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Science Translational Medicine

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https://www.readbyqxmd.com/read/30209246/thrombopoietin-receptor-independent-stimulation-of-hematopoietic-stem-cells-by-eltrombopag
#1
Yun-Ruei Kao, Jiahao Chen, Swathi-Rao Narayanagari, Tihomira I Todorova, Maria M Aivalioti, Mariana Ferreira, Pedro M Ramos, Celine Pallaud, Ioannis Mantzaris, Aditi Shastri, James B Bussel, Amit Verma, Ulrich Steidl, Britta Will
Eltrombopag (EP), a small-molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited...
September 12, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30209245/a-database-of-tissue-specific-rhythmically-expressed-human-genes-has-potential-applications-in-circadian-medicine
#2
Marc D Ruben, Gang Wu, David F Smith, Robert E Schmidt, Lauren J Francey, Yin Yeng Lee, Ron C Anafi, John B Hogenesch
The discovery that half of the mammalian protein-coding genome is regulated by the circadian clock has clear implications for medicine. Recent studies demonstrated that the circadian clock influences therapeutic outcomes in human heart disease and cancer. However, biological time is rarely given clinical consideration. A key barrier is the absence of information on tissue-specific molecular rhythms in the human body. We have applied the cyclic ordering by periodic structure (CYCLOPS) algorithm, designed to reconstruct sample temporal order in the absence of time-of-day information, to the gene expression collection of 13 tissues from 632 human donors...
September 12, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30209244/anp32a-regulates-atm-expression-and-prevents-oxidative-stress-in-cartilage-brain-and-bone
#3
Frederique M F Cornelis, Silvia Monteagudo, Laura-An K A Guns, Wouter den Hollander, Rob G H H Nelissen, Lies Storms, Tine Peeters, Ilse Jonkers, Ingrid Meulenbelt, Rik J Lories
Osteoarthritis is the most common joint disorder with increasing global prevalence due to aging of the population. Current therapy is limited to symptom relief, yet there is no cure. Its multifactorial etiology includes oxidative stress and overproduction of reactive oxygen species, but the regulation of these processes in the joint is insufficiently understood. We report that ANP32A protects the cartilage against oxidative stress, preventing osteoarthritis development and disease progression. ANP32A is down-regulated in human and mouse osteoarthritic cartilage...
September 12, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30209243/evaluation-of-mutant-huntingtin-and-neurofilament-proteins-as-potential-markers-in-huntington-s-disease
#4
Lauren M Byrne, Filipe B Rodrigues, Eileanor B Johnson, Peter A Wijeratne, Enrico De Vita, Daniel C Alexander, Giuseppe Palermo, Christian Czech, Scott Schobel, Rachael I Scahill, Amanda Heslegrave, Henrik Zetterberg, Edward J Wild
Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers...
September 12, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30209242/sarcoplasmic-reticulum-calcium-leak-contributes-to-arrhythmia-but-not-to-heart-failure-progression
#5
Belal A Mohamed, Nico Hartmann, Petros Tirilomis, Karolina Sekeres, Wener Li, Stefan Neef, Claudia Richter, Elisabeth M Zeisberg, Lars Kattner, Michael Didié, Kaomei Guan, Jan D Schmitto, Stephan E Lehnart, Stefan Luther, Niels Voigt, Tim Seidler, Samuel Sossalla, Gerd Hasenfuss, Karl Toischer
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36- versus placebo-treated mice...
September 12, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30185653/eosinophils-increase-airway-sensory-nerve-density-in-mice-and-in-human-asthma
#6
Matthew G Drake, Gregory D Scott, Emily D Blum, Katherine M Lebold, Zhenying Nie, James J Lee, Allison D Fryer, Richard W Costello, David B Jacoby
In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects...
September 5, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30185652/a-machine-learning-approach-for-somatic-mutation-discovery
#7
Derrick E Wood, James R White, Andrew Georgiadis, Beth Van Emburgh, Sonya Parpart-Li, Jason Mitchell, Valsamo Anagnostou, Noushin Niknafs, Rachel Karchin, Eniko Papp, Christine McCord, Peter LoVerso, David Riley, Luis A Diaz, Siân Jones, Mark Sausen, Victor E Velculescu, Samuel V Angiuoli
Variability in the accuracy of somatic mutation detection may affect the discovery of alterations and the therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery approach based on machine learning that outperformed existing methods in identifying experimentally validated tumor alterations (sensitivity of 97% versus 90 to 99%; positive predictive value of 98% versus 34 to 92%). Analysis of paired tumor-normal exome data from 1368 TCGA (The Cancer Genome Atlas) samples using this method revealed concordance for 74% of mutation calls but also identified likely false-positive and false-negative changes in TCGA data, including in clinically actionable genes...
September 5, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30185651/human-thymopoiesis-is-influenced-by-a-common-genetic-variant-within-the-tcra-tcrd-locus
#8
Emmanuel Clave, Itauá Leston Araujo, Cécile Alanio, Etienne Patin, Jacob Bergstedt, Alejandra Urrutia, Silvia Lopez-Lastra, Yan Li, Bruno Charbit, Cameron Ross MacPherson, Milena Hasan, Breno Luiz Melo-Lima, Corinne Douay, Noémie Saut, Marine Germain, David-Alexandre Trégouët, Pierre-Emmanuel Morange, Magnus Fontes, Darragh Duffy, James P Di Santo, Lluis Quintana-Murci, Matthew L Albert, Antoine Toubert
The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function...
September 5, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30185650/hypercapnia-increases-airway-smooth-muscle-contractility-via-caspase-7-mediated-mir-133a-rhoa-signaling
#9
Masahiko Shigemura, Emilia Lecuona, Martín Angulo, Tetsuya Homma, Diego A Rodríguez, Francisco J Gonzalez-Gonzalez, Lynn C Welch, Luciano Amarelle, Seok-Jo Kim, Naftali Kaminski, G R Scott Budinger, Julian Solway, Jacob I Sznajder
The elevation of carbon dioxide (CO2 ) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO2 acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO2 activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells...
September 5, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158154/preventing-loss-of-mechanosensation-by-the-nuclear-membranes-of-alveolar-cells-reduces-lung-injury-in-mice-during-mechanical-ventilation
#10
Inés López-Alonso, Jorge Blázquez-Prieto, Laura Amado-Rodríguez, Adrián González-López, Aurora Astudillo, Manuel Sánchez, Covadonga Huidobro, Cecilia López-Martínez, Claudia C Dos Santos, Guillermo M Albaiceta
The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may result in clinically relevant alveolar damage. We report that mechanical ventilation in mice increased the expression of Lamin-A, a major determinant of nuclear membrane stiffness, in alveolar epithelial cells. Lamin-A expression increased and nuclear membrane compliance decreased in human bronchial epithelial cells after a mechanical stretch stimulus and in a murine model of lung injury after positive-pressure ventilation...
August 29, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158153/hdac-inhibition-improves-autophagic-and-lysosomal-function-to-prevent-loss-of-subcutaneous-fat-in-a-mouse-model-of-cockayne-syndrome
#11
Marc Majora, Kevin Sondenheimer, Maren Knechten, Ingo Uthe, Charlotte Esser, Alfonso Schiavi, Natascia Ventura, Jean Krutmann
Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the csb gene, affects multiple organs including skin where it manifests with hypersensitivity toward ultraviolet (UV) radiation and loss of subcutaneous fat. There is no curative treatment for CS, and its pathogenesis is only partially understood. Originally considered for its role in DNA repair, Cockayne syndrome group B (CSB) protein most likely serves additional functions. Using CSB-deficient human fibroblasts, Caenorhabditis elegans , and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy...
August 29, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158152/inhibition-of-sodium-hydrogen-exchanger-3-in-the-gastrointestinal-tract-by-tenapanor-reduces-paracellular-phosphate-permeability
#12
Andrew J King, Matthew Siegel, Ying He, Baoming Nie, Ji Wang, Samantha Koo-McCoy, Natali A Minassian, Qumber Jafri, Deng Pan, Jill Kohler, Padmapriya Kumaraswamy, Kenji Kozuka, Jason G Lewis, Dean Dragoli, David P Rosenbaum, Debbie O'Neill, Allein Plain, Peter J Greasley, Ann-Cathrine Jönsson-Rylander, Daniel Karlsson, Margareta Behrendt, Maria Strömstedt, Tina Ryden-Bergsten, Thomas Knöpfel, Eva M Pastor Arroyo, Nati Hernando, Joanne Marks, Mark Donowitz, Carsten A Wagner, R Todd Alexander, Jeremy S Caldwell
Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia...
August 29, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158151/glycoconjugate-vaccines-principles-and-mechanisms
#13
REVIEW
Rino Rappuoli
Bacterial conjugate vaccines are used in infants, adolescents, and the elderly, and they are among the safest and most successful vaccines developed during the last 40 years. Conjugation of polysaccharides to proteins provides T cell epitopes that are necessary in the germinal centers for the affinity maturation of polysaccharide-specific B cells. Collective analysis of data from animal experiments and clinical trials, reviewed with current knowledge of immunology, revealed possible mechanistic explanations that may improve our understanding of conjugate vaccines...
August 29, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158150/a-bifunctional-nociceptin-and-mu-opioid-receptor-agonist-is-analgesic-without-opioid-side-effects-in-nonhuman-primates
#14
Huiping Ding, Norikazu Kiguchi, Dennis Yasuda, Pankaj R Daga, Willma E Polgar, James J Lu, Paul W Czoty, Shiroh Kishioka, Nurulain T Zaveri, Mei-Chuan Ko
Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors...
August 29, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30158149/erratum-for-the-research-article-long-acting-mic-1-gdf15-molecules-to-treat-obesity-evidence-from-mice-to-monkeys-by-y-xiong-k-walker-x-min-c-hale-t-tran-r-komorowski-j-yang-j-davda-n-nuanmanee-d-kemp-x-wang-h-liu-s-miller-k-j-lee-z-wang-m-m-v%C3%A3-niant
#15
https://www.readbyqxmd.com/read/30135250/apobec-mutation-drives-early-onset-squamous-cell-carcinomas-in-recessive-dystrophic-epidermolysis-bullosa
#16
Raymond J Cho, Ludmil B Alexandrov, Nicoline Y den Breems, Velina S Atanasova, Mehdi Farshchian, Elizabeth Purdom, Tran N Nguyen, Cristian Coarfa, Kimal Rajapakshe, Marco Prisco, Joya Sahu, Patrick Tassone, Evan J Greenawalt, Eric A Collisson, Wei Wu, Hui Yao, Xiaoping Su, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Raabia Hashmi, Ignacia Fuentes, Stephen C Benz, Justin Golovato, Erik A Ehli, Christel M Davis, Gareth E Davies, Kyle R Covington, Dedee F Murrell, Julio C Salas-Alanis, Francis Palisson, Anna L Bruckner, William Robinson, Cristina Has, Leena Bruckner-Tuderman, Matthias Titeux, Marcel F Jonkman, Elham Rashidghamat, Su M Lwin, Jemima E Mellerio, John A McGrath, Johann W Bauer, Alain Hovnanian, Kenneth Y Tsai, Andrew P South
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors...
August 22, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30135249/cleavage-of-the-leptin-receptor-by-matrix-metalloproteinase-2-promotes-leptin-resistance-and-obesity-in-mice
#17
Rafi Mazor, Dinorah Friedmann-Morvinski, Tom Alsaigh, Oded Kleifeld, Erik B Kistler, Liat Rousso-Noori, Cheng Huang, Joyce B Li, Inder M Verma, Geert W Schmid-Schönbein
Obesity and related morbidities pose a major health threat. Obesity is associated with increased blood concentrations of the anorexigenic hormone leptin; however, obese individuals are resistant to its anorexigenic effects. We examined the phenomenon of reduced leptin signaling in a high-fat diet-induced obesity model in mice. Obesity promoted matrix metalloproteinase-2 (Mmp-2) activation in the hypothalamus, which cleaved the leptin receptor's extracellular domain and impaired leptin-mediated signaling. Deletion of Mmp-2 restored leptin receptor expression and reduced circulating leptin concentrations in obese mice...
August 22, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30135248/deciduous-autologous-tooth-stem-cells-regenerate-dental-pulp-after-implantation-into-injured-teeth
#18
Kun Xuan, Bei Li, Hao Guo, Wei Sun, Xiaoxing Kou, Xiaoning He, Yongjie Zhang, Jin Sun, Anqi Liu, Li Liao, Shiyu Liu, Wenjia Liu, Chenghu Hu, Songtao Shi, Yan Jin
Pulp necrosis arrests root development in injured immature permanent teeth, which may result in tooth loss. However, dental pulp regeneration and promotion of root development remains challenging. We show that implantation of autologous tooth stem cells from deciduous teeth regenerated dental pulp with an odontoblast layer, blood vessels, and nerves in two animal models. These results prompted us to enroll 40 patients with pulp necrosis after traumatic dental injuries in a randomized, controlled clinical trial...
August 22, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30135247/an-extracellular-matrix-fragment-drives-epithelial-remodeling-and-airway-hyperresponsiveness
#19
Dhiren F Patel, Teresa Peiró, Amelia Shoemark, Samia Akthar, Simone A Walker, Aleksander M Grabiec, Patricia L Jackson, Tracy Hussell, Amit Gaggar, Xin Xu, Jennifer L Trevor, Jindong Li, Chad Steele, Gael Tavernier, J Edwin Blalock, Robert M Niven, Lisa G Gregory, Angela Simpson, Clare M Lloyd, Robert J Snelgrove
It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4 H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4 ) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4 H exacerbated AHR, despite the absence of LTB4 This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling...
August 22, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30111646/a-protective-langerhans-cell-keratinocyte-axis-that-is-dysfunctional-in-photosensitivity
#20
William D Shipman, Susan Chyou, Anusha Ramanathan, Peter M Izmirly, Sneh Sharma, Tania Pannellini, Dragos C Dasoveanu, Xiaoping Qing, Cynthia M Magro, Richard D Granstein, Michelle A Lowes, Eric G Pamer, Daniel H Kaplan, Jane E Salmon, Babak J Mehrara, James W Young, Robert M Clancy, Carl P Blobel, Theresa T Lu
Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis...
August 15, 2018: Science Translational Medicine
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