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https://www.readbyqxmd.com/read/29045900/molecular-and-functional-characterization-of-lymphoid-progenitor-subsets-reveals-a-bipartite-architecture-of-human-lymphopoiesis
#1
Kutaiba Alhaj Hussen, Thien-Phong Vu Manh, Fabien Guimiot, Elisabeth Nelson, Emna Chabaane, Marc Delord, Maxime Barbier, Claire Berthault, Nicolas Dulphy, Antonio José Alberdi, Odile Burlen-Defranoux, Gerard Socié, Jean Christophe Bories, Jerôme Larghero, Valérie Vanneaux, Els Verhoeyen, Thierry Wirth, Marc Dalod, Jean Claude Gluckman, Ana Cumano, Bruno Canque
The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127(-) and CD127(+) early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127(-) and CD127(+) ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials...
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/29045893/hiv-1-latency-by-transition
#2
Boris Julg, Dan H Barouch
The latent HIV-1 reservoir represents the major barrier for the development of an HIV-1 cure. In this issue of Immunity, Shan et al. (2017) highlight that effector-to-memory transitioning (EMT) CD4(+) T cells are particularly permissive for the establishment of latent HIV-1 infection.
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/29045846/identification-of-genetically-intact-hiv-1-proviruses-in-specific-cd4-t-cells-from-effectively-treated-participants
#3
Bonnie Hiener, Bethany A Horsburgh, John-Sebastian Eden, Kirston Barton, Timothy E Schlub, Eunok Lee, Susanne von Stockenstrom, Lina Odevall, Jeffrey M Milush, Teri Liegler, Elizabeth Sinclair, Rebecca Hoh, Eli A Boritz, Daniel Douek, Rémi Fromentin, Nicolas Chomont, Steven G Deeks, Frederick M Hecht, Sarah Palmer
Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4(+) T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045828/prolonged-ikk%C3%AE-inhibition-improves-ongoing-ctl-antitumor-responses-by-incapacitating-regulatory-t-cells
#4
Christoph Heuser, Janine Gotot, Eveline Christina Piotrowski, Marie-Sophie Philipp, Christina Johanna Felicia Courrèges, Martin Sylvester Otte, Linlin Guo, Jonathan Leo Schmid-Burgk, Veit Hornung, Annkristin Heine, Percy Alexander Knolle, Natalio Garbi, Edgar Serfling, César Evaristo, Friedrich Thaiss, Christian Kurts
Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3(+) Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045782/non-covalent-protein-arginine-deiminase-pad-inhibitors-are-efficacious-in-animal-models-of-multiple-sclerosis
#5
Elizabeth J Curiel Tejeda, Angelica M Bello, Ewa Wasilewski, Adam Koebel, Shannon Dunn, Lakshmi P Kotra
Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid based core structure, derived from a hydantoin core, with unique heterocycles on the side chains, were synthesized as potential non-covalent inhibitors of PAD enzymes. Amongst the various heterocycles investigated, compound 23 carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12...
October 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29045749/immune-checkpoint-inhibitor-related-myocarditis
#6
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Immune checkpoint inhibitors have demonstrated significant clinical benefit in many cancers. The clinical benefit afforded by these treatments can be accompanied by a unique and distinct spectrum of adverse events. Recently, several fatal cases of immune checkpoint inhibitor-related myocarditis were reported. Although its frequency is comparatively lower than that of other immune-related adverse events, myocarditis can lead to circulatory collapse and lethal ventricular arrhythmia. Immune checkpoints, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), play important roles in establishing peripheral tolerance to the heart...
October 17, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29045731/the-chimpanzee-model-of-viral-hepatitis-advances-in-understanding-the-immune-response-and-treatment-of-viral-hepatitis
#7
Robert E Lanford, Christopher M Walker, Stanley M Lemon
Chimpanzees (Pan troglodytes) have contributed to diverse fields of biomedical research due to their close genetic relationship to humans and in many instances due to the lack of any other animal model. This review focuses on the contributions of the chimpanzee model to research on hepatitis viruses where chimpanzees represented the only animal model (hepatitis B and C) or the most appropriate animal model (hepatitis A). Research with chimpanzees led to the development of vaccines for HAV and HBV that are used worldwide to protect hundreds of millions from these diseases and, where fully implemented, have provided immunity for entire generations...
October 17, 2017: ILAR Journal
https://www.readbyqxmd.com/read/29045618/cd27-co-stimulation-increases-the-abundance-of-regulatory-t-cells-and-reduces-atherosclerosis-in-hyperlipidaemic-mice
#8
Holger Winkels, Svenja Meiler, Dirk Lievens, David Engel, Charlotte Spitz, Christina Bürger, Linda Beckers, Angelika Dandl, Sigrid Reim, Maiwand Ahmadsei, Helene Hartwig, Lesca M Holdt, Michael Hristov, Remco T A Megens, Martin M Schmitt, Eric A Biessen, Jannie Borst, Alexander Faussner, Christian Weber, Esther Lutgens, Norbert Gerdes
Aims: The co-stimulatory receptor CD27 modulates responses of T cells, B cells, and NK cells. Various T cell subsets participate in atherogenesis. However, the role of CD27 in atherosclerosis remains unexplored. Methods and results: Here we investigated the effect of bone marrow-derived and systemic CD27 deficiency in Apolipoprotein E-deficient (Apoe-/-) mice in early and advanced stages of atherosclerosis. Lethally-irradiated Apoe-/- mice reconstituted with Cd27-/-Apoe-/- bone marrow and consuming an atherogenic diet displayed a markedly increased plaque size and lesional inflammation compared to mice receiving Cd27+/+Apoe-/- bone marrow...
October 16, 2017: European Heart Journal
https://www.readbyqxmd.com/read/29045493/the-sequence-preference-of-dna-methylation-variation-in-mammalians
#9
Ling Zhang, Chan Gu, Lijiang Yang, Fuchou Tang, Yi Qin Gao
Methylation of cytosine at the 5 position of the pyrimidine ring is the most prevalent and significant epigenetic modifications in mammalian DNA. The CpG methylation level shows a bimodal distribution but the bimodality can be overestimated due to the heterogeneity of per-base depth. Here, we developed an algorithm to eliminate the effect of per-base depth inhomogeneity on the bimodality and obtained a random CpG methylation distribution. By quantifying the deviation of the observed methylation distribution and the random one using the information formula, we find that in tetranucleotides 5'-N5CGN3-3' (N5, N3 = A, C, G or T), GCGN3 and CCGN3 show less apparent deviation than ACGN3 and TCGN3, indicating that GCGN3 and CCGN3 are less variant in their level of methylation...
2017: PloS One
https://www.readbyqxmd.com/read/29045460/conjugated-nanoliposome-with-the-her2-neu-derived-peptide-gp2-as-an-effective-vaccine-against-breast-cancer-in-mice-xenograft-model
#10
Atefeh Razazan, Javad Behravan, Atefeh Arab, Nastaran Barati, Leila Arabi, Zahra Gholizadeh, Mahdi Hatamipour, Amin Reza Nikpoor, Amir Abbas Momtazi-Borojeni, Fatemeh Mosaffa, Mohamad Hosein Ghahremani, Mahmoud Reza Jaafari
One of the challenging issues in vaccine development is peptide and adjuvant delivery into target cells. In this study, we developed a vaccine and therapeutic delivery system to increase cytotoxic T lymphocyte (CTL) response against a breast cancer model overexpressing HER2/neu. Gp2, a HER2/neu-derived peptide, was conjugated to Maleimide-mPEG2000-DSPE micelles and post inserted into liposomes composed of DMPC, DMPG phospholipids, and fusogenic lipid dioleoylphosphatidylethanolamine (DOPE) containing monophosphoryl lipid A (MPL) adjuvant (DMPC-DMPG-DOPE-MPL-Gp2)...
2017: PloS One
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#11
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29045188/rapid-evolution-of-thyroid-dysfunction-in-patients-treated-with-nivolumab
#12
Grenye O'Malley, Hanna J Lee, Samir Parekh, Matthew D Galsky, Cardinale B Smith, Philip Friedlander, Robert T Yanagisawa, Emily J Gallagher
OBJECTIVE: To describe the evolution of thyroid dysfunction in a series of patients with cancer treated with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) monoclonal antibody, nivolumab. METHODS: Cases of thyroid dysfunction after initiation of checkpoint inhibitor treatment were identified from the Division of Endocrinology clinical practice at Mount Sinai Hospital, New York from April 2016 to February 2017. Charts were reviewed to identify patients treated with nivolumab with new onset of thyroid dysfunction...
October 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29045159/cracking-the-vaccine-code-in-tuberculosis
#13
Maziar Divangahi, Marcel A Behr
Considerable effort has been devoted to developing a T cell mediated vaccine against tuberculosis (TB).  However, to date, the evidence that this approach can provide protection against Mycobacterium tuberculosis infection has been limited in pre-clinical models and disappointing in a clinical trial. Our fundamental lack of understanding of protective immunity against TB is still the major impediment to vaccine development. In this perspective article, we aim to distinguish the innate immune mechanisms of host-resistance from T cell mediated host-tolerance, and call for novel approaches to be investigated, in the quest for a new TB vaccine...
October 18, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29045040/neurexin-gene-family-variants-as-risk-factors-for-autism-spectrum-disorder
#14
Jia Wang, Jianhua Gong, Li Li, Yanlin Chen, Lingfei Liu, HuaiTing Gu, Xiu Luo, Fang Hou, Jiajia Zhang, Ranran Song
Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are presynaptic cell-adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals. Thus, neurexins are attractive candidate genes for autism. Since gene families have greater power to reveal genetic association than single genes, we designed this case-control study to investigate six genetic variants in three neurexin genes (NRXN1, NRXN2, and NRXN3) in a Chinese population including 529 ASD patients and 1,923 healthy controls...
October 16, 2017: Autism Research: Official Journal of the International Society for Autism Research
https://www.readbyqxmd.com/read/29045007/chromatin-remodeling-factor-osino80-is-involved-in-regulation-of-gibberellin-biosynthesis-and-is-crucial-for-rice-plant-growth-and-development
#15
Chao Li, Yuhao Liu, Wen-Hui Sun, Yu Yu, Aiwu Dong
The phytohormone gibberellin (GA) plays essential roles in plant growth and development. Here, we report that OsINO80, a conserved ATP-dependent chromatin-remodeling factor in rice (Oryza sativa), functions in diverse biological processes and GA biosynthesis. OsINO80-knockdown mutants, derived from either T-DNA insertion or RNA interference, display typical GA-deficient phenotypes, including dwarfism, reduced cell length, late flowering, retarded seed germination and impaired reproductive development. Consistently, transcriptome analyses reveal that OsINO80 knockdown results in down-regulation by more than two-fold of over 1000 genes, including the GA biosynthesis genes CPS1 and GA3ox2, and the dwarf phenotype of OsINO80-knockdown mutants can be rescued by the application of exogenous GA3...
October 17, 2017: Journal of Integrative Plant Biology
https://www.readbyqxmd.com/read/29044710/tracking-the-progression-of-osteolytic-and-osteosclerotic-lesions-in-mice-using-serial-in-vivo-micro-ct-applications-to-the-assessment-of-bisphosphonate-treatment-efficacy
#16
G M Campbell, R J Tower, T Damm, P Kneissl, A Rambow, C Schem, S Tiwari, C C Glüer
The metastasis of tumour cells to bone can lead to osteolytic and osteosclerotic lesions, which cause severe, highly-localized bone destruction and abnormal bone apposition, respectively. Accurate quantification of lesion progression is critical to understand underlying mechanisms and assess treatment efficacy; however, standard structural parameters may be insensitive to local changes. We developed methods to quantify osteolytic and osteosclerotic lesions using micro-computed tomography (micro-CT) within in vivo mouse datasets...
October 18, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29044238/addendum-guidance-of-regulatory-t-cell-development-by-satb1-dependent-super-enhancer-establishment
#17
Yohko Kitagawa, Naganari Ohkura, Yujiro Kidani, Alexis Vandenbon, Keiji Hirota, Ryoji Kawakami, Keiko Yasuda, Daisuke Motooka, Shota Nakamura, Motonari Kondo, Ichiro Taniuchi, Terumi Kohwi-Shigematsu, Shimon Sakaguchi
This corrects the article DOI: 10.1038/ni.3646.
October 18, 2017: Nature Immunology
https://www.readbyqxmd.com/read/29044226/bone-marrow-transplant-induced-alterations-in-notch-signaling-promote-pathologic-th17-responses-to-%C3%AE-herpesvirus-infection
#18
S J Gurczynski, X Zhou, M Flaherty, C A Wilke, B B Moore
Idiopathic pneumonia syndrome (IPS) is a common, often fatal, complication following hematopoietic stem cell transplantation (HSCT) characterized by severe pneumonitis and interstitial fibrosis. Fully reconstituted syngeneic bone marrow transplant (BMT) mice infected with murine γ-herpesvirus-68 develop interleukin-17 (IL-17)-driven pneumonitis and fibrosis, which mimics clinical manifestations of IPS. We found CD103+ and CD11b+ dendritic cells (DCs) are selectively deficient for the Notch ligand, DLL4, following BMT and CD4+ T cells isolated from lungs and spleens of infected BMT mice display Notch signaling defects...
October 18, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/29044097/dna-binding-of-the-tet-transactivator-curtails-antigen-induced-lymphocyte-activation-in-mice
#19
Eleonora Ottina, Victor Peperzak, Katia Schoeler, Emma Carrington, Roswitha Sgonc, Marc Pellegrini, Simon Preston, Marco J Herold, Andreas Strasser, Andreas Villunger
The Tet-On/Off system for conditional transgene expression constitutes state-of-the-art technology to study gene function by facilitating inducible expression in a timed and reversible manner. Several studies documented the suitability and versatility of this system to trace lymphocyte fate and to conditionally express oncogenes or silence tumour suppressor genes in vivo. Here, we show that expression of the tetracycline/doxycycline-controlled Tet-transactivator, while tolerated well during development and in immunologically unchallenged animals, impairs the expansion of antigen-stimulated T and B cells and thereby curtails adaptive immune responses in vivo...
October 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/29043951/verrucosispora-endophytica-sp-nov-isolated-from-the-root-of-wild-orchid-grosourdya-appendiculata-blume-rchb-f
#20
Wipaporn Ngaemthao, Tawanmol Pujchakarn, Suwanee Chunhametha, Chanwit Suriyachadkun
A novel endophytic filamentous bacterium strain A-T 7972(T), was isolated from wild orchid Grosourdya appendiculata (Blume) Rchb.f. collected in Thailand. The bacterium developed single non-motile spores with warty surface on substrate mycelia. The taxonomic position was described using a polyphasic approach. The 16S rRNA gene sequence and phylogenetic analysis indicated that strain A-T 7972(T) belonged to the genus Verrucosispora and shared the highest sequence similarity with V. lutea YIM 013(T) (98.71 %) and V...
October 18, 2017: International Journal of Systematic and Evolutionary Microbiology
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