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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/29030459/household-triclosan-and-triclocarban-effects-on-the-infant-and-maternal-microbiome
#1
Jessica V Ribado, Catherine Ley, Thomas D Haggerty, Ekaterina Tkachenko, Ami S Bhatt, Julie Parsonnet
In 2016, the US Food and Drug Administration banned the use of specific microbicides in some household and personal wash products due to concerns that these chemicals might induce antibiotic resistance or disrupt human microbial communities. Triclosan and triclocarban (referred to as TCs) are the most common antimicrobials in household and personal care products, but the extent to which TC exposure perturbs microbial communities in humans, particularly during infant development, was unknown. We conducted a randomized intervention of TC-containing household and personal care products during the first year following birth to characterize whether TC exposure from wash products perturbs microbial communities in mothers and their infants...
October 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28993429/tgf-%C3%AE-1-secreted-by-tregs-in-lymph-nodes-promotes-breast-cancer-malignancy-via-up-regulation-of-il-17rb
#2
Shih-Chia Huang, Pei-Chi Wei, Wendy W Hwang-Verslues, Wen-Hung Kuo, Yung-Ming Jeng, Chun-Mei Hu, Jin-Yuh Shew, Chiun-Sheng Huang, King-Jen Chang, Eva Y-Hp Lee, Wen-Hwa Lee
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor-draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis...
October 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28993428/disease-modifying-effects-of-ganglioside-gm1-in-huntington-s-disease-models
#3
Melanie Alpaugh, Danny Galleguillos, Juan Forero, Luis Carlos Morales, Sebastian W Lackey, Preeti Kar, Alba Di Pardo, Andrew Holt, Bradley J Kerr, Kathryn G Todd, Glen B Baker, Karim Fouad, Simonetta Sipione
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background...
October 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28947679/peroxisome-proliferator-activated-receptor-gamma-ppar%C3%AE-regulates-lactase-expression-and-activity-in-the-gut
#4
Mathurin Fumery, Silvia Speca, Audrey Langlois, Anne-Marie Davila, Caroline Dubuquoy, Marta Grauso, Anthony Martin Mena, Martin Figeac, Daniel Metzger, Christel Rousseaux, Jean-Frederic Colombel, Laurent Dubuquoy, Pierre Desreumaux, Benjamin Bertin
Lactase (LCT) deficiency affects approximately 75% of the world's adult population and may lead to lactose malabsorption and intolerance. Currently, the regulation of LCT gene expression remains poorly known. Peroxisome proliferator activator receptorγ (PPARγ) is a key player in carbohydrate metabolism. While the intestine is essential for carbohydrate digestion and absorption, the role of PPARγ in enterocyte metabolic functions has been poorly investigated. This study aims at characterizing PPARγ target genes involved in intestinal metabolic functions...
September 25, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28935714/profiling-mhc-ii-immunopeptidome-of-blood-stage-malaria-reveals-that-cdc1-control-the-functionality-of-parasite-specific-cd4-t-cells
#5
Marion Draheim, Myriam F Wlodarczyk, Karine Crozat, Jean-Michel Saliou, Tchilabalo Dilezitoko Alayi, Stanislas Tomavo, Ali Hassan, Anna Salvioni, Claudia Demarta-Gatsi, John Sidney, Alessandro Sette, Marc Dalod, Antoine Berry, Olivier Silvie, Nicolas Blanchard
In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T-cell subsets are critical to hamper pathology. Yet the antigen-presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood-stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins...
September 21, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28923828/attenuated-pdgf-signaling-drives-alveolar-and-microvascular-defects-in-neonatal-chronic-lung%C3%A2-disease
#6
Prajakta Oak, Tina Pritzke, Isabella Thiel, Markus Koschlig, Daphne S Mous, Anita Windhorst, Noopur Jain, Oliver Eickelberg, Kai Foerster, Andreas Schulze, Wolfgang Goepel, Tobias Reicherzer, Harald Ehrhardt, Robbert J Rottier, Peter Ahnert, Ludwig Gortner, Tushar J Desai, Anne Hilgendorff
Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2 In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A...
September 18, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28923827/mutant-ctnnb1-and-histological-heterogeneity-define-metabolic-subtypes-of-hepatoblastoma
#7
Stefania Crippa, Pierre-Benoit Ancey, Jessica Vazquez, Paolo Angelino, Anne-Laure Rougemont, Catherine Guettier, Vincent Zoete, Mauro Delorenzi, Olivier Michielin, Etienne Meylan
Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β-catenin-driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma...
September 18, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28899930/therapeutic-gene-editing-in-cd34-hematopoietic-progenitors-from-fanconi-anemia-patients
#8
Begoña Diez, Pietro Genovese, Francisco J Roman-Rodriguez, Lara Alvarez, Giulia Schiroli, Laura Ugalde, Sandra Rodriguez-Perales, Julian Sevilla, Cristina Diaz de Heredia, Michael C Holmes, Angelo Lombardo, Luigi Naldini, Juan Antonio Bueren, Paula Rio
Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells...
September 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28899929/pathogen-specific-b-cell-receptors-drive-chronic-lymphocytic-leukemia-by-light-chain-dependent-cross-reaction-with-autoantigens
#9
Nereida Jiménez de Oya, Marco De Giovanni, Jessica Fioravanti, Rudolf Übelhart, Pietro Di Lucia, Amleto Fiocchi, Stefano Iacovelli, Dimitar G Efremov, Federico Caligaris-Cappio, Hassan Jumaa, Paolo Ghia, Luca G Guidotti, Matteo Iannacone
Several lines of evidence indirectly suggest that antigenic stimulation through the B-cell receptor (BCR) supports chronic lymphocytic leukemia (CLL) development. In addition to self-antigens, a number of microbial antigens have been proposed to contribute to the selection of the immunoglobulins expressed in CLL. How pathogen-specific BCRs drive CLL development remains, however, largely unexplored. Here, we utilized mouse models of CLL pathogenesis to equip B cells with virus-specific BCRs and study the effect of antigen recognition on leukemia growth...
September 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28899928/treatment-of-hypertension-by-increasing-impaired-endothelial-trpv4-kca2-3-interaction
#10
Dongxu He, Qiongxi Pan, Zhen Chen, Chunyuan Sun, Peng Zhang, Aiqin Mao, Yaodan Zhu, Hongjuan Li, Chunxiao Lu, Mingxu Xie, Yin Zhou, Daoming Shen, Chunlei Tang, Zhenyu Yang, Jian Jin, Xiaoqiang Yao, Bernd Nilius, Xin Ma
The currently available antihypertensive agents have undesirable adverse effects due to systemically altering target activity including receptors, channels, and enzymes. These effects, such as loss of potassium ions induced by diuretics, bronchospasm by beta-blockers, constipation by Ca(2+) channel blockers, and dry cough by ACEI, lead to non-compliance with therapies (Moser, 1990). Here, based on new hypertension mechanisms, we explored a new antihypertensive approach. We report that transient receptor potential vanilloid 4 (TRPV4) interacts with Ca(2+)-activated potassium channel 3 (KCa2...
September 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28835507/genome-editing-for-scalable-production-of-alloantigen-free-lentiviral-vectors-for-in%C3%A2-vivo-gene%C3%A2-therapy
#11
Michela Milani, Andrea Annoni, Sara Bartolaccini, Mauro Biffi, Fabio Russo, Tiziano Di Tomaso, Andrea Raimondi, Johannes Lengler, Michael C Holmes, Friedrich Scheiflinger, Angelo Lombardo, Alessio Cantore, Luigi Naldini
Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for in vivo applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC-I) are incorporated into the LV surface and trigger allogeneic T-cell responses. By disrupting the beta-2 microglobulin gene in producer cells, we obtained MHC-free LV with substantially reduced immunogenicity...
August 23, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28818835/src-dependent-phosphorylation-of-%C3%AE-opioid-receptor-at-tyr-336-modulates-opiate-withdrawal
#12
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/28794134/mrna-mediates-passive-vaccination-against-infectious-agents-toxins-and-tumors
#13
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/28743784/spironolactone-is-an-antagonist-of-nrg1-erbb4-signaling-and-schizophrenia-relevant-endophenotypes-in-mice
#14
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/28855301/trem2-shedding-by-cleavage-at-the-h157-s158-bond-is-accelerated-for-the-alzheimer-s-disease-associated-h157y-variant
#15
Peter Thornton, Jean Sevalle, Michael J Deery, Graham Fraser, Ye Zhou, Sara Ståhl, Elske H Franssen, Roger B Dodd, Seema Qamar, Beatriz Gomez Perez-Nievas, Louise Sc Nicol, Susanna Eketjäll, Jefferson Revell, Clare Jones, Andrew Billinton, Peter H St George-Hyslop, Iain Chessell, Damian C Crowther
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28855300/an-alzheimer-associated-trem2-variant-occurs-at-the-adam-cleavage-site-and-affects-shedding-and-phagocytic-function
#16
Kai Schlepckow, Gernot Kleinberger, Akio Fukumori, Regina Feederle, Stefan F Lichtenthaler, Harald Steiner, Christian Haass
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28835508/thwarting-endogenous-stress-brca-protects-against-aldehyde-toxicity
#17
Arnab Ray Chaudhuri, André Nussenzweig
No abstract text is available yet for this article.
October 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
#18
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...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28778954/%C3%AE-klotho-sustains-postnatal-gnrh-biology-and-spins-the-thread-of-puberty
#19
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...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28778953/cdk6-protects-epithelial-ovarian-cancer-from-platinum-induced-death-via-foxo3-regulation
#20
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...
October 2017: EMBO Molecular Medicine
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