疾病模型与机制 (DMM) 是一本在线开放获取期刊，专注于使用模型系统更好地理解、诊断和治疗人类疾病。

DMM Disease Models and Mechanisms is an online open-access journal that focuses on using model systems to better understand, diagnose, and treat human diseases.

《DMM Disease Models and Mechanisms》是一本在线开放获取期刊，专注于通过模型系统深入理解、诊断和治疗人类疾病。

DMM Disease Models and Mechanisms

Tendon disorders frequently occur and recent evidence has clearly implicated the presence of immune cells and inflammatory events during early tendinopathy. However, the origin and properties of these cells remain poorly defined. Therefore, the aim of this study was to determine the presence of cells in healthy rodent and human tendon tissue fulfilling macrophage-like functions. Using various transgenic reporter mouse models, we demonstrate the presence of tendon resident cells in the dense matrix of the tendon core expressing the fractalkine (Fkn) receptor CX3CR1 and its cognate ligand CX3CL1/Fkn. Pro-inflammatory stimulation of 3D tendon-like constructs in vitro resulted in a significant increase in the expression of IL-1ß, IL-6, Mmp3, Mmp9, Cx3cl1, and epiregulin which has been reported to contribute to inflammation, wound healing, and tissue repair. Furthermore, we demonstrate that inhibition of the fractalkine receptor blocked tendon cell migration in vitro and show the presence of CX3CR1/CX3CL1/EREG expressing cells in healthy human tendons. Taken together, we demonstrate the presence of CX3CL1+/CX3CR1+ “tenophages” within the healthy tendon proper potentially fulfilling surveillance functions in tendons.

Christine Lehner

Gabriel Spitzer

Renate Gehwolf

Andrea Wagner

Nadja Weissenbacher

Christian Deininger

Katja Emmanuel

Florian Wichlas

Herbert Tempfer

Andreas Traweger

Disease Models & Mechanisms

Tenophages: a novel macrophage-like tendon cell population expressing CX3CL1 and CX3CR1

Tenophages：一种表达CX3CL1和CX3CR1的新型巨噬细胞样肌腱细胞群体

ABSTRACT The actin motor protein non-muscle myosin II (NMII) acts as a master regulator of cell morphology, with a role in several essential cellular processes, including cell migration and post-synaptic dendritic spine plasticity in neurons. NMII also generates forces that alter biochemical signaling, by driving changes in interactions between actin-associated proteins that can ultimately regulate gene transcription. In addition to its roles in normal cellular physiology, NMII has recently emerged as a critical regulator of diverse, genetically complex diseases, including neuronal disorders, cancers and vascular disease. In the context of these disorders, NMII regulatory pathways can be directly mutated or indirectly altered by disease-causing mutations. NMII regulatory pathway genes are also increasingly found in disease-associated copy-number variants, particularly in neuronal disorders such as autism and schizophrenia. Furthermore, manipulation of NMII-mediated contractility regulates stem cell pluripotency and differentiation, thus highlighting the key role of NMII-based pharmaceuticals in the clinical success of stem cell therapies. In this Review, we discuss the emerging role of NMII activity and its regulation by kinases and microRNAs in the pathogenesis and prognosis of a diverse range of diseases, including neuronal disorders, cancer and vascular disease. We also address promising clinical applications and limitations of NMII-based inhibitors in the treatment of these diseases and the development of stem-cell-based therapies.

Karen A. Newell-Litwa

Rick Horwitz

Marcelo L. Lamers

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

非肌肉肌球蛋白II在疾病中的作用：机制与治疗机会

Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we show that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression. However, HDAC6 also acts on other proteins that involve in distinct biological processes unrelated to tubulins. In order to directly examine the role of increased tubulin acetylation against tau toxicity, we generated site-directed α-tubulinK40Q mutation by the CRISPR/Cas9 technology to mimic the acetylated MTs and found that acetylation-mimicking α-tubulin rescued tau-induced MT defects and neuromuscular junction developmental abnormalities. We also showed that late administration of ACY-1215 and tubastatin A, two potent and selective inhibitors of HDAC6, rescued the tau-induced MT defects after the abnormalities had already become apparent. Our results together indicate that increased MT acetylation by either genetic manipulations or drugs might be used as potential strategies for intervening tauopathies.

Chuan-Xi Mao

Xue Wen

Shan Jin

Yong Q. Zhang

Increased acetylation of microtubules rescues human tau-induced microtubule defects and neuromuscular junction abnormalities in Drosophila

微管乙酰化增加可挽救人类tau蛋白诱导的果蝇微管缺陷和神经肌肉接头异常

SUMMARY Tyrosine site-specific recombinases (SSRs) including Cre and FLP are essential tools for DNA and genome engineering. Cre has long been recognized as the best SSR for genome engineering, particularly in mice. Obtaining another SSR that is as good as Cre will be a valuable addition to the genomic toolbox. To this end, we have developed and validated reagents for the Dre-rox system. These include an Escherichia coli-inducible expression vector based on the temperature-sensitive pSC101 plasmid, a mammalian expression vector based on the CAGGs promoter, a rox-lacZ reporter embryonic stem (ES) cell line based on targeting at the Rosa26 locus, the accompanying Rosa26-rox reporter mouse line, and a CAGGs-Dre deleter mouse line. We also show that a Dre-progesterone receptor shows good ligand-responsive induction properties. Furthermore, we show that there is no crossover recombination between Cre-rox or Dre-loxP. Hence, we add another set of efficient tools to the genomic toolbox, which will enable the development of more sophisticated mouse models for the analysis of gene function and disease.

Konstantinos Anastassiadis

Jun Fu

Christoph Patsch

Shengbiao Hu

Stefanie Weidlich

Kristin Duerschke

Frank Buchholz

Frank Edenhofer

A. Francis Stewart

Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice

Dre重组酶，类似于Cre，是一种在大肠杆菌、哺乳动物细胞和小鼠中高度高效的位点特异性重组酶

The metabolic syndrome refers to the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension. These conditions are interrelated and share underlying mediators, mechanisms and pathways. There has been recent controversy about its definition and its utility. In this article, I review the current definitions for the metabolic syndrome and why the concept is important. It identifies a subgroup of patients with shared pathophysiology who are at high risk of developing cardiovascular disease and type 2 diabetes. By considering the central features of the metabolic syndrome and how they are related, we may better understand the underlying pathophysiology and disease pathogenesis. A comprehensive definition for the metabolic syndrome and its key features would facilitate research into its causes and hopefully lead to new insights into pharmacologic and lifestyle treatment approaches.

Paul L. Huang

A comprehensive definition for metabolic syndrome

代谢综合征的综合定义

Mutations in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function. To answer this question, we used Drosophila expressing RNAi against the FTLD-associated gene, TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, a reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes a loss-of-function. Alterations were also observed in pupal brains and were partially rescued by coexpression of MCM2, which is involved in control of the cell cycle. This is suggesting that dysregulation of neuronal proliferation caused the phenotypes. We also found that TER94 KD caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by a loss-of-function of VCP.

Kohei Tsumaki

Christian J. F. Bertens

Minoru Nakayama

Saya Kato

Yuki Jonao

Ayu Kuribayashi

Konosuke Sato

Shota Ishiyama

Momoko Asakawa

Riko Aihara

Yuki Yoshioka

Hidenori Homma

Hikari Tanaka

Kyota Fujita

Hitoshi Okazawa

Masaki Sone

Loss of function of VCP/TER94 causes neurodegeneration in the Drosophila central nervous system

VCP/TER94功能丧失导致果蝇中枢神经系统神经退行性变

ABSTRACT Computational tools for predicting variant pathogenicity are widely used to support clinical variant interpretation. Recently, several models, which do not rely on known variant classifications during training, have been developed. These approaches can potentially overcome biases of current clinical databases, such as misclassifications, and can potentially better generalize to novel, unclassified variants. AlphaMissense is one such model, built on the highly successful protein structure prediction model, AlphaFold. AlphaMissense has shown great performance in benchmarks of functional and clinical data, outperforming many supervised models that were trained on similar data. However, like other in silico predictors, AlphaMissense has notable limitations. As a large deep learning model, it lacks interpretability, does not assess the functional impact of variants, and provides pathogenicity scores that are not disease specific. Improving interpretability and precision in computational tools for variant interpretation remains a promising area for advancing clinical genetics.

Ivan Molotkov

Elaine R. Mardis

Mykyta Artomov

Making sense of missense: challenges and opportunities in variant pathogenicity prediction

解读错义突变：变异致病性预测中的挑战与机遇

Ashok Venkitaraman

From mechanisms of carcinogenesis to early intervention: an interview with Ashok Venkitaraman

从致癌机制到早期干预：对Ashok Venkitaraman的采访

Lukas Sommer

Timing is everything: an inducible model for neurofibromatosis type 2 in zebrafish

时机至关重要：斑马鱼中神经纤维瘤病2型的可诱导模型

ABSTRACT The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.

Sahiba Siddiqui

Fang Liu

Anumantha G. Kanthasamy

Maura McGrail

Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation

Stat3介导Fyn激酶驱动的多巴胺能神经退行性和小胶质细胞激活

Abbreviation	Dis. Model. Mech.
Journal Impact	4.14
Quartiles(Global)	PATHOLOGY(Q1)

ISSN	1754-8403, 1754-8411
h-index	107

Publication Information	Publisher: Company of Biologists Ltd，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2008，Proportion of original research papers: 85.53%，Self Citation Rate:7.50%， Gold OA Rate: 99.12%
Journal Fees	$3750Details
Average review cycle	网友分享经验：较慢,6-12周

DMM Disease Models and Mechanisms

Journal Citation Format

A journal article with 1 author

A journal article with 2 authors

A journal article with 3 authors

A journal article with 5 or more authors

Books Citation Format

Thesis Citation Format

Web sites Citation Format

Patent Citation Format

Staying up late manually editing references? ivySCI automatically matches journals and helps you generate references with a single click.

Share Submission Experience