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Disease Models & Mechanisms

Hung-Wei Kan, Jung-Hsien Hsieh, Hsiung-Fei Chien, Yea-Huey Lin, Ti-Yen Yeh, Chi-Chao Chao, Sung-Tsang Hsieh
To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy evidenced by reduced capillary luminal area, increased capillary basement membrane thickness, and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves...
March 16, 2018: Disease Models & Mechanisms
Joshua Spurrier, Arvind Kumar Shukla, Kristina McLinden, Kory Johnson, Edward Giniger
Aging is the greatest risk factor for neurodegeneration, but the connection between the two processes remains opaque. This is in part for want of a rigorous way to define physiological age, as opposed to chronological age. Here we develop a comprehensive metric for physiological age in Drosophila, based on genome-wide expression profiling. We applied this metric to a model of adult-onset neurodegeneration, increased or decreased expression of the activating subunit of the Cdk5 protein kinase, encoded by the gene Cdk5α , the ortholog of mammalian p35...
February 21, 2018: Disease Models & Mechanisms
Ashok Daniel Prabakaran, Jimsheena Valiyakath Karakkat, Ranjit Vijayan, Jisha Chalissery, Marwa F Ibrahim, Suneesh Kaimala, Ernest A Adeghate, Ahmed Hasan Al-Marzouqi, Suraiya Anjum Ansari, Mensah-Brown Epk, Bright Starling Emerald
Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as model to link this with later adult disease. Since embryonic size variation occurs under normal growth and differentataion as well, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important...
January 30, 2018: Disease Models & Mechanisms
O Pansarasa, M Bordoni, L Dufruca, L Diamanti, D Sproviero, R Trotti, S Bernuzzi, S La Salvia, S Gagliardi, M Ceroni, C Cereda
New evidences switch the hypothesis of amyotrophic lateral sclerosis (ALS) from a "neurocentric" to a "multisystemic" or "non-neurocentric" point of view. From 2006, we focused on the study of non-neural cells, patients' peripheral blood mononuclear cells (PMBCs) and lymphoblastoid cell lines (LCLs). Here, we characterized LCLs of sporadic ALS and patients carrying SOD1, TARDBP and FUS mutations to identify ALS biologically relevant signature, and whether and how mutations differentially affect ALS-linked pathways...
January 29, 2018: Disease Models & Mechanisms
Shelly Sorrells, Sara Nik, Mattie Casey, Rosannah C Cameron, Harold Truong, Cristhian Toruno, Michelle Gulfo, Albert Lowe, Cicely Jette, Rodney A Stewart, Teresa V Bowman
RNA splicing factors are essential for the viability of all eukaryotic cells; however, in metazoans some cell types are exquisitely sensitive to disruption of splicing factors, such as neuronal cells which can lead to neurodegenerative diseases. The basis for this tissue selectivity is not well understood due to difficulties in analyzing the consequences of splicing factor defects in whole animal systems. Here, we use zebrafish mutants to show that loss of spliceosomal components, including splicing factor 3b, subunit 1 (sf3b1), caused increased DNA double-strand breaks and apoptosis in embryonic neurons with a concomitant accumulation of R-loops, which are non-canonical nucleic acid structures that promote genomic instability...
January 29, 2018: Disease Models & Mechanisms
James P Orengo, Meike E van der Heijden, Shuang Hao, Jianrong Tang, Harry T Orr, Huda Y Zoghbi
Spinocerebellar ataxia type 1 (SCA1) is characterized by adult-onset cerebellar degeneration with attendant loss of motor coordination. Bulbar function is eventually impaired, and patients tend to die from inability to clear the airway. We asked whether motor neuron degeneration is at the root of bulbar dysfunction by studying SCA1 knock-in mice. We analyzed spinal cord and brainstem motor neurons in SCA1 knock-in (Atxn1154Q) mice at 1, 3, and 6 months of age. Specifically, we assessed breathing physiology, diaphragm histology and electromyography, and motor neuron histology and immunohistochemistry...
January 29, 2018: Disease Models & Mechanisms
Sen Chen, Le Xie, Kai Xu, Hai-Yan Cao, Xia Wu, Xiao-Xiang Xu, Yu Sun, Wei-Jia Kong
Mutations in the GJB2 gene (which encodes Connexin26 (Cx26)) are the most common causes of hereditary hearing loss, and previous studies showed postnatal development arrest of the organ of Corti in different Cx26-null mouse models. To further explore the pathological changes and the mechanism behind the cochlear abnormalities in these mice, we established transgenic mouse models by conditional knockdown of cochlear Cx26 at postnatal day (P) 0 and P8. Auditory brainstem responses were recorded and the morphological features in the organ of Corti were analyzed 18 days later after Cx26 knockdown in the different groups of mice...
January 19, 2018: Disease Models & Mechanisms
Hanna Langhorst, René Jüttner, Dieter Groneberg, Azadeh Mohtashamdolatshahi, Laura Pelz, Bettina Purfürst, Kai M Schmidt-Ott, Andreas Friebe, Fritz G Rathjen
The function of the IgCAM CLMP which is implicated in congenital short-bowel syndrome in humans was studied in mice. Although the levels of mRNAs encoding Connexin43 or 45 are not or only marginally affected, respectively, absence of CLMP caused a severe reduction of both proteins in smooth muscle cells of the intestine and of Connexin43 in the ureter. Analysis of calcium signaling revealed a disordered cell-cell communication between smooth muscle cells which in turn induced an impaired and uncoordinated motility of the intestine and the ureter...
January 19, 2018: Disease Models & Mechanisms
Gema Marín-Royo, Isabel Gallardo, Ernesto Martínez-Martínez, Beatriz Gutiérrez, Raquel Jurado-López, Natalia López-Andrés, Josué Gutiérrez-Tenorio, Eduardo Rial, M V Bartolome, María Luisa Nieto, Victoria Cachofeiro
Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is at least partially acting on mitochondrial damage. Gal-3 inhibition in rats fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG)...
January 11, 2018: Disease Models & Mechanisms
Sean P Sherman, Anne G Bang
Development of technology platforms to perform compound screens of human induced pluripotent stem cell (hiPSC) derived neurons with relatively high throughput is essential to realize their potential for drug discovery. Herein we demonstrate the feasibility of high-throughput screening on hiPSC-derived neurons using a high-content, image-based approach focused on neurite growth, a process that is fundamental to formation of neural networks and nerve regeneration. From a collection of 4,421 bioactive small molecules we identified 108 hit compounds, including 37 approved drugs, which target molecules or pathways known to regulate neurite growth, as well as those not previously associated with this process...
January 11, 2018: Disease Models & Mechanisms
Chandra Prajapati, Marisa Ojala, Katriina Aalto-Setälä
Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease that affects the heart muscle with diverse clinical outcomes. HCM can cause sudden cardiac death (SCD) during or immediately after mild to rigorous physical work in young patients. However, the mechanism causing SCD as a result of exercise remains unknown, but exercise-induced ventricular arrhythmias are thought to be responsible for this fatal consequence. To understand the disease mechanism behind HCM in a better way, we generated patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from HCM patients carrying either the MYBPC3-Gln1061X or TPM1-Asp175Asn mutation...
January 3, 2018: Disease Models & Mechanisms
Marco Cocorocchio, Amy J Baldwin, Balint Stewart, Lou Kim, Adrian J Harwood, Christopher R L Thompson, Paul L R Andrews, Robin S B Williams
Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum We show curcumin causes acute effects on cell behaviour, reduces cell growth, and slows multicellular development...
December 28, 2017: Disease Models & Mechanisms
Hernán H Dieguez, Horacio E Romeo, María F González Fleitas, Marcos L Aranda, Georgia Milne, Ruth E Rosenstein, Damián Dorfman
Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease, characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Despite there are experimental murine models, the vast majority take too long to develop retinal alterations, which in general are ubiquitous, many result from non-eye specific genetic manipulations, and most do not always reproduce the hallmarks of human age-related macular degeneration...
December 28, 2017: Disease Models & Mechanisms
Kathryn Bambino, Chi Zhang, Christine Austin, Chitra Amarasiriwardena, Manish Arora, Jaime Chu, Kirsten C Sadler
The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and life style factors, however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD)...
December 28, 2017: Disease Models & Mechanisms
Youming Zhang, Thanushiyan Poobalasingam, Laura L Yates, Simone A Walker, Martin S Taylor, Lauren Chessum, Jackie Harrison, Loukia Tsaprouni, Ian M Adcock, Clare M Lloyd, William O Cookson, Miriam F Moffatt, Charlotte H Dean
We previously identified dipeptidyl-peptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D )...
December 28, 2017: Disease Models & Mechanisms
Allison R Rogala, Alexi A Schoenborn, Brian E Fee, Viviana A Cantillana, Maria J Joyce, Raad Z Gharaibeh, Sayanty Roy, Anthony A Fodor, R Balfour Sartor, Gregory A Taylor, Ajay S Gulati
Crohn's disease (CD) represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-Related GTPase M (IRGM) is an established CD risk allele. We have shown previously that conventionally-raised (CV) mice lacking the IRGM ortholog, Irgm1, exhibit abnormal Paneth cells (PCs) and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD...
December 22, 2017: Disease Models & Mechanisms
Thomas H Massey, Lesley Jones
Diseases such as Huntington's disease and certain spinocerebellar ataxias are caused by the expansion of genomic cytosine-adenine-guanine (CAG) trinucleotide repeats beyond a specific threshold. These diseases are all characterised by neurological symptoms and central neurodegeneration, but our understanding of how expanded repeats drive neuronal loss is incomplete. Recent human genetic evidence implicates DNA repair pathways, especially mismatch repair, in modifying the onset and progression of CAG repeat diseases...
January 30, 2018: Disease Models & Mechanisms
Guoxiang Wang, Yi Ping Zhang, Zhongwen Gao, Lisa B E Shields, Fang Li, Tianci Chu, Huayi Lv, Thomas Moriarty, Xiao-Ming Xu, Xiaoyu Yang, Christopher B Shields, Jun Cai
Abusive head trauma (AHT) is the leading cause of death from trauma in infants and young children. An AHT animal model was developed on 12-day-old mice subjected to 90° head extension-flexion sagittal shaking repeated 30, 60, 80 and 100 times. The mortality and time until return of consciousness were dependent on the number of repeats and severity of the injury. Following 60 episodes of repeated head shakings, the pups demonstrated apnea and/or bradycardia immediately after injury. Acute oxygen desaturation was observed by pulse oximetry during respiratory and cardiac suppression...
January 30, 2018: Disease Models & Mechanisms
Aya Yoshimura, Naoki Adachi, Hitomi Matsuno, Masaki Kawamata, Yusuke Yoshioka, Hisae Kikuchi, Haruki Odaka, Tadahiro Numakawa, Hiroshi Kunugi, Takahiro Ochiya, Yoshitaka Tamai
Extracellular vesicles (EVs) can modulate microenvironments by transferring biomolecules, including RNAs and proteins derived from releasing cells, to target cells. To understand the molecular mechanisms maintaining the neural stem cell (NSC) niche through EVs, a new transgenic (Tg) rat strain that can release human CD63-GFP-expressing EVs from the NSCs was established. Human CD63-GFP expression was controlled under the rat Sox2 promoter (Sox2/human CD63-GFP), and it was expressed in undifferentiated fetal brains...
January 30, 2018: Disease Models & Mechanisms
Ahmad M Alamri, Xuefeng Liu, Jan K Blancato, Bassem R Haddad, Weisheng Wang, Xiaogang Zhong, Sujata Choudhary, Ewa Krawczyk, Bhaskar V Kallakury, Bruce J Davidson, Priscilla A Furth
Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed that cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes, and for screening for cancer risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing...
January 29, 2018: Disease Models & Mechanisms
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