EMBO Molecular Medicine最新文献_第4页

Predictive modeling of glioblastoma recurrence for therapeutic target identification. 胶质母细胞瘤复发的预测模型用于治疗靶点的确定。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-28 DOI: 10.1038/s44321-025-00236-0

Hrvoje Miletic,Thomas Daubon

引用次数: 0

Alpha-synuclein misfolding as fluid biomarker for Parkinson's disease measured with the iRS platform. 用iRS平台测量α -突触核蛋白错误折叠作为帕金森病的液体生物标志物

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-25 DOI: 10.1038/s44321-025-00229-z

Martin Schuler, Grischa Gerwert, Marvin Mann, Nathalie Woitzik, Lennart Langenhoff, Diana Hubert, Deniz Duman, Adrian Höveler, Sandy Galkowski, Jonas Simon, Robin Denz, Sandrina Weber, Eun-Hae Kwon, Robin Wanka, Carsten Kötting, Jörn Güldenhaupt, Léon Beyer, Lars Tönges, Brit Mollenhauer, Klaus Gerwert

{"title":"Alpha-synuclein misfolding as fluid biomarker for Parkinson's disease measured with the iRS platform.","authors":"Martin Schuler, Grischa Gerwert, Marvin Mann, Nathalie Woitzik, Lennart Langenhoff, Diana Hubert, Deniz Duman, Adrian Höveler, Sandy Galkowski, Jonas Simon, Robin Denz, Sandrina Weber, Eun-Hae Kwon, Robin Wanka, Carsten Kötting, Jörn Güldenhaupt, Léon Beyer, Lars Tönges, Brit Mollenhauer, Klaus Gerwert","doi":"10.1038/s44321-025-00229-z","DOIUrl":"https://doi.org/10.1038/s44321-025-00229-z","url":null,"abstract":"Misfolding and aggregation of alpha-synuclein (αSyn) play a key role in the pathophysiology of Parkinson's disease (PD). Despite considerable advances in diagnostics, an early and differential diagnosis of PD still represents a major challenge. We innovated the immuno-infrared sensor (iRS) platform for measuring αSyn misfolding. We analyzed cerebrospinal fluid (CSF) from two cohorts comprising PD cases, atypical Parkinsonian disorders, and disease controls. We obtained an AUC of 0.90 (n = 134, 95% CI 0.85-0.96) for separating PD/MSA from controls by determination of the αSyn misfolding by iRS. Using two thresholds divided individuals as unaffected/affected by misfolding with an intermediate area in between. Comparing the affected/unaffected cases, controls versus PD/MSA cases were classified with 97% sensitivity and 92% specificity. The spectral data revealed misfolding from an α-helical/random-coil αSyn in controls to β-sheet enriched αSyn in PD and MSA cases. Moreover, a first subgroup analysis implied the potential for patient stratification in clinically overlapping cases. The iRS, directly measuring all αSyn conformers, is complementary to the αSyn seed-amplification assays (SAAs), which however only amplify seeding competent conformers.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy. 作者更正：乳酸化驱动的FTO靶向CDK2，加重糖尿病视网膜病变的微血管异常。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-25 DOI: 10.1038/s44321-025-00238-y

Xue Chen, Ying Wang, Jia-Nan Wang, Yi-Chen Zhang, Ye-Ran Zhang, Ru-Xu Sun, Bing Qin, Yuan-Xin Dai, Hong-Jing Zhu, Jin-Xiang Zhao, Wei-Wei Zhang, Jiang-Dong Ji, Song-Tao Yuan, Qun-Dong Shen, Qing-Huai Liu

引用次数: 0

Spatial gene regulatory networks driving cell state transitions during human liver disease. 人类肝脏疾病期间驱动细胞状态转变的空间基因调控网络。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-25 DOI: 10.1038/s44321-025-00230-6

Nigel L Hammond,Syed Murtuza Baker,Sokratia Georgaka,Ali Al-Anbaki,Elliot Jokl,Kara Simpson,Rosa Sanchez-Alvarez,Varinder S Athwal,Huw Purssell,Ajith K Siriwardena,Harry V M Spiers,Mike J Dixon,Leoma D Bere,Adam P Jones,Michael J Haley,Kevin N Couper,Nicoletta Bobola,Andrew D Sharrocks,Neil A Hanley,Magnus Rattray,Karen Piper Hanley

{"title":"Spatial gene regulatory networks driving cell state transitions during human liver disease.","authors":"Nigel L Hammond,Syed Murtuza Baker,Sokratia Georgaka,Ali Al-Anbaki,Elliot Jokl,Kara Simpson,Rosa Sanchez-Alvarez,Varinder S Athwal,Huw Purssell,Ajith K Siriwardena,Harry V M Spiers,Mike J Dixon,Leoma D Bere,Adam P Jones,Michael J Haley,Kevin N Couper,Nicoletta Bobola,Andrew D Sharrocks,Neil A Hanley,Magnus Rattray,Karen Piper Hanley","doi":"10.1038/s44321-025-00230-6","DOIUrl":"https://doi.org/10.1038/s44321-025-00230-6","url":null,"abstract":"Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory between hepatocytes and cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated with liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"43 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies. 多囊肾病和其他肾纤毛病的代谢重编程。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-22 DOI: 10.1038/s44321-025-00239-x

Sara Clerici,Alessandra Boletta

{"title":"Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.","authors":"Sara Clerici,Alessandra Boletta","doi":"10.1038/s44321-025-00239-x","DOIUrl":"https://doi.org/10.1038/s44321-025-00239-x","url":null,"abstract":"Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies. Besides this common manifestation, however, the renal ciliopathies present with profoundly different phenotypes, resulting in either polycystic kidney disease (PKD) or nephronophthisis (NPH) phenotypes. The past decade has seen a surge of studies highlighting metabolic reprogramming as a major feature of PKD, with a distinct involvement of mitochondrial dysfunction. This discovery has brought forward the development of novel therapeutic approaches. More recent evidence suggests that primary cilia modulate the mitochondrial production of energy in response to environmental cues. Here, we summarize the evidence available to date and propose a more general involvement of metabolic and mitochondrial alterations in the renal ciliopathies that might in principle help defining the profoundly different, and potentially opposite, manifestations observed.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"72 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression. BML-260调节磷酸酶DUSP22通过Akt独立的JNK-FOXO3a抑制改善骨骼肌萎缩。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-22 DOI: 10.1038/s44321-025-00234-2

Sang-Hoon Lee, Hyun-Jun Kim, Seon-Wook Kim, Hyunju Lee, Da-Woon Jung, Darren Reece Williams

{"title":"Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression.","authors":"Sang-Hoon Lee, Hyun-Jun Kim, Seon-Wook Kim, Hyunju Lee, Da-Woon Jung, Darren Reece Williams","doi":"10.1038/s44321-025-00234-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00234-2","url":null,"abstract":"Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or treatment with BML-260 (a small molecule previously reported to target DUSP22) prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 treatment is therapeutically effective. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations. pik3ca驱动的难治性血管畸形的胚胎细胞起源和缺氧介导的机制。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-16 DOI: 10.1038/s44321-025-00235-1

Sota Torii, Keiki Nagaharu, Nanako Nakanishi, Hidehito Usui, Yumiko Hori, Katsutoshi Hirose, Satoru Toyosawa, Eiichi Morii, Mitsunaga Narushima, Yoshiaki Kubota, Osamu Nakagawa, Kyoko Imanaka-Yoshida, Kazuaki Maruyama

{"title":"Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations.","authors":"Sota Torii, Keiki Nagaharu, Nanako Nakanishi, Hidehito Usui, Yumiko Hori, Katsutoshi Hirose, Satoru Toyosawa, Eiichi Morii, Mitsunaga Narushima, Yoshiaki Kubota, Osamu Nakagawa, Kyoko Imanaka-Yoshida, Kazuaki Maruyama","doi":"10.1038/s44321-025-00235-1","DOIUrl":"https://doi.org/10.1038/s44321-025-00235-1","url":null,"abstract":"Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos. In this study, we investigated the pathogenesis of these malformations by expressing Pik3caH1047R in the CPM. Mice expressing Pik3caH1047R in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R upregulates Vegf-a expression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SOX9-dependent fibrosis drives renal function in nephronophthisis. 肾病患者sox9依赖性纤维化驱动肾功能。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-10 DOI: 10.1038/s44321-025-00233-3

Maulin Mukeshchandra Patel,Vasileios Gerakopoulos,Bryan Lettenmaier,Eleni Petsouki,Kurt A Zimmerman,John A Sayer,Leonidas Tsiokas

{"title":"SOX9-dependent fibrosis drives renal function in nephronophthisis.","authors":"Maulin Mukeshchandra Patel,Vasileios Gerakopoulos,Bryan Lettenmaier,Eleni Petsouki,Kurt A Zimmerman,John A Sayer,Leonidas Tsiokas","doi":"10.1038/s44321-025-00233-3","DOIUrl":"https://doi.org/10.1038/s44321-025-00233-3","url":null,"abstract":"Fibrosis is a key feature of a broad spectrum of cystic kidney diseases, especially autosomal recessive kidney disorders such as nephronophthisis (NPHP). However, its contribution to kidney function decline and the underlying molecular mechanism(s) remains unclear. Here, we show that kidney-specific deletion of Fbxw7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase, results in a juvenile-adult NPHP-like pathology characterized by slow-progressing corticomedullary cysts, tubular degeneration, severe fibrosis, and gradual loss of kidney function. Expression levels of SOX9, a known substrate of FBW7, and WNT4, a potent pro-fibrotic factor and downstream effector of SOX9, were elevated upon loss of FBW7. Heterozygous deletion of Sox9 in compound mutant mice led to the normalization of WNT4 levels, reduced fibrosis, and preservation of kidney function without significant effects on cystic dilatation and tubular degeneration. These data suggest that FBW7-SOX9-WNT4-induced fibrosis drives kidney function decline in NPHP and, possibly, other forms of autosomal recessive kidney disorders.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"101 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A decisive technical leap forward for personalized medicine to treat mitochondrial diseases. 个性化医疗治疗线粒体疾病的决定性技术飞跃。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-09 DOI: 10.1038/s44321-025-00232-4

Abi S Ghifari,Martin Ott

引用次数: 0

Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture. 应用串联mtZFN结构对肌肉进行临床可翻译线粒体基因治疗。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-09 DOI: 10.1038/s44321-025-00231-5

Pavel A Nash,Keira M Turner,Christopher A Powell,Lindsey Van Haute,Pedro Silva-Pinheiro,Felix Bubeck,Ellen Wiedtke,Eloïse Marques,Dylan G Ryan,Dirk Grimm,Payam A Gammage,Michal Minczuk

{"title":"Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.","authors":"Pavel A Nash,Keira M Turner,Christopher A Powell,Lindsey Van Haute,Pedro Silva-Pinheiro,Felix Bubeck,Ellen Wiedtke,Eloïse Marques,Dylan G Ryan,Dirk Grimm,Payam A Gammage,Michal Minczuk","doi":"10.1038/s44321-025-00231-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00231-5","url":null,"abstract":"Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0