Disease Models & Mechanisms最新文献_第10页

DMM Outstanding Paper Prize 2023 winners: Lídia Faria, Ffion R. Hammond and Amy Lewis. 2023 年 DMM 优秀论文奖获得者：Lídia Faria、Ffion R. Hammond 和 Amy Lewis。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-06-05 DOI: 10.1242/dmm.050893

Rachel Hackett

引用次数: 0

The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease. 糖皮质激素受体在局部发挥作用，在疾病期间保护肌营养不良的肌肉和心脏。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-21 DOI: 10.1242/dmm.050397

Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier

{"title":"The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.","authors":"Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier","doi":"10.1242/dmm.050397","DOIUrl":"10.1242/dmm.050397","url":null,"abstract":"Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 5","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070289","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

An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner. 一种与渐冻症相关的突变以性别特异性的方式使小胶质细胞衍生的细胞外microRNA失调。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI: 10.1242/dmm.050638

Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast

{"title":"An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.","authors":"Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast","doi":"10.1242/dmm.050638","DOIUrl":"10.1242/dmm.050638","url":null,"abstract":"Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175224","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

An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner. 与ALS相关的TDP-43M337V突变以性别特异性的方式使小胶质细胞衍生的细胞外microRNA失调。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI: 10.1242/dmm.050638

Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast

{"title":"An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.","authors":"Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast","doi":"10.1242/dmm.050638","DOIUrl":"10.1242/dmm.050638","url":null,"abstract":"Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891811","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

Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models. 利用气道模型研究人类呼吸系统疾病中的肺神经内分泌细胞。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-30 DOI: 10.1242/dmm.050620

Noah Candeli, Talya Dayton

引用次数: 0

Evaluating protein prenylation of human and viral CaaX sequences using a humanized yeast system. 利用人源化酵母系统评估人类和病毒 CaaX 序列的蛋白质前酰化。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-31 DOI: 10.1242/dmm.050516

Emily R Hildebrandt, Anushka Sarkar, Rajani Ravishankar, June H Kim, Walter K Schmidt

{"title":"Evaluating protein prenylation of human and viral CaaX sequences using a humanized yeast system.","authors":"Emily R Hildebrandt, Anushka Sarkar, Rajani Ravishankar, June H Kim, Walter K Schmidt","doi":"10.1242/dmm.050516","DOIUrl":"10.1242/dmm.050516","url":null,"abstract":"Prenylated proteins are prevalent in eukaryotic biology (∼1-2% of proteins) and are associated with human disease, including cancer, premature aging and infections. Prenylated proteins with a C-terminal CaaX sequence are targeted by CaaX-type prenyltransferases and proteases. To aid investigations of these enzymes and their targets, we developed Saccharomyces cerevisiae strains that express these human enzymes instead of their yeast counterparts. These strains were developed in part to explore human prenyltransferase specificity because of findings that yeast FTase has expanded specificity for sequences deviating from the CaaX consensus (i.e. atypical sequence and length). The humanized yeast strains displayed robust prenyltransferase activity against CaaX sequences derived from human and pathogen proteins containing typical and atypical CaaX sequences. The system also recapitulated prenylation of heterologously expressed human proteins (i.e. HRas and DNAJA2). These results reveal that substrate specificity is conserved for yeast and human farnesyltransferases but is less conserved for type I geranylgeranyltransferases. These yeast systems can be easily adapted for investigating the prenylomes of other organisms and are valuable new tools for helping define the human prenylome, which includes physiologically important proteins for which the CaaX modification status is unknown.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179119","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

Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back. 胰腺癌微观和宏观环境建模：从患者到临床前模型再到临床前模型。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-19 DOI: 10.1242/dmm.050624

Eloise G Lloyd, Joaquín Araos Henríquez, Giulia Biffi

引用次数: 0

Improving access to gene therapy for rare diseases. 改善罕见病基因治疗的可及性。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-19 DOI: 10.1242/dmm.050623

Thomas A Fox, Claire Booth

引用次数: 0

Striatal parvalbumin interneurons, not cholinergic interneurons, are activated in a mouse model of cerebellar dystonia. 在小脑肌张力障碍小鼠模型中，纹状体旁白质中间神经元而非胆碱能中间神经元被激活。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-15 DOI: 10.1242/dmm.050338

Taku Matsuda, Ryoma Morigaki, Hiroaki Hayasawa, Hiroshi Koyama, Teruo Oda, Kazuhisa Miyake, Yasushi Takagi

{"title":"Striatal parvalbumin interneurons, not cholinergic interneurons, are activated in a mouse model of cerebellar dystonia.","authors":"Taku Matsuda, Ryoma Morigaki, Hiroaki Hayasawa, Hiroshi Koyama, Teruo Oda, Kazuhisa Miyake, Yasushi Takagi","doi":"10.1242/dmm.050338","DOIUrl":"https://doi.org/10.1242/dmm.050338","url":null,"abstract":"Dystonia is supposed to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted the established cerebellar dystonia mice model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe), and striatal neurons were activated in the model. Next, we examined whether dopamine D1 receptor agonists (D1 agonist) and dopamine D2 receptor antagonists (D2 antagonist) or selective ablation of striatal parvalbumin (PV) interneurons could modulate their involuntary movements. The cerebellar dystonia mice had a higher number of c-fos-positive cells in the EPN, SNr, and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons than the control mice. Furthermore, systemic administration of combined D1 agonist and D2 antagonist and selective ablation of striatal PV interneurons relieved their involuntary movements. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"203 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591639","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

Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice. 抗Caspase的ROCK1表达可延长Eµ-Myc B细胞淋巴瘤小鼠的存活期。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-15 DOI: 10.1242/dmm.050631

Katerina Mardilovich, Gregory Naylor, Linda Julian, Narisa Phinichkusolchit, Karen Keeshan, Karen Blyth, Michael F Olson

{"title":"Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice.","authors":"Katerina Mardilovich, Gregory Naylor, Linda Julian, Narisa Phinichkusolchit, Karen Keeshan, Karen Blyth, Michael F Olson","doi":"10.1242/dmm.050631","DOIUrl":"https://doi.org/10.1242/dmm.050631","url":null,"abstract":"Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due to Eµ-Myc transgene expression. Eµ-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to Eµ-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in Eµ-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in Eµ-Myc; Rock1 NC mice bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic Eµ-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with Eµ-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the Eµ-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of Eµ-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"165 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591641","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