Photoreceptor glucose metabolism determines normal retinal vascular growth
Abstract
The neural cells and factors determining normal vascular growth are not well defined even though vision‐threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia mod...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Zhongjie Fu, Chatarina A L öfqvist, Raffael Liegl, Zhongxiao Wang, Ye Sun, Yan Gong, Chi‐Hsiu Liu, Steven S Meng, Samuel B Burnim, Ivana Arellano, My T Chouinard, Rubi Duran, Alexander Poblete, Steve S Cho, James D Akula, Michael Kinter, David Ley, Ing Tags: Research Article Source Type: research
Targeting RNA G ‐quadruplexes as new treatment strategy for C9orf72 ALS/FTD
The recent discovery of a pathogenic expansion of a (GGGGCC)n repeat in the C9orf72 gene in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) led to a burst of mechanistic discoveries. In this issue, Simone et al () describe novel compounds targeting the G‐quadruplex (G‐Q) structure of the (GGGGCC)n repeat RNA that alleviate the hallmarks of C9orf72 disease in patient‐derived neurons and increase survival in a Drosophila model. Lack of overt off‐target effects and toxicity suggest that these small molecules are promising lead compounds to the development of a therapy.
Edbauer and Schludi comm...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Martin H Schludi, Dieter Edbauer Tags: News & Views Source Type: research
Genomic structural variations lead to dysregulation of important coding and non ‐coding RNA species in dilated cardiomyopathy
In this study, we evaluate genome‐wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non‐coding RNAs and 1,756 protein‐coding transcripts. 65.3% of the SV‐eQTLs do not harbor a significant SNV‐eQTL, and for the regions with both c...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Jan Haas, Stefan Mester, Alan Lai, Karen S Frese, Farbod Sedaghat ‐Hamedani, Elham Kayvanpour, Tobias Rausch, Rouven Nietsch, Jes‐Niels Boeckel, Avisha Carstensen, Mirko Völkers, Carsten Dietrich, Dietmar Pils, Ali Amr, Daniel B Holzer, Diana Martins Tags: Research Article Source Type: research
Fighting vessel dysmorphia to improve glioma chemotherapy
High‐grade gliomas are aggressive and abundantly vascular tumors, and as in most cancer types, blood vessels in advanced lesions are highly abnormal. Poor perfusion and vascular leakage in tumor tissue resulting in hypoxia, necrosis, and high interstitial fluid pressure can hamper the efficient delivery of chemotherapy. Tumor angiogenesis is known to be supported by host leukocytes recruited to the tumor microenvironment, but the mechanisms leading to dysfunctional vascular network formation are incompletely understood. In this issue of EMBO Molecular Medicine, Mathivet et al () present an elegant study, where longitudi...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Marja Lohela, Kari Alitalo Tags: News & Views Source Type: research
Co ‐infection with Chikungunya virus alters trafficking of pathogenic CD8+ T cells into the brain and prevents Plasmodium‐induced neuropathology
Abstract
Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co‐infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co‐infection. Here, we investigate the effects of Chikungunya virus (CHIKV) co‐infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM) model, we show that concurrent co‐infection induced the most prominent changes in ECM manifestation. Concurrent co‐infecti...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Teck ‐Hui Teo, Shanshan W Howland, Carla Claser, Sin Yee Gun, Chek Meng Poh, Wendy WL Lee, Fok‐Moon Lum, Lisa FP Ng, Laurent Rénia Tags: Research Article Source Type: research
G ‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
Abstract
Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. ...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Roberto Simone, Rubika Balendra, Thomas G Moens, Elisavet Preza, Katherine M Wilson, Amanda Heslegrave, Nathan S Woodling, Teresa Niccoli, Javier Gilbert ‐Jaramillo, Samir Abdelkarim, Emma L Clayton, Mica Clarke, Marie‐Therese Konrad, Andrew J Nicoll, Tags: Report Source Type: research
A complex genomic locus drives mtDNA replicase POLG expression to its disease ‐related nervous system regions
Abstract
DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS‐specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925‐RNA and MIR9‐3, which are coexpressed with POLG. The MIR9‐3 targe...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Joni Nikkanen, Juan Cruz Landoni, Diego Balboa, Maarja Haugas, Juha Partanen, Anders Paetau, Pirjo Isohanni, Virginia Brilhante, Anu Suomalainen Tags: Report Source Type: research
iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases
Abstract
Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogeneity in current research practices and a reporting bias toward certain diseases. Moreover, we identified 663 CNS cell‐derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro. We clustered these phenotypes into a taxonomy and characterized...
Source: EMBO Molecular Medicine - October 19, 2017 Category: Molecular Biology Authors: Ethan W Hollingsworth, Jacob E Vaughn, Josh C Orack, Chelsea Skinner, Jamil Khouri, Sofia B Lizarraga, Mark E Hester, Fumihiro Watanabe, Kenneth S Kosik, Jaime Imitola Tags: Research Article Source Type: research
Defamation lawsuits: academic sword or shield?
Scientists and academics are used to defending their theories, methods, and results in the classroom, at conferences, and in peer‐reviewed publications. But Pieter Cohen, an assistant professor at Harvard Medical School, learned that he had to defend his research in a defamation suit while reading a supplement industry trade publication (Robins, ). Cohen is known as a “dogged detective” for scrutinizing dietary supplements and for advocating for their stricter oversight by the US Food and Drug Administration (FDA).
Libel lawsuits have been abused in the USA and UK to cow scientists and publishers into silence. Alth...
Source: EMBO Molecular Medicine - October 16, 2017 Category: Molecular Biology Authors: Elizabeth Hall ‐Lipsy, Sarah Malanga Tags: Commentary Source Type: research
Disease ‐modifying effects of ganglioside GM1 in Huntington's disease models
In this study, we provide evidence that intraventricular administration of GM1 has profound disease‐modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L‐Ser and D‐Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions a...
Source: EMBO Molecular Medicine - October 9, 2017 Category: Molecular Biology Authors: Melanie Alpaugh, Danny Galleguillos, Juan Forero, Luis Carlos Morales, Sebastian W Lackey, Preeti Kar, Alba Di Pardo, Andrew Holt, Bradley J Kerr, Kathryn G Todd, Glen B Baker, Karim Fouad, Simonetta Sipione Tags: Research Article Source Type: research
Akt inhibition improves long ‐term tumour control following radiotherapy by altering the microenvironment
Abstract
Radiotherapy is an important anti‐cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti‐cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long‐term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironment. AZD5363 reduces the downstream effectors VEGF and HIF‐1α, but has no effect on tumour vascularity or oxygen...
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Emma J Searle, Brian A Telfer, Debayan Mukherjee, Duncan M Forster, Barry R Davies, Kaye J Williams, Ian J Stratford, Tim M Illidge Tags: Research Article Source Type: research
Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways
This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.
Oncogenic isocitrate dehydrogenase (IDH) mutations are a major glioma subtype determinant. Mass spectrometry imaging (MSI) and LC‐MS on patient‐derived orthotopic IDH‐mutated glioma xenografts reveal IDH‐specific adaptive mechanisms in metabolic pathways. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Fred Fack, Saverio Tardito, Guillaume Hochart, Anais Oudin, Liang Zheng, Sabrina Fritah, Anna Golebiewska, Petr V Nazarov, Amandine Bernard, Ann ‐Christin Hau, Olivier Keunen, William Leenders, Morten Lund‐Johansen, Jonathan Stauber, Eyal Gottlieb, Ro Tags: Research Article Source Type: research
iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases
Abstract
Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogeneity in current research practices and a reporting bias toward certain diseases. Moreover, we identified 663 CNS cell‐derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro. We clustered these phenotypes into a taxonomy and characterized...
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Ethan W Hollingsworth, Jacob E Vaughn, Josh C Orack, Chelsea Skinner, Jamil Khouri, Sofia B Lizarraga, Mark E Hester, Fumihiro Watanabe, Kenneth S Kosik, Jaime Imitola Tags: Research Article Source Type: research
Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth
Abstract
Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype ...
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Thomas Mathivet, Claire Bouleti, Matthias Van Woensel, Fabio Stanchi, Tina Verschuere, Li ‐Kun Phng, Joost Dejaegher, Marly Balcer, Ken Matsumoto, Petya B Georgieva, Jochen Belmans, Raf Sciot, Christian Stockmann, Massimiliano Mazzone, Steven De Vleesch Tags: Research Article Source Type: research
Household triclosan and triclocarban effects on the infant and maternal microbiome
This study reveals an effect on mothers through oral rather than skin exposure. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Jessica V Ribado, Catherine Ley, Thomas D Haggerty, Ekaterina Tkachenko, Ami S Bhatt, Julie Parsonnet Tags: Research Article Source Type: research
