Disease Models & Mechanisms最新文献_第10页

An appetite for research: an interview with Sadaf Farooqi. 对研究的兴趣：对Sadaf Farooqi的采访。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-28 DOI: 10.1242/dmm.052379

Sadaf Farooqi

{"title":"An appetite for research: an interview with Sadaf Farooqi.","authors":"Sadaf Farooqi","doi":"10.1242/dmm.052379","DOIUrl":"10.1242/dmm.052379","url":null,"abstract":"Professor Sadaf Farooqi is a clinician and researcher investigating the genetics underpinning obesity. Her research uncovered the first known genes that cause severe obesity, highlighting the significant role of appetite in regulating weight gain. Sadaf's work has been instrumental in proving that many observations in mice are also true in humans, paving the way for novel treatments and shifts in policy. After studying medicine at the University of Birmingham, Birmingham, UK, Sadaf completed her PhD on the genetics of severe childhood obesity at the University of Cambridge, Cambridge, UK, marking the beginning of her impressive research career in this field. She is currently Professor of Metabolism and Medicine at the University of Cambridge and Honorary Consultant in Diabetes and Endocrinology at Addenbrooke's Hospital, Cambridge, UK. Sadaf previously served on the Board of Directors for Disease Models & Mechanisms' publisher, The Company of Biologists. Here, we discuss the fascinating insights from her work on obesity and appetite, her approach to exploring new research questions, and how these discoveries can ultimately impact patients and society.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Correction: A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy. 更正：一种携带多外显子Dmd缺失的杜氏肌营养不良小鼠模型表现出进行性肌营养不良和早发性心肌病。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-04 DOI: 10.1242/dmm.052372

Tatianna Wai, Ying Wong, Abdalla Ahmed, Grace Yang, Eleonora Maino, Sydney Steiman, Elzbieta Hyatt, Parry Chan, Kyle Lindsay, Nicole Wong, Diane Golebiowski, Joel Schneider, Paul Delgado-Olguı N, Evgueni A Ivakine, Ronald D Cohn

引用次数: 0

Mutations in the bone morphogenetic protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations. 骨形态发生蛋白信号通路的突变使斑马鱼和人类对乙醇诱导的颌骨畸形敏感。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-08 DOI: 10.1242/dmm.052223

John R Klem, Tae-Hwi Schwantes-An, Marco Abreu, Michael Suttie, Raèden Gray, Hieu D L Vo, Grace Conley, Tatiana M Foroud, Leah Wetherill, C Ben Lovely

{"title":"Mutations in the bone morphogenetic protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations.","authors":"John R Klem, Tae-Hwi Schwantes-An, Marco Abreu, Michael Suttie, Raèden Gray, Hieu D L Vo, Grace Conley, Tatiana M Foroud, Leah Wetherill, C Ben Lovely","doi":"10.1242/dmm.052223","DOIUrl":"10.1242/dmm.052223","url":null,"abstract":"Fetal alcohol spectrum disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Signaling via bone morphogenetic protein (Bmp) is a key regulatory step of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish carrying mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating that ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. By integrating FASD patient data, we provide the first evidence that variants of the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp-ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modeling ANKRD26 5'-UTR mutation-related thrombocytopenia. 模拟斑马鱼ANKRD26 5'-UTR突变相关的血小板减少症。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-28 DOI: 10.1242/dmm.052222

Liang Zheng, Zhijian Wu, Noritaka Yada, Szumam Liu, Cindy Lin, Antonia Bignotti, Xinyang Zhao, X Long Zheng

{"title":"Modeling ANKRD26 5'-UTR mutation-related thrombocytopenia.","authors":"Liang Zheng, Zhijian Wu, Noritaka Yada, Szumam Liu, Cindy Lin, Antonia Bignotti, Xinyang Zhao, X Long Zheng","doi":"10.1242/dmm.052222","DOIUrl":"10.1242/dmm.052222","url":null,"abstract":"Mutations in the 5'-untranslated region (5'-UTR) of ankyrin repeat domain-containing protein 26 (ANKRD26) are associated with hereditary thrombocytopenia 2 (THC2). However, the causative role of these mutations and the mechanisms underlying THC2 are not fully established. Here, we report, for the first time, that zebrafish carrying a deletion of two nucleotides (Δ2) in the 5'-UTR of ankrd26 recapitulate some of the key laboratory features of THC2. ankrd26ku6 (homozygous for the Δ2 deletion in the 5'-UTR) fish larvae exhibited significantly increased expression of ankrd26 mRNA and protein. Adult ankrd26ku6 fish exhibited spontaneous thrombocytopenia. Furthermore, the thrombocytes from ankrd26ku6 fish showed enhanced ability to adhere and aggregate on a collagen surface under flow. Proteomic profiling demonstrated marked upregulation of Ninjurin 1 in young thrombocytes from ankrd26ku6 fish compared with those from wild-type controls. The ankrd26ku6 fish with a homozygous nacre allele developed myelodysplastic syndrome at old age. ANKRD26 protein levels were also significantly increased in platelets and plasma from patients with immune thrombotic thrombocytopenic purpura compared with those from unaffected controls. We conclude that ANKRD26 overexpression, resulting from either hereditary or acquired mechanisms, contributes to thrombocytopenia, thrombosis and hematologic malignancies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Expanding the neuroimmune research toolkit with in vivo brain organoid technologies. 用体内脑类器官技术扩展神经免疫研究工具箱。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-15 DOI: 10.1242/dmm.052200

Ai Tian, Afrin Bhattacharya, Julien Muffat, Yun Li

{"title":"Expanding the neuroimmune research toolkit with in vivo brain organoid technologies.","authors":"Ai Tian, Afrin Bhattacharya, Julien Muffat, Yun Li","doi":"10.1242/dmm.052200","DOIUrl":"https://doi.org/10.1242/dmm.052200","url":null,"abstract":"Human pluripotent stem cell-derived microglia-like cells (MLCs) and brain organoid systems have revolutionized the study of neuroimmune interactions, providing new opportunities to model human-specific brain development and disease. Over the past decade, advances in protocol design have improved the fidelity, reproducibility and scalability of MLC and brain organoid generation. Co-culturing of MLCs and brain organoids have enabled direct investigations of human microglial interactions in vitro, although opportunities remain to improve microglial maturation and long-term survival. To address these limitations, innovative xenotransplantation approaches have introduced MLCs, organoids or neuroimmune organoids into the rodent brain, providing a vascularized environment that supports prolonged development and potential behavioral readouts. These expanding in vitro and in vivo toolkits offer complementary strategies to study neuroimmune interactions in health and disease. In this Perspective, we discuss the strengths, limitations and synergies of these models, highlighting important considerations for their future applications.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 4","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Microvascular aberrations found in human polycystic kidneys are an early feature in a Pkd1 mutant mouse model. 在人类多囊肾中发现的微血管畸变是Pkd1突变小鼠模型的早期特征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-28 DOI: 10.1242/dmm.052024

Daniyal J Jafree, Charith Perera, Mary Ball, Daniele Tolomeo, Gideon Pomeranz, Laura Wilson, Benjamin Davis, William J Mason, Eva Maria Funk, Maria Kolatsi-Joannou, Radu Polschi, Saif Malik, Benjamin J Stewart, Karen L Price, Hannah Mitchell, Reza Motallebzadeh, Yoshiharu Muto, Robert Lees, Sarah Needham, Dale Moulding, Jennie C Chandler, Sonal Nandanwar, Claire L Walsh, Paul J D Winyard, Peter J Scambler, René Hägerling, Menna R Clatworthy, Benjamin D Humphreys, Mark F Lythgoe, Simon Walker-Samuel, Adrian S Woolf, David A Long

{"title":"Microvascular aberrations found in human polycystic kidneys are an early feature in a Pkd1 mutant mouse model.","authors":"Daniyal J Jafree, Charith Perera, Mary Ball, Daniele Tolomeo, Gideon Pomeranz, Laura Wilson, Benjamin Davis, William J Mason, Eva Maria Funk, Maria Kolatsi-Joannou, Radu Polschi, Saif Malik, Benjamin J Stewart, Karen L Price, Hannah Mitchell, Reza Motallebzadeh, Yoshiharu Muto, Robert Lees, Sarah Needham, Dale Moulding, Jennie C Chandler, Sonal Nandanwar, Claire L Walsh, Paul J D Winyard, Peter J Scambler, René Hägerling, Menna R Clatworthy, Benjamin D Humphreys, Mark F Lythgoe, Simon Walker-Samuel, Adrian S Woolf, David A Long","doi":"10.1242/dmm.052024","DOIUrl":"10.1242/dmm.052024","url":null,"abstract":"Therapies targeting blood vessels hold promise for autosomal dominant polycystic kidney disease (ADPKD), the most common inherited disorder causing kidney failure. However, the onset and nature of kidney vascular abnormalities in ADPKD are poorly defined. Accordingly, we employed a combination of single-cell transcriptomics; three-dimensional imaging with geometric, topological and fractal analyses; and multimodal magnetic resonance imaging with arterial spin labelling to investigate aberrant microvasculature in ADPKD kidneys. Within human ADPKD kidneys with advanced cystic pathology and excretory failure, we identified a molecularly distinct blood microvascular subpopulation, characterised by impaired angiogenic signalling and metabolic dysfunction, differing from endothelial injury profiles observed in non-cystic human kidney diseases. Next, Pkd1 mutant mouse kidneys were examined postnatally, when cystic pathology is well established, but before excretory failure. An aberrant endothelial subpopulation was also detected, concurrent with reduced cortical blood perfusion. Disorganised kidney cortical microvasculature was also present in Pkd1 mutant mouse fetal kidneys when tubular dilation begins. Thus, aberrant features of cystic kidney vasculature are harmonised between human and mouse ADPKD, supporting early targeting of the vasculature as a strategy to ameliorate ADPKD progression.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Patient-specific mutation of contact site protein Tomm70 causes neurodegeneration. 接触位点蛋白Tomm70的患者特异性突变导致斑马鱼模型的神经变性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-28 DOI: 10.1242/dmm.052029

Vranda Garg, Wiebke Möbius, Ralf Heinrich, Torben Ruhwedel, Roshan Priyarangana Perera, Patricia Scholz, Till Ischebeck, Gabriela Salinas, Christian Dullin, Martin C Göpfert, Jacob Engelmann, Roland Dosch, Bart R H Geurten

{"title":"Patient-specific mutation of contact site protein Tomm70 causes neurodegeneration.","authors":"Vranda Garg, Wiebke Möbius, Ralf Heinrich, Torben Ruhwedel, Roshan Priyarangana Perera, Patricia Scholz, Till Ischebeck, Gabriela Salinas, Christian Dullin, Martin C Göpfert, Jacob Engelmann, Roland Dosch, Bart R H Geurten","doi":"10.1242/dmm.052029","DOIUrl":"10.1242/dmm.052029","url":null,"abstract":"TOMM70 is a receptor at the contact site between mitochondria and the endoplasmic reticulum, and TOMM70 has been identified as a risk gene for hereditary spastic paraplegia. Furthermore, de novo missense variants of TOMM70 have been identified to cause neurological impairments in two unrelated patients. Here, we show that mutant zebrafish ruehreip25ca also harbour a missense mutation in tomm70, affecting the same conserved isoleucine residue as in one of the human patients. Using this model, we demonstrate how loss of Tomm70 function leads to impairment. At the molecular level, the mutation affected the interaction of Tomm70 with the endoplasmic reticulum protein Lam6, a known sterol transporter. At the neuronal level, the mutation impaired mitochondrial transport to the axons and dendrites, leading to demyelination of large calibre axons in the spinal cord. These neurodegenerative defects in zebrafish were associated with reduced endurance and swimming efficiency, and alterations in the C-start escape response, which correlated with decreased spiking in giant Mauthner neurons. Thus, in zebrafish, a mutation in the endoplasmic reticulum-mitochondria contact site protein Tomm70 recreates some of the neurodegenerative phenotypes characteristic of hereditary spastic paraplegia.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

The physiological functions of ascorbate in the development of cancer. 抗坏血酸在癌症发展中的生理功能。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-04-01 Epub Date: 2025-04-11 DOI: 10.1242/dmm.052201

Michalis Agathocleous

引用次数: 0

Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival. sf3b4的缺失导致剪接缺陷和基因失调，从而破坏颅面发育和存活。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-24 DOI: 10.1242/dmm.052169

Casey Griffin, Kelsey Coppenrath, Doha Khan, Ziyan Lin, Marko Horb, Jean-Pierre Saint-Jeannet

{"title":"Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival.","authors":"Casey Griffin, Kelsey Coppenrath, Doha Khan, Ziyan Lin, Marko Horb, Jean-Pierre Saint-Jeannet","doi":"10.1242/dmm.052169","DOIUrl":"10.1242/dmm.052169","url":null,"abstract":"Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia. These disorders result from haploinsufficiency of SF3B4 (splicing factor 3b, subunit 4), a component of the pre-mRNA spliceosomal machinery. Although the spliceosome is present and functions in all cells of the body, most spliceosomopathies - including Nager and Rodriguez syndromes - are cell- or tissue-specific in their pathology. To understand the pathomechanism underlying these conditions, we generated a Xenopus tropicalis sf3b4 mutant line using CRISPR/Cas9 gene-editing technology. Homozygous deletion of sf3b4 is detrimental to the development of cranial neural crest (NC)-derived cartilage progenitors. Temporal RNA-sequencing analyses of mutant embryos identified an increase in exon-skipping events, followed by important transcriptional changes associated with an enrichment for terms consistent with defects in NC cell migration and survival. We propose that disruption of these processes may underly the pathogenesis of Nager and Rodriguez syndromes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

CIB2 function is distinct from that of whirlin in the organization of sterocilia architecture. CIB2与Whirlin在耳蜗立体纤毛阶梯型发育中的作用不同。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-04-03 DOI: 10.1242/dmm.052043

Arnaud P J Giese, Andrew Parker, Sakina Rehman, Steve D M Brown, Saima Riazuddin, Craig W Vander Kooi, Michael R Bowl, Zubair M Ahmed

{"title":"CIB2 function is distinct from that of whirlin in the organization of sterocilia architecture.","authors":"Arnaud P J Giese, Andrew Parker, Sakina Rehman, Steve D M Brown, Saima Riazuddin, Craig W Vander Kooi, Michael R Bowl, Zubair M Ahmed","doi":"10.1242/dmm.052043","DOIUrl":"10.1242/dmm.052043","url":null,"abstract":"Humans and mice with mutations in genes encoding CIB2 and whirlin (WHRN) are deaf. We previously reported that CIB2 binds to WHRN and is essential for stereocilia staircase architecture of cochlear hair cells. Here, we refine the interaction domains of both proteins and show that these proteins play unique roles in stereocilia bundle formation and organization. We found that the EF2 domain of CIB2 binds to the HHD2 region of WHRN. AlphaFold2 multimer independently identified the same interacting regions and gave a thorough structural model. Next, we investigated genetic interaction between murine Cib2 and Whrn. Hearing in mice double heterozygous for functionally null alleles (Cib2KO/+;Whrnwi/+) was similar to that in age-matched wild-type mice, indicating that partial deficiency for both Cib2 and Whrn does not impair hearing. Double homozygous mutant mice (Cib2KO/KO;Whrnwi/wi) were deaf, and their cochlear stereocilia exhibited a predominant phenotype seen in single Whrnwi/wi mutants. Overexpression of WHRN in Cib2KO/KO mice did not rescue the stereocilia morphology. These data suggest that CIB2 is multifunctional, with key independent functions in the development and/or maintenance of the stereocilia staircase pattern in auditory hair cells.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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