Oral administration of pyrophosphate inhibits connective tissue calcification
Abstract
Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in ABCC6 and ENPP1, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed that the bioavailability of orally administered PPi is negligible. Here, we demonstrate increased PPi concentration in the circulation of humans after oral PPi administration. Furthermore, in mouse models of PXE and GACI, oral PPi provided via drinking water attenuated their ectopic calcification phenot...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: D óra Dedinszki, Flóra Szeri, Eszter Kozák, Viola Pomozi, Natália Tőkési, Tamás Róbert Mezei, Kinga Merczel, Emmanuel Letavernier, Ellie Tang, Olivier Le Saux, Tamás Arányi, Koen van de Wetering, András Váradi Tags: Report Source Type: research
A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human ‐type receptors
Abstract
In June 2013, the first case of human infection with an avian H6N1 virus was reported in a Taiwanese woman. Although this was a single non‐fatal case, the virus continues to circulate in Taiwanese poultry. As with any emerging avian virus that infects humans, there is concern that acquisition of human‐type receptor specificity could enable transmission in the human population. Despite mutations in the receptor‐binding pocket of the human H6N1 isolate, it has retained avian‐type (NeuAcα2‐3Gal) receptor specificity. However, we show here that a single nucleotide substitution, resulting in a change from Gl...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Robert P Vries, Netanel Tzarum, Wenjie Peng, Andrew J Thompson, Iresha N Ambepitiya Wickramasinghe, Alba T Torrents Pena, Marielle J van Breemen, Kim M Bouwman, Xueyong Zhu, Ryan McBride, Wenli Yu, Rogier W Sanders, Monique H Verheije, Ian A Wilson, James Tags: Research Article Source Type: research
Macrophage deficiency of miR ‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis
Abstract
Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR‐21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR‐21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR‐21 expression influences foa...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Alberto Canfr án‐Duque, Noemi Rotllan, Xinbo Zhang, Marta Fernández‐Fuertes, Cristina Ramírez‐Hidalgo, Elisa Araldi, Lidia Daimiel, Rebeca Busto, Carlos Fernández‐Hernando, Yajaira Suárez Tags: Research Article Source Type: research
Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells
Abstract
Clinical application of lentiviral vector (LV)‐based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV‐mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma‐retroviral vector. However, reverse‐transcribed LV DNA did trigger p53 signaling, activated also by non‐integrating Adeno‐associated vector, ultimately...
Source: EMBO Molecular Medicine - June 30, 2017 Category: Molecular Biology Authors: Francesco Piras, Michela Riba, Carolina Petrillo, Dejan Lazarevic, Ivan Cuccovillo, Sara Bartolaccini, Elia Stupka, Bernhard Gentner, Davide Cittaro, Luigi Naldini, Anna Kajaste ‐Rudnitski Tags: Research Article Source Type: research
Calcineurin –NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy
Abstract
Myeloid leucocytes mediate host protection against infection and critically regulate inflammatory responses in body tissues. Pattern recognition receptor signalling is crucial for myeloid cell responses to pathogens, but growing evidence suggests an equally potent role for Calcineurin–NFAT signalling in control of myeloid cell function. All major subsets of myeloid leucocytes employ Calcineurin–NFAT signalling during immune responses to pathogens and/or tissue damage, but the influence this pathway exerts on pathogen clearance and host susceptibility to infection is not fully understood. Recent data from exper...
Source: EMBO Molecular Medicine - June 12, 2017 Category: Molecular Biology Authors: Kamila Bendickova, Federico Tidu, Jan Fric Tags: Review Source Type: research
Synergistic antibacterial effect of silver and ebselen against multidrug ‐resistant Gram‐negative bacterial infections
Abstract
Multidrug‐resistant (MDR) Gram‐negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of ...
Source: EMBO Molecular Medicine - June 12, 2017 Category: Molecular Biology Authors: Lili Zou, Jun Lu, Jun Wang, Xiaoyuan Ren, Lanlan Zhang, Yu Gao, Martin E Rottenberg, Arne Holmgren Tags: Research Article Source Type: research
HPV/E7 induces chemotherapy ‐mediated tumor suppression by ceramide‐dependent mitophagy
Abstract
Human papillomavirus (HPV) infection is linked to improved survival in response to chemo‐radiotherapy for patients with oropharynx head and neck squamous cell carcinoma (HNSCC). However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Here, using molecular, pharmacologic and genetic tools, we show that HPV early protein 7 (E7) enhances ceramide‐mediated lethal mitophagy in response to chemotherapy‐induced cellular stress in HPV‐positive HNSCC cells by selectively targeting retinoblastoma protein (RB). Inhibition of RB by HPV‐E7 relieves E2F5,...
Source: EMBO Molecular Medicine - June 12, 2017 Category: Molecular Biology Authors: Raquela J Thomas, Natalia Oleinik, Shanmugam Panneer Selvam, Silvia G Vaena, Mohammed Dany, Rose N Nganga, Ryan Depalma, Kyla D Baron, Jisun Kim, Zdzislaw M Szulc, Besim Ogretmen Tags: Research Article Source Type: research
Orkambi ® and amplifier co‐therapy improves function from a rare CFTR mutation in gene‐edited cells and patient tissue
Abstract
The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508. It has been predicted that Orkambi® could treat patients with rarer mutations of similar “theratype”; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function—similar to ΔF508‐CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that thi...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Steven V Molinski, Saumel Ahmadi, Wan Ip, Hong Ouyang, Adriana Villella, John P Miller, Po ‐Shun Lee, Kethika Kulleperuma, Kai Du, Michelle Di Paola, Paul DW Eckford, Onofrio Laselva, Ling Jun Huan, Leigh Wellhauser, Ellen Li, Peter N Ray, Régis Pomès Tags: Research Article Source Type: research
REST suppression mediates neural conversion of adult human fibroblasts via microRNA ‐dependent and ‐independent pathways
Abstract
Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient‐ and disease‐specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient‐derived material for large‐scale applications. Here, we investigate the difference in reprogramm...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Janelle Drouin ‐Ouellet, Shong Lau, Per Ludvik Brattås, Daniella Rylander Ottosson, Karolina Pircs, Daniela A Grassi, Lucy M Collins, Romina Vuono, Annika Andersson Sjöland, Gunilla Westergren‐Thorsson, Caroline Graff, Lennart Minthon, Håkan Toress Tags: Research Article Source Type: research
Oncolytic adenovirus expressing bispecific antibody targets T ‐cell cytotoxicity in cancer biopsies
Abstract
Oncolytic viruses exploit the cancer cell phenotype to complete their lytic life cycle, releasing progeny virus to infect nearby cells and repeat the process. We modified the oncolytic group B adenovirus EnAdenotucirev (EnAd) to express a bispecific single‐chain antibody, secreted from infected tumour cells into the microenvironment. This bispecific T‐cell engager (BiTE) binds to EpCAM on target cells and cross‐links them to CD3 on T cells, leading to clustering and activation of both CD4 and CD8 T cells. BiTE transcription can be controlled by the virus major late promoter, limiting expression to cancer cel...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Joshua D Freedman, Joachim Hagel, Eleanor M Scott, Ioannis Psallidas, Avinash Gupta, Laura Spiers, Paul Miller, Nikolaos Kanellakis, Rebecca Ashfield, Kerry D Fisher, Margaret R Duffy, Leonard W Seymour Tags: Research Article Source Type: research
A normal genetic variation modulates synaptic MMP ‐9 protein levels and the severity of schizophrenia symptoms
Abstract
Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neu...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Katarzyna Lepeta, Katarzyna J Purzycka, Katarzyna Pachulska ‐Wieczorek, Marina Mitjans, Martin Begemann, Behnam Vafadari, Krystian Bijata, Ryszard W Adamiak, Hannelore Ehrenreich, Magdalena Dziembowska, Leszek Kaczmarek Tags: Research Article Source Type: research
Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
Abstract
Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. > 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Michael P Smith, Emily J Rowling, Zsofia Miskolczi, Jennifer Ferguson, Loredana Spoerri, Nikolas K Haass, Olivia Sloss, Sophie McEntegart, Imanol Arozarena, Alex Kriegsheim, Javier Rodriguez, Holly Brunton, Jivko Kmarashev, Mitchell P Levesque, Reinhard D Tags: Research Article Source Type: research
Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
Abstract
γ‐Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ‐secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre+). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10‐fold accumulation of membrane‐bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of γ‐secretase such as Aplp2, Lrp1, and Sdc3 accumulate to less...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Hermien Acx, Lutgarde Serneels, Enrico Radaelli, Serge Muyldermans, C écile Vincke, Elise Pepermans, Ulrike Müller, Lucía Chávez‐Gutiérrez, Bart De Strooper Tags: Research Article Source Type: research
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review
(Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Marilena V Iorio, Carlo M Croce Tags: Corrigendum Source Type: research
GDF15 is a heart ‐derived hormone that regulates body growth
Abstract
The endocrine system is crucial for maintaining whole‐body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart‐derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 ...
Source: EMBO Molecular Medicine - June 1, 2017 Category: Molecular Biology Authors: Ting Wang, Jian Liu, Caitlin McDonald, Katherine Lupino, Xiandun Zhai, Benjamin J Wilkins, Hakon Hakonarson, Liming Pei Tags: Research Article Source Type: research
