析,量化了 99mTc-UCMSC-EVs 在体内的生物分布、快速消除和适宜的稳定性,为未来应用中的适应症选择、剂量方案设计和毒性评估提供了有用信息。
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引用次数: 0
Genome-wide association study identifies DRAM1 associated with Tourette syndrome in Taiwan. 全基因组关联研究发现 DRAM1 与台湾的妥瑞症有关。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-10 DOI: 10.1016/j.bj.2024.100725
Wei-De Lin, Ting-Yuan Liu, Yu-Chia Chen, I-Ching Chou, Fuu-Jen Tsai

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population.

Methods: GWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1,007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed.

Results: Genome-wide significant locus, rs12313062 (p=1.43 × 10-8) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption.

Conclusions: This study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area.

背景:图雷特综合征(TS)是一种以运动和发声抽搐为特征的神经发育障碍。此前,通过全基因组关联研究(GWAS),在欧洲后裔人群中发现了几个与 TS 相关的易感基因位点。然而,TS 的确切致病机制尚不清楚;此外,以前针对 TS 的全基因组关联研究的结果是基于西方人群的,可能并不适用于其他人群。因此,我们在台湾的 TS 和慢性抽搐症(CTDs)患者中开展了一项 GWAS 研究,旨在阐明该人群中 TS 的遗传基础和潜在风险因素:对台湾 TS/CTDs 群体进行了 GWAS 分析,样本量为 1,007 名 TS 患者和 25,522 名祖先匹配对照。此外,还计算并评估了多基因风险评分:结果:在染色体12q23.2上发现了与DRAM1相关的全基因组重要位点rs12313062(p=1.43×10-8)和其他9个单核苷酸多态性,这是TS/CTDs群体中发现的一个新的易感位点。DRAM1是一种受p53调控的溶酶体跨膜蛋白,可调节自噬和细胞凋亡,对与自噬破坏相关的神经精神疾病具有潜在影响:本研究首次在台湾人群中开展了TS的GWAS,在染色体12q23.2上发现了一个与DRAM1相关的重要位点。这些发现为TS的神经生物学提供了新的见解,也为这一领域未来的研究提供了潜在的方向。
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引用次数: 0
Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction. 奥利昔肟通过减轻线粒体功能障碍防止顺铂引起的急性肾损伤。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-01 DOI: 10.1016/j.bj.2024.100730
Peipei Wang, Ouyang Jing, Kaiqian Zhou, Dandan Hu, Shengnan Zhang, Aihua Zhang, Yunwen Yang
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引用次数: 0
Aging like fine wine: Mischievous microbes and other factors influencing senescence 像美酒一样老去:调皮的微生物和其他影响衰老的因素。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-01 DOI: 10.1016/j.bj.2024.100722
Aila Akosua Kattner

In this issue, a special section is dedicated to the factors affecting senescence. It examines the interplay between immunosenescence and chronic kidney disease, probes into Peto's paradox, and explores how epigenetic switches can potentially mitigate senescence and inflammation. Additionally, insights are offered on understanding a specific Ras mechanism in yeast for potential therapeutic interventions against cancer and for longevity. Furthermore, the remarkable endurance of last year's Nobel Prize winner in Physiology or Medicine is also highlighted. Moreover, the discovery of potential biomarkers for hepatocellular carcinoma, the link between osteoarthritis and the circadian clock, and the multifaceted role of DNAJA3 in B cell lifecycle are discussed. Further, study findings shed light on the influence of extracellular matrix molecules on cleft palate formation, the renal protective effects of combination therapy in diabetic kidney disease, and novel approaches to detect developmental dysplasia of the hip. Finally, a correspondence delves into the role of autonomic regulation in cognitive decline.

本期特刊专门讨论了影响衰老的因素。它探讨了免疫衰老与慢性肾病之间的相互作用,探究了佩托悖论,并探索了表观遗传开关如何有可能缓解衰老和炎症。此外,还就如何理解酵母中一种特殊的 Ras 机制,从而对癌症和长寿进行潜在的治疗干预提出了见解。此外,还重点介绍了去年诺贝尔生理学或医学奖得主的非凡耐力。此外,还讨论了肝细胞癌潜在生物标志物的发现、骨关节炎与昼夜节律时钟之间的联系以及 DNAJA3 在 B 细胞生命周期中的多方面作用。此外,研究结果还揭示了细胞外基质分子对腭裂形成的影响、联合疗法对糖尿病肾病的肾脏保护作用以及检测髋关节发育不良的新方法。最后,一篇通讯深入探讨了自律神经调节在认知能力下降中的作用。
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引用次数: 0
Hepatocyte nuclear factor 4 located in different developmental stages in Schistosoma japonicum and involved in important metabolic pathways. 肝细胞核因子 4 位于日本血吸虫的不同发育阶段,参与重要的代谢途径。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-01 DOI: 10.1016/j.bj.2024.100726
Kaijuan Wu, Shuaiqin Huang, Yiming Zhao, Abdulrahim Umar, Hao Chen, Zhengwang Yu, Jing Huang
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引用次数: 0
Blood oxygenation state in COVID-19 patients: Unexplored role of 2,3-bisphosphoglycerate. COVID-19 患者的血液氧合状态:尚未探索的 2,3-二磷酸甘油酯的作用
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-01 DOI: 10.1016/j.bj.2024.100723
Maria Sofia Bertilacchi, Rebecca Piccarducci, Alessandro Celi, Lorenzo Germelli, Chiara Romei, Brian Bartholmai, Greta Barbieri, Chiara Giacomelli, Claudia Martini
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引用次数: 0
Doxycycline cotherapy with albendazole relieves neural function damage in C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis. 多西环素联合阿苯达唑疗法可缓解C57BL/6和BALB/c小鼠感染坎顿氏安氏梭菌后的神经功能损伤。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-04-01 DOI: 10.1016/j.bj.2024.100727
Eny Sofiyatun, Kuang-Yao Chen, Chih-Jen Chou, Hsin-Chia Lee, Yi-An Day, Pei-Jui Chiang, Cheng-Hsun Chiu, Wei-June Chen, Kai-Yuan Jhan, Lian-Chen Wang
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引用次数: 0
Epigenetic modifications of cfDNA in liquid biopsy for the cancer care continuum. 液体活检中 cfDNA 的表观遗传学修饰,促进癌症治疗的连续性。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-03-22 DOI: 10.1016/j.bj.2024.100718
Jodie Wong, Rohit Muralidhar, Liang Wang, Chiang-Ching Huang

This review provides a comprehensive overview of the latest advancements in the clinical utility of liquid biopsy, with a particular focus on epigenetic approaches aimed at overcoming challenges in cancer diagnosis and treatment. It begins by elucidating key epigenetic terms, including methylomics, fragmentomics, and nucleosomics. The review progresses to discuss methods for analyzing circulating cell-free DNA (cfDNA) and highlights recent studies showcasing the clinical relevance of epigenetic modifications in areas such as diagnosis, drug treatment response, minimal residual disease (MRD) detection, and prognosis prediction. While acknowledging hurdles like the complexity of interpreting epigenetic data and the absence of standardization, the review charts a path forward. It advocates for the integration of multi-omic data through machine learning algorithms to refine predictive models and stresses the importance of collaboration among clinicians, researchers, and data scientists. Such cooperative efforts are essential to fully leverage the potential of epigenetic features in clinical practice.

本综述全面概述了液体活检临床应用的最新进展,尤其关注旨在克服癌症诊断和治疗难题的表观遗传学方法。文章首先阐明了关键的表观遗传学术语,包括甲基组学、片段组学和核糖体学。综述接着讨论了分析循环游离细胞DNA(cfDNA)的方法,并重点介绍了最近的研究,这些研究展示了表观遗传修饰在诊断、药物治疗反应、最小残留病(MRD)检测和预后预测等领域的临床意义。在承认表观遗传学数据解读的复杂性和缺乏标准化等障碍的同时,该综述描绘了一条前进的道路。它提倡通过机器学习算法整合多组学数据,以完善预测模型,并强调临床医生、研究人员和数据科学家之间合作的重要性。这种合作对于在临床实践中充分利用表观遗传特征的潜力至关重要。
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引用次数: 0
Reflecting on the 1998 enterovirus outbreak: A 25-year retrospective and learned lessons. 反思 1998 年肠病毒爆发:25 年回顾与经验教训。
IF 5.5 3区 医学 Q1 Medicine Pub Date : 2024-03-14 DOI: 10.1016/j.bj.2024.100715
Peng-Nien Huang, Shao-Hsuan Hsia, Kuan-Ying Arthur Huang, Chih-Jung Chen, En-Tzu Wang, Shin-Ru Shih, Tzou-Yien Lin

Enterovirus A71 (EV-A71) infections pose a significant public health concern in the Asia-Pacific region. EV-A71 is primarily responsible for causing hand, foot, and mouth disease (HFMD) in children. However, this virus can also lead to severe and potentially fatal neurological consequences in affected individuals. This review aims to provide a comprehensive understanding of the molecular virology, epidemiology, and recombination events associated with EV-A71. The literature extensively covers the clinical manifestations and neurological symptoms that accompany EV-A71 infections. One of the complications explored in this review is brainstem encephalitis, which can arise as a result of EV-A71 infections. Brainstem encephalitis refers to inflammation of the brainstem, a critical region responsible for various bodily functions. The review examines the underlying mechanisms, diagnostic criteria, treatment options, and prognosis for central nervous system infections involving EV-A71. Neurological complications associated with EV-A71 infections are diverse and can have severe consequences. These complications may include aseptic meningitis, acute flaccid paralysis, and acute transverse myelitis. The review delves into the pathophysiology of these complications, shedding light on the molecular mechanisms through which EV-A71 affects the central nervous system. Accurate diagnosis of EV-A71 infections is crucial for appropriate management and treatment. Treatment options for EV-A71 infections primarily focus on supportive care, as there are currently no specific antiviral drugs available for this virus. The review highlights the importance of managing symptoms, such as fever, dehydration, and pain relief, to alleviate the burden on affected individuals. Prognosis for individuals with central nervous system (CNS) infections involving EV-A71 can vary depending on the severity of the complications. The review provides insights into the long-term outcomes and potential neurological sequelae associated with EV-A71 infections. In conclusion, EV-A71 infections have emerged as a major public health concern in the Asia-Pacific region. This review aims to enhance our understanding of the molecular virology, epidemiology, and neurological complications associated with EV-A71. By examining the underlying mechanisms, diagnostic criteria, treatment options, and prognosis, this review contributes to the development of effective strategies for the prevention, diagnosis, and management of EV-A71 infections. The paper presents a comprehensive analysis of worldwide data pertaining to outbreaks of EV-A71 and HFMD. The subsequent discourse delves into the advancement and strategic formulation pertaining to the creation of vaccines targeting EV-A71. In summary, this study provides a comprehensive examination of the potential obstacles and considerations involved in the management and treatment of EV-A71 infections. Additionally, it proposes suggestions for future research

肠道病毒 A71(EV-A71)感染是亚太地区的一个重大公共卫生问题。EV-A71 主要导致儿童手足口病(HFMD)。然而,这种病毒也会导致患者出现严重的、可能致命的神经系统后果。本综述旨在全面介绍与 EV-A71 相关的分子病毒学、流行病学和重组事件。文献广泛涉及 EV-A71 感染的临床表现和神经系统症状。本综述探讨的并发症之一是脑干脑炎,它可能是 EV-A71 感染的结果。脑干脑炎是指脑干的炎症,脑干是负责各种身体功能的重要区域。本综述探讨了涉及 EV-A71 的中枢神经系统感染的基本机制、诊断标准、治疗方案和预后。与 EV-A71 感染相关的神经系统并发症多种多样,并可能造成严重后果。这些并发症可能包括无菌性脑膜炎、急性弛缓性麻痹和急性横贯性脊髓炎。本综述深入探讨了这些并发症的病理生理学,揭示了 EV-A71 影响中枢神经系统的分子机制。EV-A71 感染的准确诊断对于适当的管理和治疗至关重要。EV-A71 感染的治疗方案主要侧重于支持性护理,因为目前还没有针对这种病毒的特效抗病毒药物。综述强调了控制发烧、脱水和止痛等症状以减轻患者负担的重要性。EV-A71 中枢神经系统(CNS)感染患者的预后会因并发症的严重程度而有所不同。本综述深入探讨了与 EV-A71 感染相关的长期预后和潜在的神经系统后遗症。总之,EV-A71 感染已成为亚太地区主要的公共卫生问题。本综述旨在加深我们对与 EV-A71 相关的分子病毒学、流行病学和神经系统并发症的了解。通过研究其潜在机制、诊断标准、治疗方案和预后,本综述有助于制定预防、诊断和管理 EV-A71 感染的有效策略。本文全面分析了与 EV-A71 和手足口病爆发有关的全球数据。随后的论述深入探讨了针对 EV-A71 疫苗的研发进展和战略制定。总之,本研究全面探讨了 EV-A71 感染管理和治疗中的潜在障碍和注意事项。此外,它还为未来的研发工作提出了建议,目的是为这种病毒感染制定有效的治疗方法。
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引用次数: 0
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