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https://www.readbyqxmd.com/read/28515367/association-of-impaired-neuronal-migration-with-cognitive-deficits-in-extremely-preterm-infants
#1
Ken-Ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515366/experimental-lupus-is-aggravated-in-mouse-strains-with-impaired-induction-of-neutrophil-extracellular-traps
#2
Deborah Kienhöfer, Jonas Hahn, Julia Stoof, Janka Zsófia Csepregi, Christiane Reinwald, Vilma Urbonaviciute, Caroline Johnsson, Christian Maueröder, Malgorzata J Podolska, Mona H Biermann, Moritz Leppkes, Thomas Harrer, Malin Hultqvist, Peter Olofsson, Luis E Munoz, Attila Mocsai, Martin Herrmann, Georg Schett, Rikard Holmdahl, Markus H Hoffmann
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515365/ceramide-synthesis-regulates-t-cell-activity-and-gvhd-development
#3
M Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515364/nicotinamide-metabolism-regulates-glioblastoma-stem-cell-maintenance
#4
Jinkyu Jung, Leo J Y Kim, Xiuxing Wang, Qiulian Wu, Tanwarat Sanvoranart, Christopher G Hubert, Briana C Prager, Lisa C Wallace, Xun Jin, Stephen C Mack, Jeremy N Rich
Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515363/lung-cd103-dendritic-cells-restrain-allergic-airway-inflammation-through-il-12-production
#5
Laura Conejero, Sofía C Khouili, Sarai Martínez-Cano, Helena M Izquierdo, Paola Brandi, David Sancho
DCs are necessary and sufficient for induction of allergic airway inflammation. CD11b+ DCs direct the underlying Th2 immunity, but debate surrounds the function of CD103+ DCs in lung immunity and asthma after an allergic challenge. We challenged Batf3-/- mice, which lacked lung CD103+ DCs, with the relevant allergen house dust mite (HDM) as a model to ascertain their role in asthma. We show that acute and chronic HDM exposure leads to defective Th1 immunity in Batf3-deficient mice. In addition, chronic HDM challenge in Batf3-/- mice results in increased Th2 and Th17 immune responses and exacerbated airway inflammation...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515362/insulin-supplementation-attenuates-cancer-induced-cardiomyopathy-and-slows-tumor-disease-progression
#6
James T Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M Bengel, Denise Hilfiker-Kleiner
Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515361/lupus-and-proliferative-nephritis-are-pad4-independent-in-murine-models
#7
Rachael A Gordon, Jan M Herter, Florencia Rosetti, Allison M Campbell, Hiroshi Nishi, Michael Kashgarian, Sheldon I Bastacky, Anthony Marinov, Kevin M Nickerson, Tanya N Mayadas, Mark J Shlomchik
Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed that inhibition of NETs by targeting the NADPH oxidase complex via cytochrome b-245, β polypeptide (cybb) deletion exacerbated disease in the MRL.Faslpr lupus mouse model. While these data challenge the paradigm that NETs promote lupus, it is conceivable that global regulatory properties of cybb and cybb-independent NETs confound these findings...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515360/a-human-psmb11-variant-affects-thymoproteasome-processing-and-cd8-t-cell-production
#8
Izumi Ohigashi, Yuki Ohte, Kazuya Setoh, Hiroshi Nakase, Akiko Maekawa, Hiroshi Kiyonari, Yoko Hamazaki, Miho Sekai, Tetsuo Sudo, Yasuharu Tabara, Hiromi Sawai, Yosuke Omae, Rika Yuliwulandari, Yasuhito Tanaka, Masashi Mizokami, Hiroshi Inoue, Masanori Kasahara, Nagahiro Minato, Katsushi Tokunaga, Keiji Tanaka, Fumihiko Matsuda, Shigeo Murata, Yousuke Takahama
The Psmb11-encoded β5t subunit of the thymoproteasome, which is specifically expressed in cortical thymic epithelial cells (cTECs), is essential for the optimal positive selection of functionally competent CD8+ T cells in mice. Here, we report that a human genomic PSMB11 variation, which is detectable at an appreciable allele frequency in human populations, alters the β5t amino acid sequence that affects the processing of catalytically active β5t proteins. The introduction of this variation in the mouse genome revealed that the heterozygotes showed reduced β5t expression in cTECs and the homozygotes further exhibited reduction in the cellularity of CD8+ T cells...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515359/t-cell-progenitor-therapy-facilitated-thymopoiesis-depends-upon-thymic-input-and-continued-thymic-microenvironment-interaction
#9
Michelle J Smith, Dawn K Reichenbach, Sarah L Parker, Megan J Riddle, Jason Mitchell, Kevin C Osum, Mahmood Mohtashami, Heather E Stefanski, Brian T Fife, Avinash Bhandoola, Kristin A Hogquist, Georg A Holländer, Juan Carlos Zúñiga-Pflücker, Jakub Tolar, Bruce R Blazar
Infusion of in vitro-derived T cell progenitor (proT) therapy with hematopoietic stem cell transplant aids the recovery of the thymus damaged by total body irradiation. To understand the interaction between proTs and the thymic microenvironment, WT mice were lethally irradiated and given T cell-deficient (Rag1-/-) marrow with WT in vitro-generated proTs, limiting mature T cell development to infused proTs. ProTs within the host thymus led to a significant increase in thymic epithelial cells (TECs) by day 21 after transplant, increasing actively cycling TECs...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515358/irf5-distinguishes-severe-asthma-in-humans-and-drives-th1-phenotype-and-airway-hyperreactivity-in-mice
#10
Timothy B Oriss, Mahesh Raundhal, Christina Morse, Rachael E Huff, Sudipta Das, Rachel Hannum, Marc C Gauthier, Kathryn L Scholl, Krishnendu Chakraborty, Seyed M Nouraie, Sally E Wenzel, Prabir Ray, Anuradha Ray
Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515357/e2f1-inhibits-circulating-cholesterol-clearance-by-regulating-pcsk9-expression-in-the-liver
#11
Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, Pierre-Damien Denechaud, Lluis Fajas
Cholesterol accumulation in the liver is an early event in nonalcoholic fatty liver disease (NAFLD). Here, we demonstrate that E2F1 plays a crucial role in maintaining cellular cholesterol homeostasis by regulating cholesterol uptake via proprotein convertase subtilisin/kexin 9 (PCSK9), an enzyme that promotes low-density lipoprotein receptor (LDLR) degradation upon activation. E2f1-/- mice display reduced total plasma cholesterol levels and increased cholesterol content in the liver. In this study, we show that E2f1 deletion in cellular and mouse models leads to a marked decrease in Pcsk9 expression and an increase in LDLR expression...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515356/licensing-delineates-helper-and-effector-nk-cell-subsets-during-viral-infection
#12
Anthony E Zamora, Ethan G Aguilar, Can M Sungur, Lam T Khuat, Cordelia Dunai, G Raymond Lochhead, Juan Du, Claire Pomeroy, Bruce R Blazar, Dan L Longo, Jeffrey M Venstrom, Nicole Baumgarth, William J Murphy
Natural killer (NK) cells can be divided into phenotypic subsets based on expression of receptors that bind self-MHC-I molecules, a concept termed licensing or education. Here we show NK cell subsets with different migratory, effector, and immunoregulatory functions in dendritic cell and antigen (ag)-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells localized in draining lymph nodes and produced GM-CSF, which correlated with the expansion and activation of dendritic cells, and resulted in greater and sustained ag-specific T cell responses...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469092/transcriptional-dissection-of-melanoma-identifies-a-high-risk-subtype-underlying-tp53-family-genes-and-epigenome-deregulation
#13
Brateil Badal, Alexander Solovyov, Serena Di Cecilia, Joseph Minhow Chan, Li-Wei Chang, Ramiz Iqbal, Iraz T Aydin, Geena S Rajan, Chen Chen, Franco Abbate, Kshitij S Arora, Antoine Tanne, Stephen B Gruber, Timothy M Johnson, Douglas R Fullen, Leon Raskin, Robert Phelps, Nina Bhardwaj, Emily Bernstein, David T Ting, Georg Brunner, Eric E Schadt, Benjamin D Greenbaum, Julide Tok Celebi
BACKGROUND: Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes. METHODS: We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions. We utilized a next-generation sequencing platform that enabled a comprehensive analysis of protein-coding and -noncoding RNA transcripts...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469091/increased-de-novo-ceramide-synthesis-and-accumulation-in-failing-myocardium
#14
Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J Kennel, Danielle L Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y Deng, Shunichi Homma, Isaac J George, Hiroo Takayama, Yoshifumi Naka, Ira J Goldberg, P Christian Schulze
Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469090/metabolite-profiling-identifies-anandamide-as-a-biomarker-of-nonalcoholic-steatohepatitis
#15
W Taylor Kimberly, John F O'Sullivan, Anjali K Nath, Michelle Keyes, Xu Shi, Martin G Larson, Qiong Yang, Michelle T Long, Ramachandran Vasan, Randall T Peterson, Thomas J Wang, Kathleen E Corey, Robert E Gerszten
The discovery of metabolite-phenotype associations may highlight candidate biomarkers and metabolic pathways altered in disease states. We sought to identify novel metabolites associated with obesity and one of its major complications, nonalcoholic fatty liver disease (NAFLD), using a liquid chromatography-tandem mass spectrometry method. In 997 individuals in Framingham Heart Study Generation 3 (FHS Gen 3), we identified an association between anandamide (AEA) and BMI. Further examination revealed that AEA was associated with radiographic hepatic steatosis...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469089/imaging-protective-mast-cells-in-living-mice-during-severe-contact-hypersensitivity
#16
Laurent L Reber, Riccardo Sibilano, Philipp Starkl, Axel Roers, Michele A Grimbaldeston, Mindy Tsai, Nicolas Gaudenzio, Stephen J Galli
Contact hypersensitivity (CHS) is a common skin disease induced by epicutaneous sensitization to haptens. Conflicting results have been obtained regarding pathogenic versus protective roles of mast cells (MCs) in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. Here we describe a fluorescent imaging approach that enables in vivo selective labeling and tracking of MC secretory granules by real-time intravital 2-photon microscopy in living mice, and permits the identification of such MCs as a potential source of cytokines in different disease models...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469088/18f-fdg-as-an-inflammation-biomarker-for-imaging-dengue-virus-infection-and-treatment-response
#17
Ann-Marie Chacko, Satoru Watanabe, Keira J Herr, Shirin Kalimuddin, Jing Yang Tham, Joanne Ong, Marie Reolo, Raymond M F Serrano, Yin Bun Cheung, Jenny G H Low, Subhash G Vasudevan
Development of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever. We explored a biomarker approach using 18F-fluorodeoxyglucose (18F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18F-FDG uptake was seen in intestines and selected tissues over the time course of infection...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469087/models-of-lung-transplant-research-a-consensus-statement-from-the-national-heart-lung-and-blood-institute-workshop
#18
REVIEW
Vibha N Lama, John A Belperio, Jason D Christie, Souheil El-Chemaly, Michael C Fishbein, Andrew E Gelman, Wayne W Hancock, Shaf Keshavjee, Daniel Kreisel, Victor E Laubach, Mark R Looney, John F McDyer, Thalachallour Mohanakumar, Rebecca A Shilling, Angela Panoskaltsis-Mortari, David S Wilkes, Jerry P Eu, Mark R Nicolls
Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469086/iron-accelerates-hemoglobin-oxidation-increasing-mortality-in-vascular-diseased-guinea-pigs-following-transfusion-of-stored-blood
#19
Jin Hyen Baek, Ayla Yalamanoglu, Yamei Gao, Ricardo Guenster, Donat R Spahn, Dominik J Schaer, Paul W Buehler
Non-transferrin-bound iron (NTBI) and free hemoglobin (Hb) accumulate in circulation following stored RBC transfusions. This study investigated transfusion, vascular disease, and mortality in guinea pigs after stored RBC transfusion alone and following cotransfusion with apo-transferrin (apo-Tf) and haptoglobin (Hp). The effects of RBC exchange transfusion dose (1, 3, and 9 units), storage period (14 days), and mortality were evaluated in guinea pigs with a vascular disease phenotype. Seven-day mortality and the interaction between iron and Hb as cocontributors to adverse outcome were studied...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28469085/gdf15-is-elevated-in-mice-following-retinal-ganglion-cell-death-and-in-glaucoma-patients
#20
Norimitsu Ban, Carla J Siegfried, Jonathan B Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S Apte
Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death...
May 4, 2017: JCI Insight
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