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EMBO Molecular Medicine

Alba Signes, Raffaele Cerutti, Anna S Dickson, Cristiane Benincá, Elizabeth C Hinchy, Daniele Ghezzi, Rosalba Carrozzo, Enrico Bertini, Michael P Murphy, James A Nathan, Carlo Viscomi, Erika Fernandez-Vizarra, Massimo Zeviani
Loss-of-function mutations in APOPT1 , a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e...
December 14, 2018: EMBO Molecular Medicine
Zofia Ma Chrzanowska-Lightowlers, Robert N Lightowlers
No abstract text is available yet for this article.
December 14, 2018: EMBO Molecular Medicine
Paola Bonsi, Giulia Ponterio, Valentina Vanni, Annalisa Tassone, Giuseppe Sciamanna, Sara Migliarini, Giuseppina Martella, Maria Meringolo, Benjamin Dehay, Evelyne Doudnikoff, Venetia Zachariou, Rose E Goodchild, Nicola B Mercuri, Marcello D'Amelio, Massimo Pasqualetti, Erwan Bezard, Antonio Pisani
Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β-arrestin 2 and D2 receptor binding proteins...
December 14, 2018: EMBO Molecular Medicine
Ann Saada
No abstract text is available yet for this article.
December 10, 2018: EMBO Molecular Medicine
Jayasimman Rajendran, Janne Purhonen, Saara Tegelberg, Olli-Pekka Smolander, Matthias Mörgelin, Jan Rozman, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Petri Auvinen, Eero Mervaala, Howard T Jacobs, Marten Szibor, Vineta Fellman, Jukka Kallijärvi
Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)-deficient Bcs1l p.S78G knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms...
December 10, 2018: EMBO Molecular Medicine
Junning Yang, Claire Simonneau, Robert Kilker, Laura Oakley, Matthew D Byrne, Zuzana Nichtova, Ioana Stefanescu, Fnu Pardeep-Kumar, Sushil Tripathi, Eric Londin, Pascale Saugier-Veber, Belinda Willard, Mathew Thakur, Stephen Pickup, Hiroshi Ishikawa, Horst Schroten, Richard Smeyne, Arie Horowitz
Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high...
December 5, 2018: EMBO Molecular Medicine
Hanan Al-Moyed, Andreia P Cepeda, SangYong Jung, Tobias Moser, Sebastian Kügler, Ellen Reisinger
Normal hearing and synaptic transmission at afferent auditory inner hair cell (IHC) synapses require otoferlin. Deafness DFNB9, caused by mutations in the OTOF gene encoding otoferlin, might be treated by transferring wild-type otoferlin cDNA into IHCs, which is difficult due to the large size of this transgene. In this study, we generated two adeno-associated viruses (AAVs), each containing half of the otoferlin cDNA Co-injecting these dual-AAV2/6 half-vectors into the cochleae of 6- to 7-day-old otoferlin knock-out ( Otof -/- ) mice led to the expression of full-length otoferlin in up to 50% of IHCs...
December 3, 2018: EMBO Molecular Medicine
Jie Zhou, Dong Wang, Bosco Ho-Yin Wong, Cun Li, Vincent Kwok-Man Poon, Lei Wen, Xiaoyu Zhao, Man Chun Chiu, Xiaojuan Liu, Ziwei Ye, Shuofeng Yuan, Kong-Hung Sze, Jasper Fuk-Woo Chan, Hin Chu, Kelvin Kai-Wang To, Kwok Yung Yuen
Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFNβ- and IFN-stimulated genes (ISGs) in combination with PolyI:C stimulation...
November 28, 2018: EMBO Molecular Medicine
Marc Suárez-Calvet, Anja Capell, Miguel Ángel Araque Caballero, Estrella Morenas-Rodríguez, Katrin Fellerer, Nicolai Franzmeier, Gernot Kleinberger, Erden Eren, Yuetiva Deming, Laura Piccio, Celeste M Karch, Carlos Cruchaga, Katrina Paumier, Randall J Bateman, Anne M Fagan, John C Morris, Johannes Levin, Adrian Danek, Mathias Jucker, Colin L Masters, Martin N Rossor, John M Ringman, Leslie M Shaw, John Q Trojanowski, Michael Weiner, Michael Ewers, Christian Haass
Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset...
November 27, 2018: EMBO Molecular Medicine
Agustín Hidalgo-Gutiérrez, Eliana Barriocanal-Casado, Mohammed Bakkali, M Elena Díaz-Casado, Laura Sánchez-Maldonado, Miguel Romero, Ramy K Sayed, Cornelia Prehn, Germaine Escames, Juan Duarte, Darío Acuña-Castroviejo, Luis C López
Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9 R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β-resorcylic acid (β-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. β-RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival...
November 27, 2018: EMBO Molecular Medicine
Matthew J Schiewer, Amy C Mandigo, Nicolas Gordon, Fangjin Huang, Sanchaika Gaur, Renée de Leeuw, Shuang G Zhao, Joseph Evans, Sumin Han, Theodore Parsons, Ruth Birbe, Peter McCue, Christopher McNair, Saswati N Chand, Ylenia Cendon-Florez, Peter Gallagher, Jennifer J McCann, Neermala Poudel Neupane, Ayesha A Shafi, Emanuela Dylgjeri, Lucas J Brand, Tapio Visakorpi, Ganesh V Raj, Costas D Lallas, Edouard J Trabulsi, Leonard G Gomella, Adam P Dicker, Wm Kevin Kelly, Benjamin E Leiby, Beatrice Knudsen, Felix Y Feng, Karen E Knudsen
PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes...
November 21, 2018: EMBO Molecular Medicine
Athanasia Stoupa, Frédéric Adam, Dulanjalee Kariyawasam, Catherine Strassel, Sanjay Gawade, Gabor Szinnai, Alexandre Kauskot, Dominique Lasne, Carsten Janke, Kathiresan Natarajan, Alain Schmitt, Christine Bole-Feysot, Patrick Nitschke, Juliane Léger, Fabienne Jabot-Hanin, Frédéric Tores, Anita Michel, Arnold Munnich, Claude Besmond, Raphaël Scharfmann, François Lanza, Delphine Borgel, Michel Polak, Aurore Carré
The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co-segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β-tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non-functional α/β-tubulin dimers that cannot be incorporated into microtubules...
November 16, 2018: EMBO Molecular Medicine
Hongyong Zhang, Jiaojiao Huang, Zechen Li, Guosong Qin, Nan Zhang, Tang Hai, Qianlong Hong, Qiantao Zheng, Ying Zhang, Ruigao Song, Jing Yao, Chunwei Cao, Jianguo Zhao, Qi Zhou
Porcine-derived xenogeneic sources for transplantation are a promising alternative strategy for providing organs for treatment of end-stage organ failure in human patients because of the shortage of human donor organs. The recently developed blastocyst or pluripotent stem cell (PSC) complementation strategy opens a new route for regenerating allogenic organs in miniature pigs. Since the eye is a complicated organ with highly specialized constituent tissues derived from different primordial cell lineages, the development of an intact eye from allogenic cells is a challenging task...
November 16, 2018: EMBO Molecular Medicine
Keaton I Jones, Jiske Tiersma, Arseniy E Yuzhalin, Alex N Gordon-Weeks, Jon Buzzelli, Jae Hong Im, Ruth J Muschel
Emerging evidence suggests a role for radiation in eliciting anti-tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony-stimulating factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour-associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype...
November 15, 2018: EMBO Molecular Medicine
Alexandre Pellan Cheng, Philip Burnham, Iwijn De Vlaminck
No abstract text is available yet for this article.
November 6, 2018: EMBO Molecular Medicine
Florent Mouliere, Richard Mair, Dineika Chandrananda, Francesco Marass, Christopher G Smith, Jing Su, James Morris, Colin Watts, Kevin M Brindle, Nitzan Rosenfeld
Glioma is difficult to detect or characterize using current liquid biopsy approaches. Detection of cell-free tumor DNA (cftDNA) in cerebrospinal fluid (CSF) has been proposed as an alternative to detection in plasma. We used shallow whole-genome sequencing (sWGS, at a coverage of < 0.4×) of cell-free DNA from the CSF of 13 patients with primary glioma to determine somatic copy number alterations and DNA fragmentation patterns. This allowed us to determine the presence of cftDNA in CSF without any prior knowledge of point mutations present in the tumor...
November 6, 2018: EMBO Molecular Medicine
Paulina Richter-Pechańska, Joachim B Kunz, Beat Bornhauser, Caroline von Knebel Doeberitz, Tobias Rausch, Büşra Erarslan-Uysal, Yassen Assenov, Viktoras Frismantas, Blerim Marovca, Sebastian M Waszak, Martin Zimmermann, Julia Seemann, Margit Happich, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Kseniya Bakharevich, Renate Kirschner-Schwabe, Cornelia Eckert, Martina U Muckenthaler, Jan O Korbel, Jean-Pierre Bourquin, Andreas E Kulozik
We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors...
November 2, 2018: EMBO Molecular Medicine
Xiufei Liu, Hua Qu, Yi Zheng, Qian Liao, Linlin Zhang, Xiaoyu Liao, Xin Xiong, Yuren Wang, Rui Zhang, Hui Wang, Qiang Tong, Zhenqi Liu, Hui Dong, Gangyi Yang, Zhiming Zhu, Jing Xu, Hongting Zheng
While adult mammalian skeletal muscle is stable due to its post-mitotic nature, muscle regeneration is still essential throughout life for maintaining functional fitness. During certain diseases, such as the modern pandemics of obesity and diabetes, the regeneration process becomes impaired, which leads to the loss of muscle function and contributes to the global burden of these diseases. However, the underlying mechanisms of the impairment are not well defined. Here, we identify mGPDH as a critical regulator of skeletal muscle regeneration...
November 2, 2018: EMBO Molecular Medicine
Hans-Georg Sprenger, Gulzar Wani, Annika Hesseling, Tim König, Maria Patron, Thomas MacVicar, Sofia Ahola, Timothy Wai, Esther Barth, Elena I Rugarli, Matteo Bergami, Thomas Langer
Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i -AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin-like GTPase OPA1. Mutations in YME1L cause a multi-systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell-type-specific defects in mice lacking YME1L in the nervous system...
November 2, 2018: EMBO Molecular Medicine
Marta Castroviejo-Bermejo, Cristina Cruz, Alba Llop-Guevara, Sara Gutiérrez-Enríquez, Mandy Ducy, Yasir Hussein Ibrahim, Albert Gris-Oliver, Benedetta Pellegrino, Alejandra Bruna, Marta Guzmán, Olga Rodríguez, Judit Grueso, Sandra Bonache, Alejandro Moles-Fernández, Guillermo Villacampa, Cristina Viaplana, Patricia Gómez, Marc Vidal, Vicente Peg, Xavier Serres-Créixams, Graham Dellaire, Jacques Simard, Paolo Nuciforo, Isabel T Rubio, Rodrigo Dientsmann, J Carl Barrett, Carlos Caldas, José Baselga, Cristina Saura, Javier Cortés, Olivier Déas, Jos Jonkers, Jean-Yves Masson, Stefano Cairo, Jean-Gabriel Judde, Mark J O'Connor, Orland Díez, Judith Balmaña, Violeta Serra
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci...
October 30, 2018: EMBO Molecular Medicine
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