Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner [RESEARCH ARTICLE]
ABSTRACT Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular, the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, in our analyses, within a timescale of minutes, mitochondrial respiration and glycolysis were hampered, which occurred in a pH-independent manner. Using metabolomics, an accumulation of glucose and numerous amino acids, including branched chain am...
Source: DMM Disease Models and Mechanisms - November 4, 2020 Category: Biomedical Science Authors: Drews, L., Zimmermann, M., Westhoff, P., Brilhaus, D., Poss, R. E., Bergmann, L., Wiek, C., Brenneisen, P., Piekorz, R. P., Mettler-Altmann, T., Weber, A. P. M., Reichert, A. S. Tags: RESEARCH ARTICLE Source Type: research

First person - Zakia Abdelhamed [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Zakia Abdelhamed is first author on ‘A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice’, published in DMM. Zakia is a research associate in the lab of Dr Rolf Stottmann at Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, investigating animal models that recapitulate a human condition for understanding disease pathogenesis. (Source: DMM Dis...
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

First person - Gabriel Matos-Rodrigues [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Gabriel Matos-Rodrigues is first author on ‘Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome’, published in DMM. Gabriel conducted the research described in this article while a PhD student in Rodrigo A. P. Martins's lab at Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. He is now a PhD student in the lab of Bernard S. Lo...
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma [RESEARCH ARTICLE]
ABSTRACT Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cel...
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Authors: Fu, D.-J., De Micheli, A. J., Bidarimath, M., Ellenson, L. H., Cosgrove, B. D., Flesken-Nikitin, A., Nikitin, A. Y. Tags: Cancer RESEARCH ARTICLE Source Type: research

Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Authors: Matos-Rodrigues, G. E., Tan, P. B., Rocha-Martins, M., Charlier, C. F., Gomes, A. L., Cabral-Miranda, F., Grigaravicius, P., Hofmann, T. G., Frappart, P.-O., Martins, R. A. P. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice [RESEARCH ARTICLE]
ABSTRACT Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1G93A murine model. SOD1G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age ...
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Authors: Ruiz-Ruiz, C., Garcia-Magro, N., Negredo, P., Avendano, C., Bhattacharya, A., Ceusters, M., Garcia, A. G. Tags: Neuromuscular RESEARCH ARTICLE Source Type: research

A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - October 30, 2020 Category: Biomedical Science Authors: Abdelhamed, Z., Lukacs, M., Cindric, S., Omran, H., Stottmann, R. W. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Cellular and animal models for facioscapulohumeral muscular dystrophy [REVIEW]
ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 an...
Source: DMM Disease Models and Mechanisms - October 28, 2020 Category: Biomedical Science Authors: DeSimone, A. M., Cohen, J., Lek, M., Lek, A. Tags: Neuromuscular, Model Systems in Drug Discovery REVIEW Source Type: research

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy [RESEARCH ARTICLE]
ABSTRACT Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments. To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN, an HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vecto...
Source: DMM Disease Models and Mechanisms - October 28, 2020 Category: Biomedical Science Authors: Tang, P., Das, J. R., Li, J., Yu, J., Ray, P. E. Tags: Model Systems in Drug Discovery RESEARCH ARTICLE Source Type: research

Modeling neurodegeneration in Caenorhabditis elegans [AT A GLANCE]
ABSTRACT The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode Caenorhabditis elegans has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ~60 years. More recently, the considerable attributes of C. elegans have been applied to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. Transgenic nematodes with genes encoding normal and disease var...
Source: DMM Disease Models and Mechanisms - October 26, 2020 Category: Biomedical Science Authors: Caldwell, K. A., Willicott, C. W., Caldwell, G. A. Tags: Neurodegenerative disorders, C. elegans, Model Systems in Drug Discovery AT A GLANCE Source Type: research

First person - Gideon Hughes [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Gideon Hughes is first author on ‘Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease’, published in DMM. Gideon conducted the research described in this article while a PhD student in Betsy Pownall's lab at the University of York, York, UK. He is now a postdoc in the lab of Henry Roehl at the University of Sheffield, Sheffield, UK, using the zebrafish as...
Source: DMM Disease Models and Mechanisms - October 16, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - October 16, 2020 Category: Biomedical Science Authors: Hughes, G. L., Lones, M. A., Bedder, M., Currie, P. D., Smith, S. L., Pownall, M. E. Tags: Neurodegenerative disorders, Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

First person - Eva Saskoi [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Éva Saskői is first author on ‘The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model’, published in DMM. Éva is a PhD student in the lab of Krisztina Takács-Vellai at Eötvös Lorand University, Budapest, Hungary, investigating the developmental functions of tumor suppressor homologs in Caenorhabditis elegans. (So...
Source: DMM Disease Models and Mechanisms - October 15, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - October 15, 2020 Category: Biomedical Science Authors: Saskoi, E., Hujber, Z., Nyiro, G., Liko, I., Matyasi, B., Petovari, G., Meszaros, K., Kovacs, A. L., Patthy, L., Supekar, S., Fan, H., Svab, G., Tretter, L., Sarkar, A., Nazir, A., Sebestyen, A., Patocs, A., Mehta, A., Takacs-Vellai, K. Tags: Cancer metabolism, Rare diseases, C. elegans RESEARCH ARTICLE Source Type: research

CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons [RESEARCH ARTICLE]
ABSTRACT C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP–/– mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patien...
Source: DMM Disease Models and Mechanisms - October 12, 2020 Category: Biomedical Science Authors: Schuster, S., Heuten, E., Velic, A., Admard, J., Synofzik, M., Ossowski, S., Macek, B., Hauser, S., Schöls, L. Tags: Stem Cells, Neurodegenerative disorders RESEARCH ARTICLE Source Type: research

First person - Shohei Yoshimoto [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Shohei Yoshimoto is first author on ‘Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids’, published in DMM. Shohei is a research scientist in the lab of Professor Shuichi Hashimoto at Fukuoka Dental College, Fukuoka, Japan, investigating salivary gland disorders. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Pre-existing antibody-mediated adverse effects prevent the clinical development of a bacterial anti-inflammatory protein [RESEARCH ARTICLE]
ABSTRACT Bacterial pathogens have evolved to secrete strong anti-inflammatory proteins that target the immune system. It was long speculated whether these virulence factors could serve as therapeutics in diseases in which abnormal immune activation plays a role. We adopted the secreted chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) as a model virulence factor-based therapeutic agent for diseases in which C5AR1 stimulation plays an important role. We show that the administration of CHIPS in human C5AR1 knock-in mice successfully dampens C5a-mediated neutrophil migration during immune complex-initiated inflam...
Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Authors: Tromp, A. T., Zhao, Y., Jongerius, I., Heezius, E. C. J. M., Abrial, P., Ruyken, M., van Strijp, J. A. G., de Haas, C. J. C., Spaan, A. N., van Kessel, K. P. M., Henry, T., Haas, P.-J. A. Tags: Model Systems in Drug Discovery RESEARCH ARTICLE Source Type: research

Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Authors: Yoshimoto, S., Yoshizumi, J., Anzai, H., Morishita, K., Okamura, K., Hiraki, A., Hashimoto, S. Tags: Organoids RESEARCH ARTICLE Source Type: research

Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy [RESEARCH ARTICLE]
This study examined BAV-associated aortopathy in Nos3–/– mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3–/– mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3–/– mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in ~13% of Nos3–/– mice. Moreover, Nos3–/– mice were pr...
Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Authors: Peterson, J. C., Wisse, L. J., Wirokromo, V., van Herwaarden, T., Smits, A. M., Gittenberger-de Groot, A. C., Goumans, M.-J. T. H., VanMunsteren, J. C., Jongbloed, M. R. M., DeRuiter, M. C. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy [RESEARCH ARTICLE]
In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Authors: Teramoto, N., Sugihara, H., Yamanouchi, K., Nakamura, K., Kimura, K., Okano, T., Shiga, T., Shirakawa, T., Matsuo, M., Nagata, T., Daimon, M., Matsuwaki, T., Nishihara, M. Tags: Rat as a Disease Model, Neuromuscular RESEARCH ARTICLE Source Type: research

First person - Patricia Shaw [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Patricia Shaw is first author on ‘Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome’, published in DMM. Patricia is a PhD student in the lab of Tarik Haydar at Boston University School of Medicine, USA, researching the underlying genetic and cellular mechanisms that contribute to brain development, and investigatin...
Source: DMM Disease Models and Mechanisms - September 24, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 24, 2020 Category: Biomedical Science Authors: Shaw, P. R., Klein, J. A., Aziz, N. M., Haydar, T. F. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

First person - Jelmer Hoeksma [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Jelmer Hoeksma is first author on ‘Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish’, published in DMM. Jelmer is a PhD student/technician in the lab of Jeroen den Hertog at Hubrecht Institute, Utrecht, The Netherlands, identifying biologically active fungal compounds and uncovering their mode of action in vivo. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 23, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 23, 2020 Category: Biomedical Science Authors: Hoeksma, J., van der Zon, G. C. M., ten Dijke, P., den Hertog, J. Tags: Developmental Disorders, Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

Travel grants and how to use them (when there's no travel) [EDITORIAL]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - September 20, 2020 Category: Biomedical Science Authors: Nicholson, A., Hmeljak, J. Tags: EDITORIAL Source Type: research

Fibrodysplasia ossificans progressiva: current concepts from bench to bedside [CLINICAL PUZZLE]
ABSTRACT Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signall...
Source: DMM Disease Models and Mechanisms - September 20, 2020 Category: Biomedical Science Authors: Kaliya-Perumal, A.-K., Carney, T. J., Ingham, P. W. Tags: Rare diseases CLINICAL PUZZLE Source Type: research

A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy [RESEARCH ARTICLE]
ABSTRACT Duchenne muscular dystrophy (DMD) is a life-threatening neuromuscular disease caused by the lack of dystrophin, resulting in progressive muscle wasting and locomotor dysfunctions. By adulthood, almost all patients also develop cardiomyopathy, which is the primary cause of death in DMD. Although there has been extensive effort in creating animal models to study treatment strategies for DMD, most fail to recapitulate the complete skeletal and cardiac disease manifestations that are presented in affected patients. Here, we generated a mouse model mirroring a patient deletion mutation of exons 52-54 (Dmd 52-54). The D...
Source: DMM Disease Models and Mechanisms - September 20, 2020 Category: Biomedical Science Authors: Wong, T. W. Y., Ahmed, A., Yang, G., Maino, E., Steiman, S., Hyatt, E., Chan, P., Lindsay, K., Wong, N., Golebiowski, D., Schneider, J., Delgado-Olguin, P., Ivakine, E. A., Cohn, R. D. Tags: Neuromuscular RESEARCH ARTICLE Source Type: research

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes [RESEARCH ARTICLE]
ABSTRACT Drosophila nephrocytes share functional, structural and molecular similarities with human podocytes. It is known that podocytes express the rabphilin 3A (RPH3A)-RAB3A complex, and its expression is altered in mouse and human proteinuric disease. Furthermore, we previously identified a polymorphism that suggested a role for RPH3A protein in the development of urinary albumin excretion. As endocytosis and vesicle trafficking are fundamental pathways for nephrocytes, the objective of this study was to assess the role of the RPH3A orthologue in Drosophila, Rabphilin (Rph), in the structure and function of nephrocytes....
Source: DMM Disease Models and Mechanisms - September 20, 2020 Category: Biomedical Science Authors: Selma-Soriano, E., Llamusi, B., Fernandez-Costa, J. M., Ozimski, L. L., Artero, R., Redon, J. Tags: Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a [RESEARCH ARTICLE]
ABSTRACT Most patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS-G6pc–/– mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed be...
Source: DMM Disease Models and Mechanisms - September 17, 2020 Category: Biomedical Science Authors: Resaz, R., Cangelosi, D., Morini, M., Segalerba, D., Mastracci, L., Grillo, F., Bosco, M. C., Bottino, C., Colombo, I., Eva, A. Tags: Rare diseases RESEARCH ARTICLE Source Type: research

Neonatal and infant immunity for tuberculosis vaccine development: importance of age-matched animal models [REVIEW]
ABSTRACT Neonatal and infant immunity differs from that of adults in both the innate and adaptive arms, which are critical contributors to immune-mediated clearance of infection and memory responses elicited during vaccination. The tuberculosis (TB) research community has openly admitted to a vacuum of knowledge about neonatal and infant immune responses to Mycobacterium tuberculosis (Mtb) infection, especially in the functional and phenotypic attributes of memory T cell responses elicited by the only available vaccine for TB, the Bacillus Calmette–Guérin (BCG) vaccine. Although BCG vaccination has variable ef...
Source: DMM Disease Models and Mechanisms - September 14, 2020 Category: Biomedical Science Authors: Ramos, L., Lunney, J. K., Gonzalez-Juarrero, M. Tags: REVIEW Source Type: research

Cell and animal models of SARS-CoV-2 pathogenesis and immunity [SPECIAL ARTICLE]
ABSTRACT The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and>22 million people infected and>775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans leading to coronavirus disease 2019 (COVID-19). The development of effective clinical interventions, such as antivirals and vaccines that can limit or even prevent the burden and spread of SARS-CoV-2, is a global health priority. Testing of leading antivirals, monoclonal antibody therapies and vaccines against SARS-CoV-2 will require robust animal and cell models...
Source: DMM Disease Models and Mechanisms - August 31, 2020 Category: Biomedical Science Authors: Leist, S. R., Schäfer, A., Martinez, D. R. Tags: SPECIAL ARTICLE Source Type: research

First person - Pratibha Singh [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Pratibha Singh is first author on ‘Maltodextrin-induced intestinal injury in a neonatal mouse model’, published in DMM. Pratibha is a postdoctoral research fellow in the lab of Dr Camilia R. Martin at Harvard Medical School, Boston, MA, USA, investigating nutrient-driven immunomodulation in neonatal health and disease. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

First person - Hui-Ying Tsai and Shih-Cheng Wu [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Hui-Ying Tsai and Shih-Cheng Wu are co-first authors on ‘Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction’, published in DMM. Hui-Ying is a research assistant in the lab of Chun-Hong Chen at National Health Research Institutes, Zhunan, Taiwan. Her research interest is modeling the human neurological disease maple syrup urine disease in Dr...
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders [REVIEW]
ABSTRACT The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the ...
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Gamache, J., Yun, Y., Chiba-Falek, O. Tags: Neurodegenerative disorders REVIEW Source Type: research

A regulated NMD mouse model supports NMD inhibition as a viable therapeutic option to treat genetic diseases [RESEARCH ARTICLE]
ABSTRACT Nonsense-mediated mRNA decay (NMD) targets mRNAs that contain a premature termination codon (PTC) for degradation, preventing their translation. By altering the expression of PTC-containing mRNAs, NMD modulates the inheritance pattern and severity of genetic diseases. NMD also limits the efficiency of suppressing translation termination at PTCs, an emerging therapeutic approach to treat genetic diseases caused by in-frame PTCs (nonsense mutations). Inhibiting NMD may help rescue partial levels of protein expression. However, it is unclear whether long-term, global NMD attenuation is safe. We hypothesize that a deg...
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Echols, J., Siddiqui, A., Dai, Y., Havasi, V., Sun, R., Kaczmarczyk, A., Keeling, K. M. Tags: RESEARCH ARTICLE Source Type: research

Maltodextrin-induced intestinal injury in a neonatal mouse model [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Singh, P., Sanchez-Fernandez, L. L., Ramiro-Cortijo, D., Ochoa-Allemant, P., Perides, G., Liu, Y., Medina-Morales, E., Yakah, W., Freedman, S. D., Martin, C. R. Tags: RESEARCH ARTICLE Source Type: research

Loss of the Drosophila branched-chain {alpha}-ketoacid dehydrogenase complex results in neuronal dysfunction [RESEARCH ARTICLE]
This article has an associated First Person interview with the joint first authors of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Tsai, H.-Y., Wu, S.-C., Li, J.-C., Chen, Y.-M., Chan, C.-C., Chen, C.-H. Tags: Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

Generation and characterization of an Il2rg knockout Syrian hamster model for XSCID and HAdV-C6 infection in immunocompromised patients [RESEARCH ARTICLE]
ABSTRACT Model animals are indispensable for the study of human diseases, and in general, of complex biological processes. The Syrian hamster is an important model animal for infectious diseases, behavioral science and metabolic science, for which more experimental tools are becoming available. Here, we describe the generation and characterization of an interleukin-2 receptor subunit gamma (Il2rg) knockout (KO) Syrian hamster strain. In humans, mutations in IL2RG can result in a total failure of T and natural killer (NK) lymphocyte development and nonfunctional B lymphocytes (X-linked severe combined immunodeficiency; XSCI...
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Li, R., Ying, B., Liu, Y., Spencer, J. F., Miao, J., Tollefson, A. E., Brien, J. D., Wang, Y., Wold, W. S. M., Wang, Z., Toth, K. Tags: RESEARCH ARTICLE Source Type: research

suz12 inactivation in p53- and nf1-deficient zebrafish accelerates the onset of malignant peripheral nerve sheath tumors and expands the spectrum of tumor types [RESEARCH ARTICLE]
ABSTRACT Polycomb repressive complex 2 (PRC2) is an epigenetic regulator of gene expression that possesses histone methyltransferase activity. PRC2 trimethylates lysine 27 of histone H3 proteins (H3K27me3) as a chromatin modification associated with repressed transcription of genes frequently involved in cell proliferation or self-renewal. Loss-of-function mutations in the PRC2 core subunit SUZ12 have been identified in a variety of tumors, including malignant peripheral nerve sheath tumors (MPNSTs). To determine the consequences of SUZ12 loss in the pathogenesis of MPNST and other cancers, we used CRISPR-Cas9 to disrupt t...
Source: DMM Disease Models and Mechanisms - August 26, 2020 Category: Biomedical Science Authors: Oppel, F., Ki, D. H., Zimmerman, M. W., Ross, K. N., Tao, T., Shi, H., He, S., Aster, J. C., Look, A. T. Tags: Cancer, Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

Integrating fish models in tuberculosis vaccine development [REVIEW]
ABSTRACT Tuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette–Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant strains. Novel vaccination strategies concentrate mainly on replacing BCG or boosting its efficacy and depend on animal models that accurately recapitulate the human disease. However, efforts to produce...
Source: DMM Disease Models and Mechanisms - August 22, 2020 Category: Biomedical Science Authors: Saralahti, A. K., Uusi-Mäkelä, M. I. E., Niskanen, M. T., Rämet, M. Tags: Model Systems in Drug Discovery, Zebrafish as a Disease Model REVIEW Source Type: research

First person - Mohd. Salman [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Mohd. Salman is first author on ‘Nrf2/HO-1 mediates the neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury in rats’, published in DMM. Mohd. is a PhD student in the lab of Prof. Suhel Parvez at Jamia Hamdard, New Delhi, India, investigating the cellular and molecular mechanisms involved in traumatic brain injury, ische...
Source: DMM Disease Models and Mechanisms - August 18, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Nrf2/HO-1 mediates the neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury in rats [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - August 18, 2020 Category: Biomedical Science Authors: Salman, M., Tabassum, H., Parvez, S. Tags: Rat as a Disease Model RESEARCH ARTICLE Source Type: research

The transcription factor Maz is essential for normal eye development [RESEARCH ARTICLE]
ABSTRACT Wnt/β-catenin signaling has an essential role in eye development. Faulty regulation of this pathway results in ocular malformations, owing to defects in cell-fate determination and differentiation. Herein, we show that disruption of Maz, the gene encoding Myc-associated zinc-finger transcription factor, produces developmental eye defects in mice and humans. Expression of key genes involved in the Wnt cascade, Sfrp2, Wnt2b and Fzd4, was significantly increased in mice with targeted inactivation of Maz, resulting in abnormal peripheral eye formation with reduced proliferation of the progenitor cells in the regi...
Source: DMM Disease Models and Mechanisms - August 17, 2020 Category: Biomedical Science Authors: Medina-Martinez, O., Haller, M., Rosenfeld, J. A., O'Neill, M. A., Lamb, D. J., Jamrich, M. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

DMM Outstanding Paper Prize 2019 winner: Alessandro Bailetti [EDITORIAL]
ABSTRACT Disease Models & Mechanisms (DMM) is delighted to announce (with apologies for the delay) that the winner of the DMM Prize 2019 is Alessandro Bailetti, for his paper entitled ‘Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity’ ( Bailetti et al., 2019). The prize of $1000 is awarded to the first author of the paper that is judged by the journal's editors to be the most outstanding contribution to the journal that year. To be considered for the prize, the first author must be a student or a postdoc of no more than 5&nb...
Source: DMM Disease Models and Mechanisms - August 13, 2020 Category: Biomedical Science Authors: Hackett, R. Tags: EDITORIAL Source Type: research

Systemic and heart autonomous effects of sphingosine {Delta}4 desaturase deficiency in lipotoxic cardiac pathophysiology [RESEARCH ARTICLE]
ABSTRACT Lipotoxic cardiomyopathy (LCM) is characterized by cardiac steatosis, including the accumulation of fatty acids, triglycerides and ceramides. Model systems have shown the inhibition of ceramide biosynthesis to antagonize obesity and improve insulin sensitivity. Sphingosine 4 desaturase (encoded by ifc in Drosophila melanogaster) enzymatically converts dihydroceramide into ceramide. Here, we examine ifc mutants to study the effects of desaturase deficiency on cardiac function in Drosophila. Interestingly, ifc mutants exhibited classic hallmarks of LCM: cardiac chamber dilation, contractile defects and loss of fract...
Source: DMM Disease Models and Mechanisms - August 13, 2020 Category: Biomedical Science Authors: Walls, S. M., Chatfield, D. A., Ocorr, K., Harris, G. L., Bodmer, R. Tags: Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

First person - Laura Tamberg [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Laura Tamberg is first author on ‘Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome’, published in DMM. Laura is a PhD student in the lab of Tõnis Timmusk at the Tallinn University of Technology, Tallinn, Estonia. Her research involves investigating the use of Drosophila melanogaster as a model system to understand...
Source: DMM Disease Models and Mechanisms - July 29, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

First person - Jenny Vermeer and Jonathan lent [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Jenny Vermeer and Jonathan lent are co-first authors on ‘A lineage-tracing tool to map the fate of hypoxic tumour cells’, published in DMM. Jenny conducted the research described in this article while a postdoctoral researcher in the lab of Ruth Muschel at the University of Oxford, Oxford, UK. She is now a project leader in the lab of Miranda van der Lee at Byondis, Nijmegen, The Netherlands, inve...
Source: DMM Disease Models and Mechanisms - July 29, 2020 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

A lineage-tracing tool to map the fate of hypoxic tumour cells [RESEARCH ARTICLE]
This article has an associated First Person interview with the joint first authors of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - July 29, 2020 Category: Biomedical Science Authors: Vermeer, J. A. F., Ient, J., Markelc, B., Kaeppler, J., Barbeau, L. M. O., Groot, A. J., Muschel, R. J., Vooijs, M. A. Tags: Cancer metabolism RESEARCH ARTICLE Source Type: research

Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse [RESEARCH ARTICLE]
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic ...
Source: DMM Disease Models and Mechanisms - July 29, 2020 Category: Biomedical Science Authors: Bangs, F. K., Miller, P., O'Neill, E. Tags: Cancer RESEARCH ARTICLE Source Type: research

Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV [RESEARCH ARTICLE]
ABSTRACT Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular ‘storage’ material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The Mcoln1&ndash...
Source: DMM Disease Models and Mechanisms - July 29, 2020 Category: Biomedical Science Authors: Mepyans, M., Andrzejczuk, L., Sosa, J., Smith, S., Herron, S., DeRosa, S., Slaugenhaupt, S. A., Misko, A., Grishchuk, Y., Kiselyov, K. Tags: Neurodegenerative disorders RESEARCH ARTICLE Source Type: research