Disease Models & Mechanisms最新文献_第2页

A novel zebrafish luminescent biosensor for kidney tubulopathy, metal toxicity, and drug screening. 一种用于肾小管病变、金属毒性和药物筛选的新型斑马鱼发光生物传感器。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-07 DOI: 10.1242/dmm.052673

Han Lai, Monica Goldade, Svenja Aline Keller, Isabelle Worms, Alessandro Luciani, Stephan C F Neuhauss, Vera I Slaveykova, Olivier Devuyst, Zhiyong Chen

引用次数: 0

Chiari II brain malformation is secondary to open spina bifida. Chiari II型脑畸形继发于开放性脊柱裂。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-04-24 DOI: 10.1242/dmm.052528

Maryam Clark, Timothy J Edwards, Dawn Savery, Gabriel L Galea, Nagaraj Samy, Erwin Pauws, Nicoletta Kessaris, Nicholas D E Greene, Andrew J Copp

{"title":"Chiari II brain malformation is secondary to open spina bifida.","authors":"Maryam Clark, Timothy J Edwards, Dawn Savery, Gabriel L Galea, Nagaraj Samy, Erwin Pauws, Nicoletta Kessaris, Nicholas D E Greene, Andrew J Copp","doi":"10.1242/dmm.052528","DOIUrl":"10.1242/dmm.052528","url":null,"abstract":"Chiari II brain malformation affects 90% of children with open spina bifida. Hindbrain herniation leads to hydrocephalus, together with higher-brain anomalies including cerebral cortical defects implicated in learning disability, which affects 20-25% of children with spina bifida. The causal link between Chiari II and spina bifida has long been debated, and we aimed to determine whether Chiari II arises secondary to spina bifida, rather than as a separate effect of shared genetic or non-genetic factor(s). Pax3 gene function was conditionally deleted by Cdx2cre specifically in the lower body of mice, leaving the head genetically intact. Open spina bifida was seen in all Cdx2cre/+;Pax3fl/fl fetuses, together with many features of Chiari II in the wild-type brain and skull. These included hindbrain herniation, callosal and hippocampal hypogenesis, cortical thinning with neuronal heterotopia, a thickened ventricular zone and posterior skull defects. Hence, the brain and skull defects of Chiari II arise secondary to open spina bifida, with likely disturbance of neurogenesis and neuronal migration early in gestation. The Cdx2cre/+;Pax3fl/fl mouse provides a model for improved understanding of Chiari II pathogenesis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472840","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

Nestin/CXCL12 immunohistochemistry and RNA sequencing map the bone marrow microenvironment in aplastic anemia. 再生障碍性贫血的骨髓微环境：来自Nestin/CXCL12免疫组织化学和rna测序的见解

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-05-05 DOI: 10.1242/dmm.052564

Astrid Beerlage, Carl P Zinner, Jakob R Passweg, Beatrice Drexler, Alexandar Tzankov

{"title":"Nestin/CXCL12 immunohistochemistry and RNA sequencing map the bone marrow microenvironment in aplastic anemia.","authors":"Astrid Beerlage, Carl P Zinner, Jakob R Passweg, Beatrice Drexler, Alexandar Tzankov","doi":"10.1242/dmm.052564","DOIUrl":"10.1242/dmm.052564","url":null,"abstract":"Aplastic anemia (AA) is a rare bone marrow failure syndrome characterized by immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). The contribution of the bone marrow microenvironment remains incompletely understood. Here, we analyzed 29 bone marrow biopsies from patients with moderate (mAA), severe (sAA) and very severe (vsAA) AA, along with 12 unaffected controls and seven subcortical pseudohypocellular samples. Immunohistochemistry for nestin and CXCL12 was performed to quantify stromal niches. RNA sequencing was carried out to investigate immune and niche-related gene expression patterns. Patients with sAA exhibited a significantly increased number of nestin+ niches compared to patients with mAA and controls. CXCL12+ niches showed no significant differences between groups. RNA sequencing revealed upregulation of immune response genes, as well as pathways related to interferon-gamma signaling, JAK-STAT3 activation and antigen presentation. Downregulated genes and pathways pointed to impaired DNA repair, cell cycle regulation and epigenetic stability. Our findings support a model in which AA pathogenesis is driven by immune injury and compensatory, yet dysfunctional, stromal remodeling. These data underline the importance of the bone marrow microenvironment in AA.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Loss of Cathepsin Z enhances pro-inflammatory macrophage responses and promotes tissue regeneration. 组织蛋白酶Z的缺失可增强促炎巨噬细胞反应，促进组织再生。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-04-29 DOI: 10.1242/dmm.052520

Thais Sibioni Berti Bastos, Catherine A Loynes, Zoë C Speirs, Jordana Dinorá de Lima, Leonel Witckosk Junior, André Guilherme Portela de Paula, Andressa Pacheco Czaikovski, Rebeca Bosso Santos Luz, Lais Cavalieri Paredes, Mia Norris, Gillian S Tomlinson, Wanderson Duarte da Rocha, Stephen A Renshaw, Philip M Elks, Tarcio Teodoro Braga

{"title":"Loss of Cathepsin Z enhances pro-inflammatory macrophage responses and promotes tissue regeneration.","authors":"Thais Sibioni Berti Bastos, Catherine A Loynes, Zoë C Speirs, Jordana Dinorá de Lima, Leonel Witckosk Junior, André Guilherme Portela de Paula, Andressa Pacheco Czaikovski, Rebeca Bosso Santos Luz, Lais Cavalieri Paredes, Mia Norris, Gillian S Tomlinson, Wanderson Duarte da Rocha, Stephen A Renshaw, Philip M Elks, Tarcio Teodoro Braga","doi":"10.1242/dmm.052520","DOIUrl":"https://doi.org/10.1242/dmm.052520","url":null,"abstract":"The plasticity of macrophages is well documented, with fundamental roles in modulating inflammation and promoting tissue repair, notably aiming to maintain homeostasis in multicellular organisms. However, the precise factors that regulate their polarization remain poorly understood. Cathepsin Z (CTSZ) encodes an enzyme highly expressed in macrophages and involved in various processes, such as migration, maturation and signal transduction, but its roles in regeneration are not described. Therefore, we used zebrafish models to investigate the roles of ctsz in macrophage polarization and regeneration in the context of sterile inflammation induced by caudal fin transection. CRISPR/Cas9-mediated knockdown of ctsz led to higher pro-inflammatory tnfα+ macrophages than in control animals following injury (24-48 h post-injury), as well as accelerated regenerated area. Further studies in this field could prove valuable for the development of pharmacological approaches for chronic diseases characterized by impaired tissue regeneration, such as liver fibrosis or autoimmune diseases, in which dysregulated inflammation and regeneration play critical roles.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions. 基于结构的MEN2A、巨结肠病RET变异的系统分析及其矛盾的共现。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-04-27 DOI: 10.1242/dmm.052748

Anna Fassler Bakhman, Michal Cohen, Rachel Kolodny, Mickey Kosloff

{"title":"Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions.","authors":"Anna Fassler Bakhman, Michal Cohen, Rachel Kolodny, Mickey Kosloff","doi":"10.1242/dmm.052748","DOIUrl":"10.1242/dmm.052748","url":null,"abstract":"Variants in the human receptor tyrosine kinase RET can cause RET loss-of-function and Hirschsprung's disease (HSCR), while activating RET variants drive cancers including multiple endocrine neoplasia type 2 (MEN2). Paradoxically, some variants cause both HSCR and MEN2A. We curated 77 RET extracellular positions associated with HSCR, MEN2A or both and used a structure-based approach to predict the effects of variants at these positions on RET structure. Approximately 90% of HSCR-associated positions can, upon mutation, disrupt intramolecular interactions stabilizing RET tertiary structure via distinct mechanisms. Only a minority perturb protein-protein interactions needed for signal activation. In contrast, our analysis showed that ∼75% of variants causing MEN2A lead to an unpaired cysteine that can form an intermolecular disulfide bond between two RET monomers. Other MEN2A variants are likely to enhance RET homodimerization via membrane-proximal extracellular interactions. Substitutions that, concurrently, destabilize RET structure and result in an unpaired cysteine are predicted to cause the paradoxical co-occurrence of HSCR and MEN2A. Our findings lay out a mechanistic basis for almost all identified pathological RET mutations, and suggest therapeutic strategies for targeting RET activity in HSCR and MEN2A.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Why in vivo models of disease remain indispensable. 为什么疾病的体内模型仍然是必不可少的。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-05-05 DOI: 10.1242/dmm.052997

Debora Bogani, Kirsty Hooper, Owen Sansom

引用次数: 0

Embryonic spinocerebellar ataxia type 37-associated AUUUC repeat RNA causes neurodevelopmental defects. 胚胎脊髓小脑共济失调37型AUUUC重复RNA引起斑马鱼神经发育缺陷。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-04-30 DOI: 10.1242/dmm.052636

Ana F Castro, Ana S Figueiredo, Joana R Loureiro, Maria M Azevedo, Paula Sampaio, Ana M Valentim, José Bessa, Isabel Silveira

{"title":"Embryonic spinocerebellar ataxia type 37-associated AUUUC repeat RNA causes neurodevelopmental defects.","authors":"Ana F Castro, Ana S Figueiredo, Joana R Loureiro, Maria M Azevedo, Paula Sampaio, Ana M Valentim, José Bessa, Isabel Silveira","doi":"10.1242/dmm.052636","DOIUrl":"10.1242/dmm.052636","url":null,"abstract":"Onset of many neurodegenerative and neuromuscular diseases usually starts in adulthood; however, recent advances point towards neurodevelopmental changes as drivers of late neurodegeneration. How early neuropathological features occur under these conditions remains unclear, but this knowledge would be critical for timely therapeutic intervention. Here, we provide evidence that neurodevelopmental axonal defects initiate a motor phenotype in a zebrafish model of spinocerebellar ataxia type 37 (SCA37), a degenerative hereditary disease caused by an ATTTC repeat in the DAB1 gene. We investigated neuronal defects triggered by the embryonic AUUUC repeat RNA from the DAB1 gene and their effects later in life by transiently expressing this RNA in embryos and analyzing innervation and motor function. We found abnormalities in motor neuron axonal outgrowth and muscle innervation. We also discovered disrupted embryonic motor activity, and reduced locomotor distance and velocity in late adult zebrafish, demonstrating motor impairment. Moreover, we showed that protein expression of the splicing regulator NOVA2 rescues axonal defects, indicating dysfunction of NOVA2-regulated neurodevelopmental processes. Overall, our results establish embryonic expression of the AUUUC repeat RNA as a driver of axonal and synaptic abnormalities, interfering with neuronal circuits and culminating in adult motor dysfunction.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Identification and credentialing of patient-derived xenograft models of invasive lobular carcinoma. 侵袭性小叶癌患者来源的异种移植物模型的鉴定和鉴定。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-04-29 DOI: 10.1242/dmm.052710

Jagmohan Hooda, Jennifer M Atkinson, Osama Shiraz Shah, Megan Yates, Daniel D Brown, Morgan DeBerry, Stefano Cairo, Paolo Schiavini, Hsiu-Wen Tsai, Marianna Zipeto, Rohit Bhargava, Steffi Oesterreich, Adrian V Lee

{"title":"Identification and credentialing of patient-derived xenograft models of invasive lobular carcinoma.","authors":"Jagmohan Hooda, Jennifer M Atkinson, Osama Shiraz Shah, Megan Yates, Daniel D Brown, Morgan DeBerry, Stefano Cairo, Paolo Schiavini, Hsiu-Wen Tsai, Marianna Zipeto, Rohit Bhargava, Steffi Oesterreich, Adrian V Lee","doi":"10.1242/dmm.052710","DOIUrl":"10.1242/dmm.052710","url":null,"abstract":"Invasive lobular cancer (ILC) is the most common special breast cancer subtype, accounting for 10-15% of all cases. The pathognomonic feature of ILC is loss of E-cadherin (encoded by CDH1), leading to discohesive single-file growth. Although ILCs show better prognostic factors than 'no special type' (NST) breast cancer, patients with ILC have worse long-term outcomes. We identified and validated patient-derived xenograft (PDX) models of ILC from 122 breast cancer PDX models based on truncating CDH1 mutations and/or low CDH1 mRNA expression. Eight PDX models were selected for validation using immunohistochemistry for E-cadherin, p120, estrogen receptor, progesterone receptor and HER2. Seven models were confirmed as ILC, and one showed mixed NST-ILC features. Confirmed ILC PDX models showed enrichment of truncating CDH1 mutations, significantly lower CDH1 mRNA expression and predominantly luminal subtypes compared to NST models, consistent with human ILC characteristics. Commonly altered genes included PIK3CA (57%), CDH1 (57%) and TP53 (57%). These validated ILC PDX models provide valuable tools to advance understanding of ILC biology and support development of targeted therapies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 temporal dialogue between the circadian clock and chronic inflammatory diseases. 生物钟与慢性炎症性疾病之间的时间对话。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-05-07 DOI: 10.1242/dmm.052749

Siyu Chen, David Ray

{"title":"A temporal dialogue between the circadian clock and chronic inflammatory diseases.","authors":"Siyu Chen, David Ray","doi":"10.1242/dmm.052749","DOIUrl":"https://doi.org/10.1242/dmm.052749","url":null,"abstract":"The circadian clock is an intrinsic molecular system that synchronises biological processes with daily environmental cycles. Under physiological conditions, cell-intrinsic clocks and systemic cues together regulate the circadian rhythmicity of immune activity, limiting immune responses to the appropriate time and intensity for optimal energy allocation and fitness. In chronic inflammation, by contrast, persistent and profound circadian alterations may cause a pro-inflammatory shift of homeostasis and hinder resolution. Circadian-based therapeutic strategies are emerging as promising approaches to overcome the limitations of conventional anti-inflammatory therapeutics and relieve treatment burden. This Review examines the bi-directional relationship between circadian regulation and chronic inflammation across immune-mediated, metabolic and infectious conditions. Circadian rhythms shape the timing, severity and tissue specificity of inflammatory responses, while inflammatory signals from diverse pathological settings converge on shared transcriptional nodes that interface with the clock, altering temporal organisation across multiple systems. We further highlight key future directions, including defining the molecular links between the circadian clock, inflammation and metabolism for precise target identification, restoring the intrinsic capacity for temporal homeostatic regulation through personalised circadian medicine, and integrating behavioural and environmental factors into the current framework. Together, they represent a path towards more precise, preventive and holistic management of chronic inflammatory diseases.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Alex's Lemonade Stand Foundation squeezes in hope for childhood cancer: an interview with Liz and Jay Scott. 亚历克斯的柠檬水摊位基金会挤压儿童癌症的希望：对利兹和杰伊·斯科特的采访。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2026-04-01 Epub Date: 2026-05-05 DOI: 10.1242/dmm.052967

Liz Scott, Jay Scott, Alex's Lemonade Stand Foundation

引用次数: 0