First person - Andrew Scott Emmert and Eri Iwasawa [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Andrew Scott Emmert and Eri Iwasawa are co-first authors on ‘ Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam’, published in DMM. Andrew Scott is a medical student in the lab of Dr June Goto and Dr Francesco T. Mangano at Cincinnati Children's Hospital Medical Center, investigating the generation and ch...
Source: DMM Disease Models and Mechanisms - November 20, 2019 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam [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 - November 20, 2019 Category: Biomedical Science Authors: Emmert, A. S., Iwasawa, E., Shula, C., Schultz, P., Lindquist, D., Dunn, R. S., Fugate, E. M., Hu, Y.-C., Mangano, F. T., Goto, J. Tags: Rat as a Disease Model RESEARCH ARTICLE Source Type: research

First person - Claudia Figueroa-Romero and Benjamin Murdock [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Claudia Figueroa-Romero and Benjamin Murdock are co-first authors on ‘ Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice’, published in DMM. Claudia is an Assistant Research Scientist in the lab of Eva L. Feldman at the Department of Neurology, University of Michigan, USA, investigating how life-long environmental exposures, including the ...
Source: DMM Disease Models and Mechanisms - November 14, 2019 Category: Biomedical Science Tags: Neuromuscular FIRST PERSON Source Type: research

Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice [RESEARCH ARTICLE]
This study serves as a starting point to more deeply comprehend the influence of gut microorganisms and the immune system on ALS onset and progression. Greater insight may help pinpoint novel biomarkers and therapeutic interventions to improve diagnosis and treatment for ALS patients. 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 - November 14, 2019 Category: Biomedical Science Authors: Figueroa-Romero, C., Guo, K., Murdock, B. J., Paez-Colasante, X., Bassis, C. M., Mikhail, K. A., Raue, K. D., Evans, M. C., Taubman, G. F., McDermott, A. J., O'Brien, P. D., Savelieff, M. G., Hur, J., Feldman, E. L. Tags: Microbiome, Neuromuscular RESEARCH ARTICLE Source Type: research

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients [RESEARCH ARTICLE]
ABSTRACT Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozyg...
Source: DMM Disease Models and Mechanisms - November 14, 2019 Category: Biomedical Science Authors: Higashikuse, Y., Mittal, N., Arimura, T., Yoon, S. H., Oda, M., Enomoto, H., Kaneda, R., Hattori, F., Suzuki, T., Kawakami, A., Gasch, A., Furukawa, T., Labeit, S., Fukuda, K., Kimura, A., Makino, S. Tags: Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

Novel mouse model of encephalocele: post-neurulation origin and relationship to open neural tube defects [RESEARCH ARTICLE]
ABSTRACT Encephalocele is a clinically important birth defect that can lead to severe disability in childhood and beyond. The embryonic and early fetal pathogenesis of encephalocele is poorly understood and, although usually classified as a ‘neural tube defect’, there is conflicting evidence on whether encephalocele results from defective neural tube closure or is a post-neurulation defect. It is also unclear whether encephalocele can result from the same causative factors as anencephaly and open spina bifida, or whether it is aetiologically distinct. This lack of information results largely from the scarce ava...
Source: DMM Disease Models and Mechanisms - November 13, 2019 Category: Biomedical Science Authors: Rolo, A., Galea, G. L., Savery, D., Greene, N. D. E., Copp, A. J. Tags: RESEARCH ARTICLE Source Type: research

Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice [RESEARCH ARTICLE]
ABSTRACT Respiratory failure is a life-threatening problem for pre-term and term infants, yet many causes remain unknown. Here, we present evidence that whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (Wfdc2), a protease inhibitor previously unrecognized in respiratory disease, may be a causal factor in infant respiratory failure. Wfdc2 transcripts are detected in the embryonic lung and analysis of a Wfdc2-GFP knock-in mouse line shows that both basal and club cells, and type II alveolar epithelial cells (AECIIs), express Wfdc2 neonatally. Wfdc2-null-mutant mice display progressive atelectasis aft...
Source: DMM Disease Models and Mechanisms - November 11, 2019 Category: Biomedical Science Authors: Nakajima, K., Ono, M., Radovic, U., Dizdarevic, S., Tomizawa, S.-i., Kuroha, K., Nagamatsu, G., Hoshi, I., Matsunaga, R., Shirakawa, T., Kurosawa, T., Miyazaki, Y., Seki, M., Suzuki, Y., Koseki, H., Nakamura, M., Suda, T., Ohbo, K. Tags: RESEARCH ARTICLE Source Type: research

Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention [RESEARCH ARTICLE]
In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of t...
Source: DMM Disease Models and Mechanisms - November 10, 2019 Category: Biomedical Science Authors: Santhosh, D., Sherman, J., Chowdhury, S., Huang, Z. Tags: RESEARCH ARTICLE Source Type: research

Targeted knockout of GABA-A receptor gamma 2 subunit provokes transient light-induced reflex seizures in zebrafish larvae [RESEARCH ARTICLE]
ABSTRACT Epilepsy is a common primary neurological disorder characterized by the chronic tendency of a patient to experience epileptic seizures, which are abnormal body movements or cognitive states that result from excessive, hypersynchronous brain activity. Epilepsy has been found to have numerous etiologies and, although about two-thirds of epilepsies were classically considered idiopathic, the majority of those are now believed to be of genetic origin. Mutations in genes involved in gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission have been associated with a broad range of epilepsy syndromes. Mutati...
Source: DMM Disease Models and Mechanisms - November 10, 2019 Category: Biomedical Science Authors: Liao, M., Kundap, U., Rosch, R. E., Burrows, D. R. W., Meyer, M. P., Ouled Amar Bencheikh, B., Cossette, P., Samarut, E. Tags: Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

SILAC-based quantitative proteomics using mass spectrometry quantifies endoplasmic reticulum stress in whole HeLa cells [RESOURCE ARTICLE]
ABSTRACT The unfolded protein response (UPR) involves extensive proteome remodeling in many cellular compartments. To date, a comprehensive analysis of the UPR has not been possible because of technological limitations. Here, we employ stable isotope labeling with amino acids in cell culture (SILAC)-based proteomics to quantify the response of over 6200 proteins to increasing concentrations of tunicamycin in HeLa cells. We further compare the effects of tunicamycin (5 µg/ml) to those of thapsigargin (1 µM) and DTT (2 mM), both activating the UPR through different mechanisms. This systematic quant...
Source: DMM Disease Models and Mechanisms - November 10, 2019 Category: Biomedical Science Authors: Itzhak, D. N., Sacco, F., Nagaraj, N., Tyanova, S., Mann, M., Murgia, M. Tags: Protein-Folding Diseases: Models & Mechanisms RESOURCE ARTICLE Source Type: research

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG [RESEARCH ARTICLE]
ABSTRACT Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were te...
Source: DMM Disease Models and Mechanisms - November 10, 2019 Category: Biomedical Science Authors: Iyer, S., Sam, F. S., DiPrimio, N., Preston, G., Verheijen, J., Murthy, K., Parton, Z., Tsang, H., Lao, J., Morava, E., Perlstein, E. O. Tags: Rare diseases, Model Systems in Drug Discovery RESEARCH ARTICLE Source Type: research

A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping [RESEARCH ARTICLE]
ABSTRACT Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the -sarcoglycan (SGCG) gene. The most common SGCG mutation is a single nucleotide deletion from a stretch of five thymine residues in SGCG exon 6 (521T). This founder mutation disrupts the transcript reading frame, abolishing protein expression. An antisense oligonucleotide exon-skipping method to reframe the human 521T transcript requires skipping four exons to generate a functional, internally truncated protein. In vivo evaluation of this multi-exon skipping, antisense-mediated therapy requires a genetically appropriate mouse m...
Source: DMM Disease Models and Mechanisms - November 3, 2019 Category: Biomedical Science Authors: Demonbreun, A. R., Wyatt, E. J., Fallon, K. S., Oosterbaan, C. C., Page, P. G., Hadhazy, M., Quattrocelli, M., Barefield, D. Y., McNally, E. M. Tags: Neuromuscular RESEARCH ARTICLE Source Type: research

Drug screens of NGLY1 deficiency in worm and fly models reveal catecholamine, NRF2 and anti-inflammatory-pathway activation as potential clinical approaches [RESEARCH ARTICLE]
ABSTRACT N-glycanase 1 (NGLY1) deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator NRF1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole-animal and cellular models of NGLY1 deficiency. Here, we describe unbiased phenotypic drug screens to identi...
Source: DMM Disease Models and Mechanisms - November 3, 2019 Category: Biomedical Science Authors: Iyer, S., Mast, J. D., Tsang, H., Rodriguez, T. P., DiPrimio, N., Prangley, M., Sam, F. S., Parton, Z., Perlstein, E. O. Tags: Rare diseases, Model Systems in Drug Discovery, Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

The latest from the preLights community - October 2019 [PREPRINT HIGHLIGHTS]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - November 3, 2019 Category: Biomedical Science Tags: PREPRINT HIGHLIGHTS Source Type: research

First person - Alexander Akerberg [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Alexander Akerberg is first author on ‘ Deep learning enables automated volumetric assessments of cardiac function in zebrafish’, published in DMM. Alexander is a postdoctoral research fellow in the lab of Caroline E. Burns and C. Geoffrey Burns at Boston Children's Hospital, MA, USA, where he enjoys building new tools while investigating the molecular mechanisms that govern cardiac form and...
Source: DMM Disease Models and Mechanisms - October 24, 2019 Category: Biomedical Science Tags: FIRST PERSON Source Type: research