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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/27881461/lysosomal-dysfunction-disrupts-presynaptic-maintenance-and-restoration-of-presynaptic-function-prevents-neurodegeneration-in-lysosomal-storage-diseases
#1
Irene Sambri, Rosa D'Alessio, Yulia Ezhova, Teresa Giuliano, Nicolina Cristina Sorrentino, Vincenzo Cacace, Maria De Risi, Mauro Cataldi, Lucio Annunziato, Elvira De Leonibus, Alessandro Fraldi
Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα)...
November 25, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861127/nec-1-alleviates-cognitive-impairment-with-reduction-of-a%C3%AE-and-tau-abnormalities-in-app-ps1-mice
#2
Seung-Hoon Yang, Dongkeun Kenneth Lee, Jisu Shin, Sejin Lee, Seungyeop Baek, Jiyoon Kim, Hoyong Jung, Jung-Mi Hah, YoungSoo Kim
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive symptoms of learning and memory deficits. Such cognitive impairments are attributed to brain atrophy resulting from progressive neuronal and synaptic loss; therefore, alleviation of neural cell death is as an important target of treatment as other classical hallmarks of AD, such as aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau. Here, we found that an anti-necroptotic molecule necrostatin-1 (Nec-1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models...
November 17, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27856619/coq-deficiency-causes-disruption-of-mitochondrial-sulfide-oxidation-a-new-pathomechanism-associated-with-this-syndrome
#3
Marta Luna-Sánchez, Agustín Hidalgo-Gutiérrez, Tatjana M Hildebrandt, Julio Chaves-Serrano, Eliana Barriocanal-Casado, Ángela Santos-Fandila, Miguel Romero, Ramy Ka Sayed, Juan Duarte, Holger Prokisch, Markus Schuelke, Felix Distelmaier, Germaine Escames, Darío Acuña-Castroviejo, Luis C López
Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism...
November 17, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27856618/coenzyme-q-deficiency-causes-impairment-of-the-sulfide-oxidation-pathway
#4
Marcello Ziosi, Ivano Di Meo, Giulio Kleiner, Xing-Huang Gao, Emanuele Barca, Maria J Sanchez-Quintero, Saba Tadesse, Hongfeng Jiang, Changhong Qiao, Richard J Rodenburg, Emmanuel Scalais, Markus Schuelke, Belinda Willard, Maria Hatzoglou, Valeria Tiranti, Catarina M Quinzii
Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2(kd/kd) mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion...
November 17, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27852619/after-surviving-cancer-what-about-late-life-effects-of-the-cure
#5
Julie Nonnekens, Jan Hj Hoeijmakers
No abstract text is available yet for this article.
November 16, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861129/an-evaluation-of-the-therapeutic-potential-of-fecal-microbiota-transplantation-to-treat-infectious-and-metabolic-diseases
#6
Albert K Groen, Max Nieuwdorp
No abstract text is available yet for this article.
November 9, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27794029/reversible-p53-inhibition-prevents-cisplatin%C3%A2-ototoxicity-without-blocking-chemotherapeutic-efficacy
#7
Nesrine Benkafadar, Julien Menardo, Jérôme Bourien, Régis Nouvian, Florence François, Didier Decaudin, Domenico Maiorano, Jean-Luc Puel, Jing Wang
Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin-induced ototoxicity remains unclear, and hearing preservation during cisplatin-based chemotherapy in patients is lacking. We found activation of the ATM-Chk2-p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin-induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival...
October 28, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27679671/red-shifted-channelrhodopsin-stimulation-restores-light-responses-in-blind-mice-macaque-retina-and-human-retina
#8
Abhishek Sengupta, Antoine Chaffiol, Emilie Macé, Romain Caplette, Mélissa Desrosiers, Maruša Lampič, Valérie Forster, Olivier Marre, John Y Lin, José-Alain Sahel, Serge Picaud, Deniz Dalkara, Jens Duebel
Targeting the photosensitive ion channel channelrhodopsin-2 (ChR2) to the retinal circuitry downstream of photoreceptors holds promise in treating vision loss caused by retinal degeneration. However, the high intensity of blue light necessary to activate channelrhodopsin-2 exceeds the safety threshold of retinal illumination because of its strong potential to induce photochemical damage. In contrast, the damage potential of red-shifted light is vastly lower than that of blue light. Here, we show that a red-shifted channelrhodopsin (ReaChR), delivered by AAV injections in blind rd1 mice, enables restoration of light responses at the retinal, cortical, and behavioral levels, using orange light at intensities below the safety threshold for the human retina...
September 27, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27908983/intra-arterial-transplantation-of-hla-matched-donor-mesoangioblasts-in-duchenne-muscular%C3%A2-dystrophy
#9
Giulio Cossu, Stefano C Previtali, Sara Napolitano, Maria Pia Cicalese, Francesco Saverio Tedesco, Francesca Nicastro, Maddalena Noviello, Urmas Roostalu, Maria Grazia Natali Sora, Marina Scarlato, Maurizio De Pellegrin, Claudia Godi, Serena Giuliani, Francesca Ciotti, Rossana Tonlorenzi, Isabella Lorenzetti, Cristina Rivellini, Sara Benedetti, Roberto Gatti, Sarah Marktel, Benedetta Mazzi, Andrea Tettamanti, Martina Ragazzi, Maria Adele Imro, Giuseppina Marano, Alessandro Ambrosi, Rossana Fiori, Maria Pia Sormani, Chiara Bonini, Massimo Venturini, Letterio S Politi, Yvan Torrente, Fabio Ciceri
No abstract text is available yet for this article.
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861130/gut-flora-connects-obesity-with-pathological-angiogenesis-in-the-eye
#10
Rebecca Scholz, Thomas Langmann
No abstract text is available yet for this article.
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861128/retinoic-acid-catabolizing-enzyme-cyp26c1-is-a-genetic-modifier-in-shox-deficiency
#11
Antonino Montalbano, Lonny Juergensen, Ralph Roeth, Birgit Weiss, Maki Fukami, Susanne Fricke-Otto, Gerhard Binder, Tsutomu Ogata, Eva Decker, Gudrun Nuernberg, David Hassel, Gudrun A Rappold
Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three-generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861126/gut-microbiota-influences-pathological-angiogenesis-in-obesity-driven-choroidal-neovascularization
#12
Elisabeth Mma Andriessen, Ariel M Wilson, Gaelle Mawambo, Agnieszka Dejda, Khalil Miloudi, Florian Sennlaub, Przemyslaw Sapieha
Age-related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late-stage NV AMD To date, the mechanisms that underscore this observation remain ill-defined. Given the impact of high-fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high-fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861125/4-aminopyridine-promotes-functional-recovery-and-remyelination-in-acute-peripheral-nerve-injury
#13
Kuang-Ching Tseng, Haiyan Li, Andrew Clark, Leigh Sundem, Michael Zuscik, Mark Noble, John Elfar
Traumatic peripheral nerve damage is a major medical problem without effective treatment options. In repurposing studies on 4-aminopyridine (4-AP), a potassium channel blocker that provides symptomatic relief in some chronic neurological afflictions, we discovered this agent offers significant promise as a small molecule regenerative agent for acute traumatic nerve injury. We found, in a mouse model of sciatic crush injury, that sustained early 4-AP administration increased the speed and extent of behavioral recovery too rapidly to be explained by axonal regeneration...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27861123/tecrl-a-new-life-threatening-inherited-arrhythmia-gene-associated-with-overlapping-clinical-features-of-both-lqts-and-cpvt
#14
Harsha D Devalla, Roselle Gélinas, Elhadi H Aburawi, Abdelaziz Beqqali, Philippe Goyette, Christian Freund, Marie-A Chaix, Rafik Tadros, Hui Jiang, Antony Le Béchec, Jantine J Monshouwer-Kloots, Tom Zwetsloot, Georgios Kosmidis, Frédéric Latour, Azadeh Alikashani, Maaike Hoekstra, Jurg Schlaepfer, Christine L Mummery, Brian Stevenson, Zoltan Kutalik, Antoine Af de Vries, Léna Rivard, Arthur Am Wilde, Mario Talajic, Arie O Verkerk, Lihadh Al-Gazali, John D Rioux, Zahurul A Bhuiyan, Robert Passier
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27821430/mitochondria-associated-membrane-collapse-is-a-common-pathomechanism-in-sigmar1-and-sod1-linked-als
#15
Seiji Watanabe, Hristelina Ilieva, Hiromi Tamada, Hanae Nomura, Okiru Komine, Fumito Endo, Shijie Jin, Pedro Mancias, Hiroshi Kiyama, Koji Yamanaka
A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria-associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS-linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP3R3)...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27821429/non-invasive-lung-cancer-diagnosis-by-detection-of-gata6-and-nkx2-1-isoforms-in-exhaled-breath-condensate
#16
Aditi Mehta, Julio Cordero, Stephanie Dobersch, Addi J Romero-Olmedo, Rajkumar Savai, Johannes Bodner, Cho-Ming Chao, Ludger Fink, Ernesto Guzmán-Díaz, Indrabahadur Singh, Gergana Dobreva, Ulf R Rapp, Stefan Günther, Olga N Ilinskaya, Saverio Bellusci, Reinhard H Dammann, Thomas Braun, Werner Seeger, Stefan Gattenlöhner, Achim Tresch, Andreas Günther, Guillermo Barreto
Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Early LC diagnosis is crucial to reduce the high case fatality rate of this disease. In this case-control study, we developed an accurate LC diagnosis test using retrospectively collected formalin-fixed paraffin-embedded (FFPE) human lung tissues and prospectively collected exhaled breath condensates (EBCs). Following international guidelines for diagnostic methods with clinical application, reproducible standard operating procedures (SOP) were established for every step comprising our LC diagnosis method...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27799291/niacin-mediated-tace-activation-ameliorates-cmt-neuropathies-with-focal-hypermyelination
#17
Alessandra Bolino, Françoise Piguet, Valeria Alberizzi, Marta Pellegatta, Cristina Rivellini, Marta Guerrero-Valero, Roberta Noseda, Chiara Brombin, Alessandro Nonis, Patrizia D'Adamo, Carla Taveggia, Stefano Carlo Previtali
Charcot-Marie-Tooth (CMT) neuropathies are highly heterogeneous disorders caused by mutations in more than 70 genes, with no available treatment. Thus, it is difficult to envisage a single suitable treatment for all pathogenetic mechanisms. Axonal Neuregulin 1 (Nrg1) type III drives Schwann cell myelination and determines myelin thickness by ErbB2/B3-PI3K-Akt signaling pathway activation. Nrg1 type III is inhibited by the α-secretase Tace, which negatively regulates PNS myelination. We hypothesized that modulation of Nrg1 levels and/or secretase activity may constitute a unifying treatment strategy for CMT neuropathies with focal hypermyelination as it could restore normal levels of myelination...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27784710/tecrl-connecting-sequence-to-consequence-for-a-new-sudden-cardiac-death-gene
#18
Matthew D Perry, Jamie I Vandenberg
No abstract text is available yet for this article.
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27807076/a-poglut1-mutation-causes-a-muscular-dystrophy-with-reduced-notch-signaling-and-satellite-cell-loss
#19
Emilia Servián-Morilla, Hideyuki Takeuchi, Tom V Lee, Jordi Clarimon, Fabiola Mavillard, Estela Area-Gómez, Eloy Rivas, Jose L Nieto-González, Maria C Rivero, Macarena Cabrera-Serrano, Leonardo Gómez-Sánchez, Jose A Martínez-López, Beatriz Estrada, Celedonio Márquez, Yolanda Morgado, Xavier Suárez-Calvet, Guillermo Pita, Anne Bigot, Eduard Gallardo, Rafael Fernández-Chacón, Michio Hirano, Robert S Haltiwanger, Hamed Jafar-Nejad, Carmen Paradas
Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development...
November 2, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27742718/targeting-key-angiogenic-pathways-with-a-bispecific-crossmab-optimized-for-neovascular-eye-diseases
#20
Jörg T Regula, Peter Lundh von Leithner, Richard Foxton, Veluchamy A Barathi, Chui Ming Gemmy Cheung, Sai Bo Bo Tun, Yeo Sia Wey, Daiju Iwata, Miroslav Dostalek, Jörg Moelleken, Kay G Stubenrauch, Everson Nogoceke, Gabriella Widmer, Pamela Strassburger, Michael J Koss, Christian Klein, David T Shima, Guido Hartmann
Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A...
November 2, 2016: EMBO Molecular Medicine
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