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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/28729482/brca1-and-brca2-tumor-suppressors-protect-against-endogenous-acetaldehyde-toxicity
#1
Eliana Mc Tacconi, Xianning Lai, Cecilia Folio, Manuela Porru, Gijs Zonderland, Sophie Badie, Johanna Michl, Irene Sechi, Mélanie Rogier, Verónica Matía García, Ankita Sati Batra, Oscar M Rueda, Peter Bouwman, Jos Jonkers, Anderson Ryan, Bernardo Reina-San-Martin, Joannie Hui, Nelson Tang, Alejandra Bruna, Annamaria Biroccio, Madalena Tarsounas
Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional...
July 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28701330/oral-administration-of-pyrophosphate-inhibits-connective-tissue-calcification
#2
Dóra 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
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 phenotype...
July 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28694323/a-single-mutation-in-taiwanese-h6n1-influenza-hemagglutinin-switches-binding-to-human-type-receptors
#3
Robert P de Vries, Netanel Tzarum, Wenjie Peng, Andrew J Thompson, Iresha N Ambepitiya Wickramasinghe, Alba T Torrents de la Pena, Marielle J van Breemen, Kim M Bouwman, Xueyong Zhu, Ryan McBride, Wenli Yu, Rogier W Sanders, Monique H Verheije, Ian A Wilson, James C Paulson
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...
July 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28694322/phenotypic-diversity-drives-paracrine-drug-tolerance
#4
Thomas Kuilman, Daniel S Peeper
No abstract text is available yet for this article.
July 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28674081/mg132-induced-progerin-clearance-is-mediated-by-autophagy-activation-and-splicing-regulation
#5
Karim Harhouri, Claire Navarro, Danielle Depetris, Marie-Geneviève Mattei, Xavier Nissan, Pierre Cau, Annachiara De Sandre-Giovannoli, Nicolas Lévy
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines...
July 3, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28674080/macrophage-deficiency-of-mir-21-promotes-apoptosis-plaque-necrosis-and-vascular-inflammation-during-atherogenesis
#6
Alberto Canfrán-Duque, Noemi Rotllan, Xinbo Zhang, Marta Fernández-Fuertes, Cristina Ramírez-Hidalgo, Elisa Araldi, Lidia Daimiel, Rebeca Busto, Carlos Fernández-Hernando, Yajaira Suárez
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...
July 3, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28667090/lentiviral-vectors-escape-innate-sensing-but-trigger-p53-in-human-hematopoietic-stem-and-progenitor-cells
#7
Francesco Piras, Michela Riba, Carolina Petrillo, Dejan Lazarevic, Ivan Cuccovillo, Sara Bartolaccini, Elia Stupka, Bernhard Gentner, Davide Cittaro, Luigi Naldini, Anna Kajaste-Rudnitski
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 leading to lower cell recovery ex vivo and engraftment in vivo These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected...
June 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28667089/orkambi%C3%A2-and-amplifier-co-therapy-improves-function-from-a-rare-cftr-mutation-in-gene-edited-cells-and-patient-tissue
#8
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, Theo J Moraes, Tanja Gonska, Felix Ratjen, Christine E Bear
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...
June 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28646119/rest-suppression-mediates-neural-conversion-of-adult-human-fibroblasts-via-microrna-dependent-and-independent-pathways
#9
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 Toresson, Roger A Barker, Johan Jakobsson, Malin Parmar
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...
June 23, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28634161/oncolytic-adenovirus-expressing-bispecific-antibody-targets-t-cell-cytotoxicity-in-cancer-biopsies
#10
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
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 cells that are permissive for virus replication...
June 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28623238/a-normal-genetic-variation-modulates-synaptic-mmp-9-protein-levels-and-the-severity-of-schizophrenia-symptoms
#11
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
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...
June 16, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28606997/hpv-e7-induces-chemotherapy-mediated-tumor-suppression-by-ceramide-dependent-mitophagy
#12
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
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)...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28606996/targeting-endothelin-receptor-signalling-overcomes-heterogeneity-driven-therapy-failure
#13
Michael P Smith, Emily J Rowling, Zsofia Miskolczi, Jennifer Ferguson, Loredana Spoerri, Nikolas K Haass, Olivia Sloss, Sophie McEntegart, Imanol Arozarena, Alex von Kriegsheim, Javier Rodriguez, Holly Brunton, Jivko Kmarashev, Mitchell P Levesque, Reinhard Dummer, Dennie T Frederick, Miles C Andrews, Zachary A Cooper, Keith T Flaherty, Jennifer A Wargo, Claudia Wellbrock
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 MITF-induced expression of endothelin 1 (EDN1)...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28606995/synergistic-antibacterial-effect-of-silver-and-ebselen-against-multidrug-resistant-gram-negative-bacterial-infections
#14
Lili Zou, Jun Lu, Jun Wang, Xiaoyuan Ren, Lanlan Zhang, Yu Gao, Martin E Rottenberg, Arne Holmgren
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...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28606994/calcineurin-nfat-signalling-in-myeloid-leucocytes-new-prospects-and-pitfalls-in-immunosuppressive-therapy
#15
REVIEW
Kamila Bendickova, Federico Tidu, Jan Fric
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...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28588032/inactivation-of-%C3%AE-secretases-leads-to-accumulation-of-substrates-and-non-alzheimer-neurodegeneration
#16
Hermien Acx, Lutgarde Serneels, Enrico Radaelli, Serge Muyldermans, Cécile Vincke, Elise Pepermans, Ulrike Müller, Lucía Chávez-Gutiérrez, Bart De Strooper
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 lesser extents...
June 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28572090/gdf15-is-a-heart-derived-hormone-that-regulates-body-growth
#17
Ting Wang, Jian Liu, Caitlin McDonald, Katherine Lupino, Xiandun Zhai, Benjamin J Wilkins, Hakon Hakonarson, Liming Pei
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...
June 1, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28566333/cdk4-phosphorylation-status-and-a-linked-gene-expression-profile-predict-sensitivity-to-palbociclib
#18
Eric Raspé, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Christos Sotiriou, Pierre P Roger
Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4...
May 31, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28559442/cxcl12%C3%AE-sdf-1-from-perisynaptic-schwann-cells-promotes-regeneration-of-injured-motor-axon%C3%A2-terminals
#19
Samuele Negro, Francesca Lessi, Elisa Duregotti, Paolo Aretini, Marco La Ferla, Sara Franceschi, Michele Menicagli, Elisanna Bergamin, Egle Radice, Marcus Thelen, Aram Megighian, Marco Pirazzini, Chiara M Mazzanti, Michela Rigoni, Cesare Montecucco
The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12α, also abbreviated as stromal-derived factor-1 (SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by α-latrotoxin. CXCL12α acts via binding to the neuronal CXCR4 receptor. A CXCL12α-neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration in vivo Recombinant CXCL12α in vivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons in vitro These findings indicate that the CXCL12α-CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury...
May 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28554943/spink2-deficiency-causes-infertility-by-inducing-sperm-defects-in-heterozygotes-and-azoospermia-in%C3%A2-homozygotes
#20
Zine-Eddine Kherraf, Marie Christou-Kent, Thomas Karaouzene, Amir Amiri-Yekta, Guillaume Martinez, Alexandra S Vargas, Emeline Lambert, Christelle Borel, Béatrice Dorphin, Isabelle Aknin-Seifer, Michael J Mitchell, Catherine Metzler-Guillemain, Jessica Escoffier, Serge Nef, Mariane Grepillat, Nicolas Thierry-Mieg, Véronique Satre, Marc Bailly, Florence Boitrelle, Karin Pernet-Gallay, Sylviane Hennebicq, Julien Fauré, Serge P Bottari, Charles Coutton, Pierre F Ray, Christophe Arnoult
Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility...
May 29, 2017: EMBO Molecular Medicine
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