Disease Models & Mechanisms最新文献_第3页

A prioritization tool for cilia-associated genes and their in vivo resources unveil new avenues for ciliopathy research. 纤毛相关基因优先排序工具及其体内资源为纤毛病研究开辟了新途径。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-12 DOI: 10.1242/dmm.052000

Robert E Van Sciver,Tamara Caspary

引用次数: 0

Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve. GATA6-CXCR7 信号缺陷导致主动脉瓣双瓣。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-10 DOI: 10.1242/dmm.050934

Rebeca Piñeiro-Sabarís,Donal MacGrogan,José Luis de la Pompa

{"title":"Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.","authors":"Rebeca Piñeiro-Sabarís,Donal MacGrogan,José Luis de la Pompa","doi":"10.1242/dmm.050934","DOIUrl":"https://doi.org/10.1242/dmm.050934","url":null,"abstract":"The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"42 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215556","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

eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle. eEF1α2 是老化肌肉肌动蛋白细胞骨架平衡所必需的。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-08-29 DOI: 10.1242/dmm.050729

Hidetaka Katow, Hyung Don Ryoo

{"title":"eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle.","authors":"Hidetaka Katow, Hyung Don Ryoo","doi":"10.1242/dmm.050729","DOIUrl":"10.1242/dmm.050729","url":null,"abstract":"The translation elongation factor eEF1α (eukaryotic elongation factor 1α) mediates mRNA translation by delivering aminoacyl-tRNAs to ribosomes. eEF1α also has other reported roles, including the regulation of actin dynamics. However, these distinct roles of eEF1α are often challenging to uncouple and remain poorly understood in aging metazoan tissues. The genomes of mammals and Drosophila encode two eEF1α paralogs, with eEF1α1 expressed ubiquitously and eEF1α2 expression more limited to neurons and muscle cells. Here, we report that eEF1α2 plays a unique role in maintaining myofibril homeostasis during aging in Drosophila. Specifically, we generated an eEF1α2 null allele, which was viable and showed two distinct muscle phenotypes. In young flies, the mutants had thinner myofibrils in indirect flight muscles that could be rescued by expressing eEF1α1. With aging, the muscles of the mutant flies began showing abnormal distribution of actin and myosin in muscles, but without a change in actin and myosin protein levels. This age-related phenotype could not be rescued by eEF1α1 overexpression. These findings support an unconventional role of Drosophila eEF1α2 in age-related homeostasis of muscle myofibers.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105256","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

Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment. 代谢涟漪效应--解读癌症中的脂质代谢如何与肿瘤微环境相互作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-16 DOI: 10.1242/dmm.050814

Patrick B Jonker, Alexander Muir

{"title":"Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.","authors":"Patrick B Jonker, Alexander Muir","doi":"10.1242/dmm.050814","DOIUrl":"10.1242/dmm.050814","url":null,"abstract":"Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281733","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

Supporting the evolution of infectious disease research. 支持传染病研究的发展。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.052112

Kirsty Hooper

引用次数: 0

Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb. Axolotl 下颌骨的再生是通过机械缝隙闭合和与肢体共享再生程序实现的。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-27 DOI: 10.1242/dmm.050743

Julia Kramer, Rita Aires, Sean D Keeley, Tom Alexander Schröder, Günter Lauer, Tatiana Sandoval-Guzmán

{"title":"Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb.","authors":"Julia Kramer, Rita Aires, Sean D Keeley, Tom Alexander Schröder, Günter Lauer, Tatiana Sandoval-Guzmán","doi":"10.1242/dmm.050743","DOIUrl":"10.1242/dmm.050743","url":null,"abstract":"The mandible plays an essential part in human life and, thus, defects in this structure can dramatically impair the quality of life in patients. Axolotls, unlike humans, are capable of regenerating their lower jaws; however, the underlying mechanisms and their similarities to those in limb regeneration are unknown. In this work, we used morphological, histological and transcriptomic approaches to analyze the regeneration of lateral resection defects in the axolotl mandible. We found that this structure can regenerate all missing tissues in 90 days through gap minimization, blastema formation and, finally, tissue growth, differentiation and integration. Moreover, transcriptomic comparisons of regenerating mandibles and limbs showed that they share molecular phases of regeneration, that these similarities peak during blastema stages and that mandible regeneration occurs at a slower pace. Altogether, our study demonstrates the existence of a shared regenerative program used in two different regenerating body structures with different embryonic origins in the axolotl and contributes to our understanding of the minimum requirements for a successful regeneration in vertebrates, bringing us closer to understand similar lesions in human mandibles.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105252","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

Preclinical evaluation of targeted therapies for central nervous system metastases. 中枢神经系统转移瘤靶向疗法的临床前评估。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1242/dmm.050836

Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar

{"title":"Preclinical evaluation of targeted therapies for central nervous system metastases.","authors":"Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar","doi":"10.1242/dmm.050836","DOIUrl":"10.1242/dmm.050836","url":null,"abstract":"The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343411","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

Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model. 在唐氏综合征小鼠模型的发育过程中，出现与三体 Dyrk1a 相关的骨骼表型的性别特异性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-23 DOI: 10.1242/dmm.050914

Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper

{"title":"Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.","authors":"Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper","doi":"10.1242/dmm.050914","DOIUrl":"10.1242/dmm.050914","url":null,"abstract":"Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970851","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

A Drosophila model for mechanistic investigation of tau protein spread. 果蝇模型：tau 蛋白扩散的机理研究

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.050858

Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck

{"title":"A Drosophila model for mechanistic investigation of tau protein spread.","authors":"Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck","doi":"10.1242/dmm.050858","DOIUrl":"10.1242/dmm.050858","url":null,"abstract":"Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3β (GSK-3β, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3β appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343408","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 highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype. 高度转移的 4T1 乳腺癌模型具有上皮-间充质混合表型的特征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-04 DOI: 10.1242/dmm.050771

Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp

{"title":"The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype.","authors":"Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp","doi":"10.1242/dmm.050771","DOIUrl":"10.1242/dmm.050771","url":null,"abstract":"Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893109","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