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"Cruising together"-ASC specks and SAA, a perfect match in chronic inflammation. "同舟共济"--ASC斑点和SAA,慢性炎症的绝配。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00109-y
Salie Maasewerd, Bernardo Simoes Franklin
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引用次数: 0
The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis. RhoB p.S73F突变通过脂质平衡失调导致脑瘫。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00113-2
Xinyu Wu, Ruonan Liu, Zhongtian Zhang, Jie Yang, Xin Liu, Liqiang Jiang, Mengmeng Fang, Shoutang Wang, Liangxue Lai, Yuning Song, Zhanjun Li

Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP.

脑性瘫痪(CP)是一种常见的神经系统疾病,给全世界的儿童、家庭和社会带来了沉重的负担。最近,RhoB p.S73F突变被确定为与CP相关的新突变。然而,RhoB p.S73F突变导致CP的机制目前尚不清楚。本研究利用 SpG-BE4max 系统生成了模拟人类 RhoB p.S73F 突变的家兔模型,该模型表现出人类 CP 的典型症状,如脑室周围白斑和痉挛性肌张力障碍性截瘫。进一步研究发现,RhoB p.S73F突变可通过LYN途径激活ACAT1,随后脂质水平的改变可能导致神经元和白质损伤,从而导致CP的发生。这项研究首次提出了准确复制人类 RhoB p.S73F 突变的遗传性 CP 哺乳动物模型,进一步揭示了 RhoB 与脂质代谢之间的关系,并提出了人类 CP 的新治疗靶点。
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引用次数: 0
Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation. 富含组氨酸糖蛋白可调节中性粒细胞和溶栓相关出血转化。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-15 DOI: 10.1038/s44321-024-00117-y
Wei Jiang, Yuexin Zhao, Rongrong Liu, Bohao Zhang, Yuhan Xie, Bin Gao, Kaibin Shi, Ming Zou, Dongmei Jia, Jiayue Ding, Xiaowei Hu, Yanli Duan, Ranran Han, DeRen Huang, Luc Van Kaer, Fu-Dong Shi

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.

使用重组组织浆细胞酶原激活剂(tPA)进行静脉溶栓仍是急性缺血性卒中(AIS)患者的主要治疗方法。然而,人们对与 tPA 相关的出血性转化(HT)的机制仍知之甚少。通过纳米液相色谱串联质谱法检测到输注 tPA 后 1 小时富含组氨酸糖蛋白(HRG)的表达高于输注 tPA 前的基线(发现队列,n = 10),随后通过 ELISA 法在验证队列(n = 157)中证实了这一点。令人惊讶的是,在随后发生 HT 的个体中未检测到 HRG 升高。在体外实验中,HRG可减少中性粒细胞的NETosis、炎症细胞因子的产生以及tPA诱导的血脑屏障迁移。在光血栓小鼠 AIS 模型中,HRG 通过抑制中性粒细胞免疫浸润和下调促炎信号通路,改善了延迟溶栓的 HT。中性粒细胞耗竭或NETosis抑制也能缓解HT,而HRG siRNA处理则会加重HT。总之,HRG 水平的波动可能反映了 tPA 治疗及其相关的 HT。HRG 对中性粒细胞的抑制作用可能会抵消 tPA 诱导的 AIS 患者免疫异常和 HT。
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引用次数: 0
Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer. 针对ERRγ的治疗可通过细胞外基质重塑抑制小细胞肺癌的转移。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1038/s44321-024-00108-z
Hong Wang, Huizi Sun, Jie Huang, Zhenhua Zhang, Guodi Cai, Chaofan Wang, Kai Xiao, Xiaofeng Xiong, Jian Zhang, Peiqing Liu, Xiaoyun Lu, Weineng Feng, Junjian Wang

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.

小细胞肺癌(SCLC)是最具侵袭性和致命性的肺癌类型,其特点是治疗方案有限、转移早且频繁。然而,小细胞肺癌转移的决定因素尚未明确。在这里,我们发现雌激素相关受体γ(ERRγ)在转移性SCLC肿瘤中过度表达,并且与SCLC的进展呈正相关。ERRγ是细胞外基质(ECM)重塑和细胞粘附(转移的两个关键步骤)的重要激活剂,它直接调控参与这些过程的主要基因的表达。遗传和药物抑制ERRγ可显著减少胶原蛋白的产生、细胞-基质粘附和微丝的产生,并最终阻止SCLC细胞的侵袭和肿瘤转移。值得注意的是,ERRγ拮抗剂能显著抑制肿瘤的生长和转移,并在多种细胞来源和患者来源的异种移植模型中恢复SCLC对化疗的易感性。综上所述,这些发现确立了ERRγ作为转移性SCLC的一个有吸引力的靶点,并为治疗这种致命疾病提供了一种潜在的药理学策略。
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引用次数: 0
Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome. 抑制 GSK3α、β 可挽救 CTNNB1 综合征临床前小鼠模型的认知表型。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00110-5
Jonathan M Alexander, Leeanne Vazquez-Ramirez, Crystal Lin, Pantelis Antonoudiou, Jamie Maguire, Florence Wagner, Michele H Jacob

CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

CTNNB1 综合征是一种罕见的单基因遗传性疾病,由 CTNNB1 新生致病性杂合子功能缺失变异引起,导致认知和运动障碍。目前尚缺乏治疗方法;我们的研究满足了这一关键需求。CTNNB1编码β-catenin,β-catenin在基于粘附蛋白的突触粘附复合物和典型Wnt信号转导中发挥双重作用,对正常脑功能至关重要。我们培育了一个 Ctnnb1 种系杂合子小鼠品系,该品系表现出认知和运动障碍,类似于人类 CTNNB1 综合征的主要特征。与野生型同系小鼠相比,Ctnnb1杂合子小鼠的大脑β-catenin、β-catenin与N-cadherin的关联、Wnt靶基因表达以及高活动时离子梯度变化的关键调控因子Na/K ATPases也出现下降。同样,海马神经元的功能特性和兴奋性也发生了改变。最重要的是,我们发现了一种糖原合酶激酶(GSK)3α、β的高选择性抑制剂,它能显著使表型正常化,接近野生型同胎鼠的水平。我们的数据为大脑分子和功能变化提供了新的视角,并首次证明了对 CTNNB1 综合征患者具有治疗潜力的有效治疗方法。
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引用次数: 0
Novel immunotherapeutics against LGR5 to target multiple cancer types. 针对多种癌症类型的 LGR5 新型免疫疗法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1038/s44321-024-00121-2
Hung-Chang Chen, Nico Mueller, Katherine Stott, Chrysa Kapeni, Eilidh Rivers, Carolin M Sauer, Flavio Beke, Stephen J Walsh, Nicola Ashman, Louise O'Brien, Amir Rafati Fard, Arman Ghodsinia, Changtai Li, Fadwa Joud, Olivier Giger, Inti Zlobec, Ioana Olan, Sarah J Aitken, Matthew Hoare, Richard Mair, Eva Serrao, James D Brenton, Alicia Garcia-Gimenez, Simon E Richardson, Brian Huntly, David R Spring, Mikkel-Ole Skjoedt, Karsten Skjødt, Marc de la Roche, Maike de la Roche

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

我们开发并验证了一种针对人类 LGR5 细胞外结构域的高度特异性多功能抗体(α-LGR5)。α-LGR5能检测到90%以上的结直肠癌(CRC)、肝细胞癌(HCC)和前B-ALL肿瘤细胞中的LGR5过表达,并被用于生成抗体-药物共轭物(α-LGR5-ADC)、双特异性T细胞激活剂(α-LGR5-BiTE)和嵌合抗原受体(α-LGR5-CAR)。α-LGR5-ADC是体外靶向LGR5+癌细胞的最有效方式,并在人类NALM6前B-ALL小鼠模型中显示出强大的抗肿瘤疗效,使肿瘤损耗率低于对照治疗的1%。α-LGR5-CAR-T细胞在体外也显示出特异性和强效的LGR5+癌细胞杀伤力,并能有效靶向肿瘤,与对照组相比,前B-ALL肿瘤负荷减少了四倍。总之,我们的研究表明,α-LGR5 不仅可以作为一种研究工具和生物标记物,还能为针对一系列表达 LGR5 的癌细胞的高效免疫疗法组合提供一个通用的构件。
{"title":"Novel immunotherapeutics against LGR5 to target multiple cancer types.","authors":"Hung-Chang Chen, Nico Mueller, Katherine Stott, Chrysa Kapeni, Eilidh Rivers, Carolin M Sauer, Flavio Beke, Stephen J Walsh, Nicola Ashman, Louise O'Brien, Amir Rafati Fard, Arman Ghodsinia, Changtai Li, Fadwa Joud, Olivier Giger, Inti Zlobec, Ioana Olan, Sarah J Aitken, Matthew Hoare, Richard Mair, Eva Serrao, James D Brenton, Alicia Garcia-Gimenez, Simon E Richardson, Brian Huntly, David R Spring, Mikkel-Ole Skjoedt, Karsten Skjødt, Marc de la Roche, Maike de la Roche","doi":"10.1038/s44321-024-00121-2","DOIUrl":"10.1038/s44321-024-00121-2","url":null,"abstract":"<p><p>We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5<sup>+</sup> cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5<sup>+</sup> cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2233-2261"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability. 集导管癌的全面分子特征描述,寻找治疗漏洞。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1038/s44321-024-00102-5
Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan

Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

集合管癌(CDC)是一种侵袭性罕见肾癌亚型,其临床需求尚未得到满足。由于其罕见性和缺乏临床前模型,人们对其潜在的分子改变和病因知之甚少。本研究旨在全面描述 CDC 的分子改变特征,并确定其治疗弱点。通过全外显子组和转录组测序,我们在 3/13 例(23%)患者中发现了 KRAS 热点突变(G12A/D/V),此外还有已知的 TP53 和 NF2 突变。3/13(23%)例患者携带由马兜铃酸(AA)暴露引起的突变特征(SBS22),众所周知,这种突变在亚洲更为普遍,这凸显了该病的地质特异性病因。我们进一步发现,细胞周期相关通路是最主要的失调通路。我们利用新建立的 CDC 临床前模型进行了药物筛选,发现 CDK9 抑制剂 LDC000067 能特异性抑制 CDC 肿瘤的生长并延长存活时间。我们的研究不仅增进了我们对亚洲 CDC 致癌性分子改变的了解,还发现细胞周期机制是治疗的薄弱环节,为治疗此类侵袭性癌症患者的临床试验奠定了基础。
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引用次数: 0
Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction. 通过全基因组测序和单线程纠错技术进行超灵敏残留疾病分子检测。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI: 10.1038/s44321-024-00115-0
Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando L Mendez, Yingyu Wang, Paul Tang, Qianqian Yao, Marcus W Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

虽然无细胞 DNA(cfDNA)全基因组测序(WGS)在检测分子残留疾病(MRD)方面前景广阔,但其性能却受到 WGS 错误率的限制。在这里,我们介绍一种高效的 cfDNA WGS 技术 AccuScan,它能在单个读数级实现全基因组纠错,错误率为 4.2 × 10-7,比以读数为中心的去噪方法低两个数量级。AccuScan 在 MRD 中的应用表明,其分析灵敏度低至 10-6 循环变异等位基因频率,样本级特异性高达 99%。AccuScan 在预测结直肠癌复发方面显示出 90% 的标志性灵敏度(术后 6 周内)和 100% 的特异性。使用术后一周内采集的样本,AccuScan 对食管癌也显示出 67% 的灵敏度和 100% 的特异性。当 AccuScan 用于监测黑色素瘤患者的免疫疗法时,循环肿瘤 DNA (ctDNA) 水平和动态轮廓与临床结果一致。总之,AccuScan 为 MRD 检测提供了高精度的 WGS 解决方案,可在百万分之一的范围内检测 ctDNA,无需大量样本输入或个性化试剂。
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引用次数: 0
Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy. 恢复神经元亚群的氧化磷酸化缺陷可预防线粒体脑病。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1038/s44321-024-00111-4
Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes

Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.

氧化磷酸化(OXPHOS)缺陷可导致严重的脑病,目前还没有治疗这些疾病的有效方法。为了评估基因替代预防疾病进展的能力,我们对两种不同的中枢神经系统缺陷小鼠模型(Ndufs3/复合体I或Cox10/复合体IV条件性基因敲除)进行了基因治疗。我们使用经腹腔注射的 AAV-PHP.eB 将缺失基因送入这些小鼠的中枢神经系统。在这两种情况下,我们观察到小鼠的存活期从 5-6 个月延长到 15 个月以上,而且没有发现疾病表型。同样,接受治疗的小鼠的分子和细胞表型也基本恢复。令人惊讶的是,在所用条件下,只有约30%的神经元表达了AAV-PHP.eB载体的转基因,却实现了这些显著的表型改善。这些研究结果表明,缺乏 OXPHOS 的神经元会受到周围神经元环境的保护,而部分补偿神经元 OXPHOS 的缺失会产生不成比例的积极影响。
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引用次数: 0
Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites. 通过单剂量孢子虫注射血期减毒疟原虫进行实验性疫苗接种。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00101-6
Julia M Sattler, Lukas Keiber, Aiman Abdelrahim, Xinyu Zheng, Martin Jäcklin, Luisa Zechel, Catherine A Moreau, Smilla Steinbrück, Manuel Fischer, Chris J Janse, Angelika Hoffmann, Franziska Hentzschel, Friedrich Frischknecht

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

目前正在探索利用疟原虫活体接种疟疾疫苗的方法,即利用减毒的蚊源性孢子虫或减毒的血期寄生虫。这两种方法都将得益于可获得血期繁殖率降低的减毒和无毒寄生虫。在这里,我们筛选了生长缓慢的啮齿类寄生虫 P. berghei 和人类寄生虫 P. falciparum 的基因缺失突变体。此外,我们还测试了伯格希氏疟原虫突变体的无毒性和解决血期感染的能力,同时保留了孢子虫的形成和肝脏感染。以 51 个基因为靶标,产生了 18 个伯格氏疟原虫基因缺失突变体,其中几个突变体可引起轻度感染。两种最弱的突变体的血液阶段感染或孢子虫感染都能被免疫反应清除。对小鼠进行免疫可使其在受到野生型孢子虫挑战后免于发病。六种恶性疟原虫基因缺失突变体中有两种生长速度缓慢。生长缓慢、无毒的恶性疟原虫突变体将成为诱导免疫反应的宝贵工具,有助于开发新的寄生虫减毒疫苗并保护现有疫苗。
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引用次数: 0
期刊
EMBO Molecular Medicine
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