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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/28818835/src-dependent-phosphorylation-of-%C3%AE-opioid-receptor-at-tyr-336-modulates-opiate-withdrawal
#1
Lei Zhang, Cherkaouia Kibaly, Yu-Jun Wang, Chi Xu, Kyu Young Song, Patrick W McGarrah, Horace H Loh, Jing-Gen Liu, Ping-Yee Law
Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ-opioid receptor (MOR) at Tyr(336) by Src after prolonged opiate treatment in vitro Here, we report that the Src-mediated MOR phosphorylation at Tyr(336) is a prerequisite for opiate withdrawal in mice...
August 17, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28801361/one-level-up-abnormal-proteolytic-regulation-of-igf-activity-plays-a-role-in-human-pathophysiology
#2
REVIEW
Jesús Argente, Julie A Chowen, Luis A Pérez-Jurado, Jan Frystyk, Claus Oxvig
The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery of mutations in members of this axis...
August 11, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28794134/mrna-mediates-passive-vaccination-against-infectious-agents-toxins-and-tumors
#3
Moritz Thran, Jean Mukherjee, Marion Pönisch, Katja Fiedler, Andreas Thess, Barbara L Mui, Michael J Hope, Ying K Tam, Nigel Horscroft, Regina Heidenreich, Mariola Fotin-Mleczek, Charles B Shoemaker, Thomas Schlake
The delivery of genetic information has emerged as a valid therapeutic approach. Various reports have demonstrated that mRNA, besides its remarkable potential as vaccine, can also promote expression without inducing an adverse immune response against the encoded protein. In the current study, we set out to explore whether our technology based on chemically unmodified mRNA is suitable for passive immunization. To this end, various antibodies using different designs were expressed and characterized in vitro and in vivo in the fields of viral infections, toxin exposure, and cancer immunotherapies...
August 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28778954/%C3%AE-klotho-sustains-postnatal-gnrh-biology-and-spins-the-thread-of-puberty
#4
Micheline Misrahi
Hypogonadotropic hypogonadism is a syndrome found to be isolated (IHH) or associated with anosmia, corresponding to the Kallmann syndrome (KS). It comprises a defect in gonadotropin-releasing hormone (GnRH) secretion and absent or delayed puberty. Genetic causes have been identified with a high genetic heterogeneity. Fibroblast growth factor receptor 1 (FGFR1), a tyrosine kinase receptor, was one of the first genes whose mutations were identified as causative in KS FGFR1 is responsible for the formation of the GnRH neuron system...
August 4, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28778953/cdk6-protects-epithelial-ovarian-cancer-from-platinum-induced-death-via-foxo3-regulation
#5
Alessandra Dall'Acqua, Maura Sonego, Ilenia Pellizzari, Ilenia Pellarin, Vincenzo Canzonieri, Sara D'Andrea, Sara Benevol, Roberto Sorio, Giorgio Giorda, Daniela Califano, Marina Bagnoli, Loredana Militello, Delia Mezzanzanica, Gennaro Chiappetta, Joshua Armenia, Barbara Belletti, Monica Schiappacassi, Gustavo Baldassarre
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription...
August 4, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28774883/the-cardiac-microenvironment-uses-non-canonical-wnt-signaling-to-activate-monocytes-after-myocardial-infarction
#6
Ingmar Sören Meyer, Andreas Jungmann, Christoph Dieterich, Min Zhang, Felix Lasitschka, Susann Werkmeister, Jan Haas, Oliver J Müller, Michael Boutros, Matthias Nahrendorf, Hugo A Katus, Stefan E Hardt, Florian Leuschner
A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment-dependent changes in inflammatory monocytes after MI RNA sequencing analysis of murine Ly6C(high) monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade...
August 3, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28765140/clinical-development-of-car-t-cells-challenges-and-opportunities-in-translating-innovative-treatment-concepts
#7
REVIEW
Jessica Hartmann, Martina Schüßler-Lenz, Attilio Bondanza, Christian J Buchholz
Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B-cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti-tumor activities, and related toxicities...
August 1, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28754744/klb-encoding-%C3%AE-klotho-is-mutated-in-patients-with-congenital-hypogonadotropic-hypogonadism
#8
Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, James Acierno, Nicolas J Niederländer, Justine Bouilly, Andrew A Dwyer, Yisrael Sidis, Daniele Cassatella, Gerasimos P Sykiotis, Richard Quinton, Christian De Geyter, Mirjam Dirlewanger, Valérie Schwitzgebel, Trevor R Cole, Andrew A Toogood, Jeremy Mw Kirk, Lacey Plummer, Urs Albrecht, William F Crowley, Moosa Mohammadi, Manuel Tena-Sempere, Vincent Prevot, Nelly Pitteloud
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%)...
July 28, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28751581/going-viral-linking-the-etiology-of-human-prostate-cancer-to-the-pca3-long-noncoding-rna-and-oncogenic-viruses
#9
Andre A Teixeira, Serena Marchiò, Emmanuel Dias-Neto, Diana N Nunes, Israel T da Silva, Bryce Chackerian, Marc Barry, Richard C Lauer, Ricardo J Giordano, Richard L Sidman, Cosette M Wheeler, Webster K Cavenee, Renata Pasqualini, Wadih Arap
No abstract text is available yet for this article.
July 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28751580/intracellular-adenosine-regulates-epigenetic-programming-in-endothelial-cells-to-promote-angiogenesis
#10
Yiming Xu, Yong Wang, Siyuan Yan, Yaqi Zhou, Qiuhua Yang, Yue Pan, Xianqiu Zeng, Xiaofei An, Zhiping Liu, Lina Wang, Jiean Xu, Yapeng Cao, David J Fulton, Neal L Weintraub, Zsolt Bagi, Md Nasrul Hoda, Xiaoling Wang, Qinkai Li, Mei Hong, Xuejun Jiang, Detlev Boison, Christian Weber, Chaodong Wu, Yuqing Huo
The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells...
July 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28751579/promoterless-gene-targeting-without-nucleases-rescues-lethality-of-a-crigler-najjar-syndrome-mouse-model
#11
Fabiola Porro, Giulia Bortolussi, Adi Barzel, Alessia De Caneva, Alessandra Iaconcig, Simone Vodret, Lorena Zentilin, Mark A Kay, Andrés F Muro
Crigler-Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduction in plasma bilirubin lasting for at least 12 months, the latest time point analyzed...
July 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28743784/spironolactone-is-an-antagonist-of-nrg1-erbb4-signaling-and-schizophrenia-relevant-endophenotypes-in-mice
#12
Michael C Wehr, Wilko Hinrichs, Magdalena M Brzózka, Tilmann Unterbarnscheidt, Alexander Herholt, Jan P Wintgens, Sergi Papiol, Maria Clara Soto-Bernardini, Mykola Kravchenko, Mingyue Zhang, Klaus-Armin Nave, Sven P Wichert, Peter Falkai, Weiqi Zhang, Markus H Schwab, Moritz J Rossner
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions...
July 25, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28743783/rethinking-the-nonprofit-foundation-an-emerging-niche-in-the-rare-disease-ecosystem
#13
Annette C Bakker, Salvatore La Rosa
No abstract text is available yet for this article.
July 25, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28743782/-18-f-av-1451-and-csf-t-tau-and-p-tau-as-biomarkers-in-alzheimer-s-disease
#14
Niklas Mattsson, Michael Schöll, Olof Strandberg, Ruben Smith, Sebastian Palmqvist, Philip S Insel, Douglas Hägerström, Tomas Ohlsson, Henrik Zetterberg, Jonas Jögi, Kaj Blennow, Oskar Hansson
To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand (18)F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of (18)F-AV-1451, and mainly in demented AD patients. (18)F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment...
July 25, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28729482/brca1-and-brca2-tumor-suppressors-protect-against-endogenous-acetaldehyde-toxicity
#15
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
#16
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
#17
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/28674081/mg132-induced-progerin-clearance-is-mediated-by-autophagy-activation-and-splicing-regulation
#18
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
#19
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
#20
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
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