Disease Models & Mechanisms最新文献_第3页

Expanding and refining the mammalian phenotype ontology to enhance disease model discovery. 扩展和完善哺乳动物表型本体，以加强疾病模型的发现。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-18 DOI: 10.1242/dmm.052385

Susan M Bello, Anna V Anagnostopoulos, Leigh C Carmody, Nicolas Matentzoglu, Cynthia L Smith

引用次数: 0

GABAergic neuronal dysfunction underlies tremor in a Drosophila model of Spinocerebellar ataxia 3. gaba能神经元功能障碍是脊髓小脑共济失调果蝇模型震颤的基础。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-18 DOI: 10.1242/dmm.052329

Animesh Banerjee, Moumita Chatterjee, Kah Junn Tan, Shermaine Tay, Kaibo Duan, Anand Kumar Andiappan, Shanshan Wu Howland, Yoshinori Aso, Sherry Shiying Aw

{"title":"GABAergic neuronal dysfunction underlies tremor in a Drosophila model of Spinocerebellar ataxia 3.","authors":"Animesh Banerjee, Moumita Chatterjee, Kah Junn Tan, Shermaine Tay, Kaibo Duan, Anand Kumar Andiappan, Shanshan Wu Howland, Yoshinori Aso, Sherry Shiying Aw","doi":"10.1242/dmm.052329","DOIUrl":"https://doi.org/10.1242/dmm.052329","url":null,"abstract":"Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine learning method, FLLIT, we previously characterised gait and tremor signatures in the Drosophila model for Spinocerebellar ataxia 3 (SCA3), and found them to be analogous to human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor, and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in or genetic hypo-activation of these neurons leads to tremor, indicating their important role in adult motor control. RNAseq and functional experiments showed that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of approximately 30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079860","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

The class A repeats of Lrp5 are required for normal development of bone, retinal vasculature, and mammary gland in vivo. Lrp5的A类重复序列是体内骨骼、视网膜血管系统和乳腺正常发育所必需的。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-11 DOI: 10.1242/dmm.052280

Cassandra R Diegel, Megan N Michalski, John L Ubels, Gabrielle Foxa Wiartalla, Cheng-Mao Lin, Zhendong A Zhong, Mitchell J McDonald, Nicole J Ethen, Madison Brookshire, Zachary B Madaj, Mingxuan Xia, Paul R Gavine, David A Antonetti, Bart O Williams

{"title":"The class A repeats of Lrp5 are required for normal development of bone, retinal vasculature, and mammary gland in vivo.","authors":"Cassandra R Diegel, Megan N Michalski, John L Ubels, Gabrielle Foxa Wiartalla, Cheng-Mao Lin, Zhendong A Zhong, Mitchell J McDonald, Nicole J Ethen, Madison Brookshire, Zachary B Madaj, Mingxuan Xia, Paul R Gavine, David A Antonetti, Bart O Williams","doi":"10.1242/dmm.052280","DOIUrl":"https://doi.org/10.1242/dmm.052280","url":null,"abstract":"Low-density lipoprotein-related receptor 5 (LRP5) is an LDLR family member with well-defined roles in mediating Wnt signaling. Its domain structure includes 4 LDLR class B and 3 LDLR class A repeats. Class B repeats mediate binding with Wnt ligands and other effectors, while the role of the LRP5 class A repeats, known to interact with apolipoproteins within the LDLR, is unclear. Complete loss of the LRP5 gene in humans causes osteoporosis pseudoglioma, a syndrome characterized by early-onset osteoporosis and changes in retinal vascularization. We and others have previously created mice and rats completely deficient for Lrp5 and reported the presence of bone and retinal vascularization defects. In this study, we created an allele of Lrp5 in mice where the entire protein except for the class A repeats is present and expressed from the endogenous locus. Unlike in vitro studies using ectopic overexpression of LRP5, our in vivo data demonstrate that the class A repeats are essential for several normal LRP5 functions, including bone homeostasis, retinal vascularization, and mammary gland development-phenotypes similar to those observed in Lrp5-null mice.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032838","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

RNAi of mitochondrial sirtuin, sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in C. elegans. 线粒体sirtuin， sir-2.2的RNAi降低了α -突触核蛋白的清除并损害了秀丽隐杆线虫的能量稳态。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-05 DOI: 10.1242/dmm.052197

Anam Naseer, Pranoy Toppo, Mahmood Akbar, Aamir Nazir

{"title":"RNAi of mitochondrial sirtuin, sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in C. elegans.","authors":"Anam Naseer, Pranoy Toppo, Mahmood Akbar, Aamir Nazir","doi":"10.1242/dmm.052197","DOIUrl":"https://doi.org/10.1242/dmm.052197","url":null,"abstract":"Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavored to study the functional implications of mitochondrial sirtuin, sir-2.2 (ortholog of human SIRT4), in regulating neuroprotection employing Caenorhabditis elegans model. We observed that upon sir-2.2 knockdown, the alpha-synuclein aggregation was increased and expression of dopamine transporter, dat-1, was reduced. Also, the levels of marker proteins for innate immunity, oxidative stress, mitophagy, UPRmt, and autophagy, were decreased, suggesting an important function of sir-2.2 in maintaining mitochondrial homeostasis, regulating protein clearance and ameliorating the disease condition. Because of their crucial role in regulating oxidative stress and mitochondrial quality control, studying mitochondrial sirtuin will provide therapeutic insights into the metabolic regulation of ageing and neurodegeneration.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999981","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

Immunological dynamics in orthotopic versus subcutaneous murine models of HPV-positive oropharyngeal cancer. 人乳头瘤病毒阳性口咽癌原位与皮下小鼠模型的免疫动力学。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-03 DOI: 10.1242/dmm.052311

Minzi Mao, Ke Qiu, Lan Feng, Yao Song, Yufang Rao, Shuo Li, Danni Cheng, Xiuli Shao, Chuanhuan Jiang, Shenglan You, Wei Xu, Geoffrey Liu, Jadwiga Jablonska, Stephan Lang, Shuaicheng Li, Fei Chen, Yu Zhao, Jianjun Ren

{"title":"Immunological dynamics in orthotopic versus subcutaneous murine models of HPV-positive oropharyngeal cancer.","authors":"Minzi Mao, Ke Qiu, Lan Feng, Yao Song, Yufang Rao, Shuo Li, Danni Cheng, Xiuli Shao, Chuanhuan Jiang, Shenglan You, Wei Xu, Geoffrey Liu, Jadwiga Jablonska, Stephan Lang, Shuaicheng Li, Fei Chen, Yu Zhao, Jianjun Ren","doi":"10.1242/dmm.052311","DOIUrl":"https://doi.org/10.1242/dmm.052311","url":null,"abstract":"The necessity of reliable preclinical models for evaluating the efficacy of novel therapeutic strategies is imperative. Nevertheless, the degree to which tumor-bearing murine models represent the immunological characteristics of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has largely been unexplored. Utilizing single-cell RNA sequencing technology, our research elucidated that subcutaneous (SC) murine models more accurately reflect the early immunogenic phase of human HPV-positive OPSCC, marked by a stage-dependent increase in effector T cell infiltration. In contrast, orthotopic (base of tongue, BOT) tumors exhibited a progressive decline in cytotoxic T cells and an accumulation of myeloid-derived suppressive cells, paralleling the immune desertification observed in advanced, immune-excluded human tumors. Additionally, our drug responsiveness analysis inferred that early-stage BOT models could more accurately replicate the response to PD1 blockade, whereas late-stage SC models could more accurately mirror the response to CTLA4 blockade akin to human samples. Our findings provide pivotal insights into the suitability of murine models for the preclinical assessment of immunotherapies in HPV-positive OPSCC.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945834","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

Reduced growth and biofilm formation at high temperatures contribute to Cryptococcus deneoformans dermatotropism. 在高温下减少生长和生物膜的形成有助于变形隐球菌的皮肤偏向性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-25 DOI: 10.1242/dmm.052141

Claudia L Charles-Niño, Gunjan M Desai, Nicholas Koroneos, Mohamed F Hamed, Neena Jain, William Lopes, Anthony Braswell, Alexander Linares, Melissa E Munzen, Joshua D Nosanchuk, Marilene H Vainstein, Luis R Martinez

{"title":"Reduced growth and biofilm formation at high temperatures contribute to Cryptococcus deneoformans dermatotropism.","authors":"Claudia L Charles-Niño, Gunjan M Desai, Nicholas Koroneos, Mohamed F Hamed, Neena Jain, William Lopes, Anthony Braswell, Alexander Linares, Melissa E Munzen, Joshua D Nosanchuk, Marilene H Vainstein, Luis R Martinez","doi":"10.1242/dmm.052141","DOIUrl":"10.1242/dmm.052141","url":null,"abstract":"Cryptococcus deneoformans (Cd) and C. neoformans (Cn) differ in geographic prevalence and dermatotropism, with Cd strains more commonly isolated from temperate regions and skin infections. Rising global temperatures prompt concerns regarding selection for environmental fungal species with increased thermotolerance, as high mammalian temperatures provide protection against many fungal species. Cd and Cn strains exhibit variations in thermal susceptibility, with Cd strains being more susceptible to higher temperatures. Here, we identified differences in capsular polysaccharide release, adhesion and biofilm formation between strains both in vivo and in vitro. Histological results suggested that the dermatotropic predilection associated with Cd relates to biofilm formation, possibly facilitating latency and extending fungal survival through protection from high temperatures. We demonstrated that Cn strains were more tolerant to mammalian and febrile temperatures than Cd strains. Similarly, Cd strains showed reduced expression of heat-shock protein 60 and 70, after prolonged exposure to high temperature. Our findings suggest that fungal adhesion, biofilm formation, inflammation and thermotolerance contribute to tissue tropism and disease manifestation by Cn and Cd, supporting the recently assigned species distinction to each of these serotypes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603803","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

Engineered bacteriophages for therapeutic and diagnostic applications. 用于治疗和诊断的工程噬菌体。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-09-30 DOI: 10.1242/dmm.052393

Kandas Traore, Damien Seyer, Agnes Mihajlovski, Antonia P Sagona

{"title":"Engineered bacteriophages for therapeutic and diagnostic applications.","authors":"Kandas Traore, Damien Seyer, Agnes Mihajlovski, Antonia P Sagona","doi":"10.1242/dmm.052393","DOIUrl":"10.1242/dmm.052393","url":null,"abstract":"Antimicrobial resistance represents one of the most serious threats to both public health and economic sustainability. One of the promising approaches to address this problem is phage therapy - treatment of pathogenic bacterial infections using bacteriophages. Bacteriophages have a narrow host spectrum of activity, minimal side effects and self-replication at the infection site, which positions them as promising candidates to complement or replace conventional antibiotics. Moreover, they can be easily genetically modified to enhance their effectiveness and safety. In this At a Glance article, we highlight the timely relevance of engineered phages as an innovative solution in a rapidly evolving healthcare landscape. First, we introduce bacteriophages' life cycle, ecology and therapeutic history, emphasizing their role in One Health strategies. Then, we describe advanced engineering techniques that can be used to expand bacteriophages' functionalities. Finally, we discuss innovative applications of engineered bacteriophages in biotechnological applications and as a potential countermeasure for antimicrobial resistance, including serving as a shuttle for delivering genes and drugs to the targeted bacterial and eukaryotic cells, targeting intracellular bacteria, contributing to vaccine development, facilitating advancements in tissue engineering and improving bacteriophages' antibacterial properties.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 9","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191378","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

Correlative 3D imaging method for analysing lesion architecture in susceptible mice infected with Mycobacterium tuberculosis. 相关三维成像方法分析易感小鼠结核分枝杆菌病变结构。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-26 DOI: 10.1242/dmm.052185

Caroline G G Beltran, Jurgen Kriel, Stefan M Botha, Margaret B Nolan, Alessandro Ciccarelli, Ben Loos, Maximiliano G Gutierrez, Gerhard Walzl

{"title":"Correlative 3D imaging method for analysing lesion architecture in susceptible mice infected with Mycobacterium tuberculosis.","authors":"Caroline G G Beltran, Jurgen Kriel, Stefan M Botha, Margaret B Nolan, Alessandro Ciccarelli, Ben Loos, Maximiliano G Gutierrez, Gerhard Walzl","doi":"10.1242/dmm.052185","DOIUrl":"10.1242/dmm.052185","url":null,"abstract":"Tuberculosis (TB) is characterized by the formation of heterogeneous, immune-rich granulomas in the lungs. Host and pathogen factors contribute to this heterogeneity, but the molecular and cellular drivers of granuloma diversity remain inadequately understood owing to limitations in experimental techniques. In this study, we developed an approach that combines passive CLARITY (PACT)-based clearing with light-sheet fluorescence microscopy to visualize lesion architecture and lung involvement in Mycobacterium tuberculosis-infected C3HeB/FeJ mice. Three-dimensional rendering of post-mortem lungs revealed critical architectural features in lesion development that traditional thin-section imaging could not detect. Wild-type M. tuberculosis infection resulted in organized granulomas, with median sizes increasing to 3.74×108 µm3 and occupying ∼10% of the total lung volume by day 70 post-infection. In contrast, infection with the avirulent ESX-1 deletion mutant strain resulted in diffuse and sparsely organized CD11b recruitment (median size of 8.22×107 µm3), primarily located in the lung periphery and minimally involving the airways (0.23% of the total lung space). Additionally, we present a method for volumetric correlative light and electron microscopy, enabling tracking of individual immune cell populations within granulomas.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708435","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

Translational lessons from the balanced immune system in bats. 蝙蝠平衡免疫系统的翻译经验。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-02-19 DOI: 10.1242/dmm.050763

Wei Lun Ng, Lin-Fa Wang

引用次数: 0

Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19. 将SARS-CoV-2感染动物模型转化为COVID-19的血管、神经和胃肠道表现。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-04-08 DOI: 10.1242/dmm.052086

James Chung, Julia Pierce, Craig Franklin, Rachel M Olson, Alan R Morrison, James Amos-Landgraf

{"title":"Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19.","authors":"James Chung, Julia Pierce, Craig Franklin, Rachel M Olson, Alan R Morrison, James Amos-Landgraf","doi":"10.1242/dmm.052086","DOIUrl":"10.1242/dmm.052086","url":null,"abstract":"Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 million deaths, it has become evident that COVID-19 is not solely a pulmonary disease. Emerging evidence has shown that, in a subset of patients, certain symptoms - including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain - all indicate a role of vascular, neurological and gastrointestinal (GI) pathology in the disease process. Many of these disease processes persist long after the acute disease has been resolved, resulting in 'long COVID' or post-acute sequelae of COVID-19 (PASC). The molecular mechanisms underlying the acute and systemic conditions associated with COVID-19 remain incompletely defined. Appropriate animal models provide a method of understanding underlying disease mechanisms at the system level through the study of disease progression, tissue pathology, immune system response to the pathogen and behavioral responses. However, very few studies have addressed PASC and whether existing models hold promise for studying this challenging problem. Here, we review the current literature on cardiovascular, neurological and GI pathobiology caused by COVID-19 in patients, along with established animal models of the acute disease manifestations and their prospects for use in PASC studies. Our aim is to provide guidance for the selection of appropriate models in order to recapitulate certain aspects of the disease to enhance the translatability of mechanistic studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802718","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