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EMBO Molecular Medicine

Martin Jakobs, Anton Fomenko, Andres M Lozano, Karl L Kiening
Deep brain stimulation (DBS) has been successfully used to treat movement disorders, such as Parkinson's disease, for more than 25 years and heralded the advent of electrical neuromodulation to treat diseases with dysregulated neuronal circuits. DBS is now superseding ablative techniques, such as stereotactic radiofrequency lesions. While serendipity has played a role in developing DBS as a therapy, research during the past two decades has shown that electrical neuromodulation is far more than a functional lesion that can be switched on and off...
March 12, 2019: EMBO Molecular Medicine
Magda R Hamczyk, Ricardo Villa-Bellosta, Víctor Quesada, Pilar Gonzalo, Sandra Vidak, Rosa M Nevado, María J Andrés-Manzano, Tom Misteli, Carlos López-Otín, Vicente Andrés
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC-specific progerin expression...
March 12, 2019: EMBO Molecular Medicine
Tobias Brummer, Stephan A Müller, Francisco Pan-Montojo, Fumiaki Yoshida, Andreas Fellgiebel, Taisuke Tomita, Kristina Endres, Stefan F Lichtenthaler
The metalloprotease ADAM10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein (APP) and lowers amyloid-beta. Yet, ADAM10 has additional substrates, which may cause mechanism-based side effects upon therapeutic ADAM10 activation. However, they may also serve-in addition to APP-as biomarkers to monitor ADAM10 activity in patients and to develop APP-selective ADAM10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein NrCAM ADAM10 controlled NrCAM surface levels and regulated neurite outgrowth in vitro in an NrCAM-dependent manner...
March 4, 2019: EMBO Molecular Medicine
Mohamed I Saad, Sultan Alhayyani, Louise McLeod, Liang Yu, Mohammad Alanazi, Virginie Deswaerte, Ke Tang, Thierry Jarde, Julian A Smith, Zdenka Prodanovic, Michelle D Tate, Jesse J Balic, D Neil Watkins, Jason E Cain, Steven Bozinovski, Elizabeth Algar, Tomohiro Kohmoto, Hiromichi Ebi, Walter Ferlin, Christoph Garbers, Saleela Ruwanpura, Irit Sagi, Stefan Rose-John, Brendan J Jenkins
Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) Kras G12D -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway...
March 4, 2019: EMBO Molecular Medicine
Justyna Magdalena Przystal, Sajee Waramit, Md Zahidul Islam Pranjol, Wenqing Yan, Grace Chu, Aitthiphon Chongchai, Gargi Samarth, Nagore Gene Olaciregui, Ghazaleh Tabatabai, Angel Montero Carcaboso, Eric Ofori Aboagye, Keittisak Suwan, Amin Hajitou
Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno-associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αv β3 integrin receptor...
February 26, 2019: EMBO Molecular Medicine
Rune Busk Damgaard, Paul R Elliott, Kirby N Swatek, Eamonn R Maher, Polina Stepensky, Orly Elpeleg, David Komander, Yackov Berkun
The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF-driven inflammation in OTULIN-related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1-linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN-Gly281Arg mutation leads to reduced activity and stability in vitro and in cells...
February 25, 2019: EMBO Molecular Medicine
Hannah Fleckenstein, Silvia Portugal
No abstract text is available yet for this article.
February 25, 2019: EMBO Molecular Medicine
Jordi Ruiz-Camp, Jennifer Quantius, Ettore Lignelli, Philipp F Arndt, Francesco Palumbo, Claudio Nardiello, David E Surate Solaligue, Elpidoforos Sakkas, Ivana Mižíková, José Alberto Rodríguez-Castillo, István Vadász, William D Richardson, Katrin Ahlbrecht, Susanne Herold, Werner Seeger, Rory E Morty
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR-34a in a hyperoxia-based mouse model of BPD, where miR-34a expression was markedly increased in platelet-derived growth factor receptor (PDGFR)α-expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR-34a; and inducible, conditional deletion of miR-34a in PDGFRα+ cells afforded partial protection to the developing lung against hyperoxia-induced perturbations to lung architecture...
February 15, 2019: EMBO Molecular Medicine
Enrique Seoane-Vazquez, Vaishali Shukla, Rosa Rodriguez-Monguio
No abstract text is available yet for this article.
February 15, 2019: EMBO Molecular Medicine
Botond Roska
Dysfunction of the key sense of vision, leading to visual handicap or blindness, has a crucial effect on day-to-day life. In this commentary, I will summarize the work in my laboratory that is focused on a basic understanding of visual processing and the use of this information to understand disease mechanism and to develop correcting therapies. We are beginning to understand how cell types of the visual system interact in local circuits and compute visual information. This has brought insight into mechanisms of cell-type-specific diseases and has allowed us to design new therapies for restoring vision in genetic forms of blindness...
January 22, 2019: EMBO Molecular Medicine
Luigi Naldini
Here I review the scientific background, current stage of development and future perspectives that I foresee in the field of genetic manipulation of hematopoietic stem cells with a special emphasis on clinical applications.
January 22, 2019: EMBO Molecular Medicine
Thomas Westergard, Kevin McAvoy, Katelyn Russell, Xinmei Wen, Yu Pang, Brandie Morris, Piera Pasinelli, Davide Trotti, Aaron Haeusler
Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)...
January 7, 2019: EMBO Molecular Medicine
Nicole Reichenbach, Andrea Delekate, Monika Plescher, Franziska Schmitt, Sybille Krauss, Nelli Blank, Annett Halle, Gabor C Petzold
Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression has remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD We found that Stat3-deficient APP/PS1 mice show decreased β-amyloid levels and plaque burden...
January 7, 2019: EMBO Molecular Medicine
Rosaria Benedetti, Lucia Altucci
No abstract text is available yet for this article.
January 4, 2019: EMBO Molecular Medicine
Vivian Chua, Marlana Orloff, Jessica Lf Teh, Takahito Sugase, Connie Liao, Timothy J Purwin, Bao Q Lam, Mizue Terai, Grazia Ambrosini, Richard D Carvajal, Gary Schwartz, Takami Sato, Andrew E Aplin
Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors...
January 4, 2019: EMBO Molecular Medicine
Janet Storm, Jakob S Jespersen, Karl B Seydel, Tadge Szestak, Maurice Mbewe, Ngawina V Chisala, Patricia Phula, Christian W Wang, Terrie E Taylor, Christopher A Moxon, Thomas Lavstsen, Alister G Craig
Sequestration of Plasmodium falciparum -infected erythrocytes (IE) within the brain microvasculature is a hallmark of cerebral malaria (CM). Using a microchannel flow adhesion assay with TNF-activated primary human microvascular endothelial cells, we demonstrate that IE isolated from Malawian paediatric CM cases showed increased binding to brain microvascular endothelial cells compared to IE from uncomplicated malaria (UM) cases. Further, UM isolates showed significantly greater adhesion to dermal than to brain microvascular endothelial cells...
January 3, 2019: EMBO Molecular Medicine
Aleksandra A Kolodziejczyk, Danping Zheng, Oren Shibolet, Eran Elinav
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro-inflammatory and anti-inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH In this review, we will explore the impact of gut microbiota and microbiota-derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease...
December 27, 2018: EMBO Molecular Medicine
Hang Zhou, Chengjie Lian, Tingting Wang, Xiaoming Yang, Caixia Xu, Deying Su, Shuhui Zheng, Xiangyu Huang, Zhiheng Liao, Taifeng Zhou, Xianjian Qiu, Yuyu Chen, Bo Gao, Yongyong Li, Xudong Wang, Guoling You, Qihua Fu, Christina Gurnett, Dongsheng Huang, Peiqiang Su
Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four-generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole-exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree...
March 2019: 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...
January 2019: 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...
January 2019: EMBO Molecular Medicine
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