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https://www.readbyqxmd.com/read/28931235/monoclonal-antibody-protects-against-acinetobacter-baumannii-infection-by-enhancing-bacterial-clearance-and-evading-sepsis
#1
Travis B Nielsen, Paul Pantapalangkoor, Brian M Luna, Kevin W Bruhn, Jun Yan, Ken Dekitani, Sarah Hsieh, Brandon Yeshoua, Bryan Pascual, Evgeny Vinogradov, Kristine M Hujer, T Nicholas Domitrovic, Robert A Bonomo, Thomas A Russo, Magda Lesczcyniecka, Thomas Schneider, Brad Spellberg
Background: Extremely drug-resistant (XDR) Acinetobacter baumannii is one of the most commonly encountered, highly resistant pathogens requiring novel therapeutic interventions. Methods: We developed C8, a monoclonal antibody (mAb), by immunizing mice with sublethal inocula of a hypervirulent XDR clinical isolate. Results: C8 targets capsular carbohydrate on the bacterial surface, enhancing opsonophagocytosis. Treating with a single dose of C8 as low as 0...
August 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28930993/confocal-imaging-of-neuropeptide-y-phluorin-a-technique-to-visualize-insulin-granule-exocytosis-in-intact-murine-and-human-islets
#2
Madina Makhmutova, Tao Liang, Herbert Gaisano, Alejandro Caicedo, Joana Almaça
Insulin secretion plays a central role in glucose homeostasis under normal physiological conditions as well as in disease. Current approaches to study insulin granule exocytosis either use electrophysiology or microscopy coupled to the expression of fluorescent reporters. However most of these techniques have been optimized for clonal cell lines or require dissociating pancreatic islets. In contrast, the method presented here allows for real time visualization of insulin granule exocytosis in intact pancreatic islets...
September 13, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28930978/influenza-a-virus-studies-in-a-mouse-model-of-infection
#3
Laura Rodriguez, Aitor Nogales, Luis Martínez-Sobrido
Influenza viruses cause over 500,000 deaths worldwide(1) and are associated with an annual cost of 12 - 14 billion USD in the United States alone considering direct medical and hospitalization expenses and work absenteeism(2). Animal models are crucial in Influenza A virus (IAV) studies to evaluate viral pathogenesis, host-pathogen interactions, immune responses, and the efficacy of current and/or novel vaccine approaches as well as antivirals. Mice are an advantageous small animal model because their immune system is evolutionarily similar to that found in humans, they are available from commercial vendors as genetically identical subjects, there are multiple strains that can be exploited to evaluate the genetic basis of infections, and they are relatively inexpensive and easy to manipulate...
September 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28930975/streamlined-single-cell-tcr-isolation-and-generation-of-retroviral-vectors-for-in-vitro-and-in-vivo-expression-of-human-tcrs
#4
Maran L Sprouse, Gabriele Blahnik, Thomas Lee, Natalie Tully, Pinaki Benarjee, Eddie A James, Maria J Redondo, Matthew L Bettini, Maria Bettini
Although, several methods for sequencing of paired T cell receptor (TCR) alpha and beta chains from single T cells have been developed, none so far have been conducive to downstream in vivo functional analysis of TCR heterodimers. We have developed an improved protocol based on a two-step multiplex-nested PCR, which results in a PCR product that spans entire variable regions of a human TCR alpha and beta chains. By identifying unique restriction sites and incorporating them into the PCR primers, we have made the PCR product compatible with direct sub-cloning into the template retroviral vector...
September 10, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28930690/the-self-inactivating-kamicas9-system-for-the-editing-of-cns-disease-genes
#5
Nicolas Merienne, Gabriel Vachey, Lucie de Longprez, Cécile Meunier, Virginie Zimmer, Guillaume Perriard, Mathieu Canales, Amandine Mathias, Lucas Herrgott, Tim Beltraminelli, Axelle Maulet, Thomas Dequesne, Catherine Pythoud, Maria Rey, Luc Pellerin, Emmanuel Brouillet, Anselme L Perrier, Renaud du Pasquier, Nicole Déglon
Neurodegenerative disorders are a major public health problem because of the high frequency of these diseases. Genome editing with the CRISPR/Cas9 system is making it possible to modify the sequence of genes linked to these disorders. We designed the KamiCas9 self-inactivating editing system to achieve transient expression of the Cas9 protein and high editing efficiency. In the first application, the gene responsible for Huntington's disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930685/human-tissue-resident-memory-t-cells-are-defined-by-core-transcriptional-and-functional-signatures-in-lymphoid-and-mucosal-sites
#6
Brahma V Kumar, Wenji Ma, Michelle Miron, Tomer Granot, Rebecca S Guyer, Dustin J Carpenter, Takashi Senda, Xiaoyun Sun, Siu-Hong Ho, Harvey Lerner, Amy L Friedman, Yufeng Shen, Donna L Farber
Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69(+) subset of memory CD4(+) and CD8(+) T cells in lung and spleen that is distinct from that of CD69(-) TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8(+) TRMs...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930664/aryl-hydrocarbon-receptor-controls-monocyte-differentiation-into-dendritic-cells-versus-macrophages
#7
Christel Goudot, Alice Coillard, Alexandra-Chloé Villani, Paul Gueguen, Adeline Cros, Siranush Sarkizova, Tsing-Lee Tang-Huau, Mylène Bohec, Sylvain Baulande, Nir Hacohen, Sebastian Amigorena, Elodie Segura
After entering tissues, monocytes differentiate into cells that share functional features with either macrophages or dendritic cells (DCs). How monocyte fate is directed toward monocyte-derived macrophages (mo-Macs) or monocyte-derived DCs (mo-DCs) and which transcription factors control these differentiation pathways remains unknown. Using an in vitro culture model yielding human mo-DCs and mo-Macs closely resembling those found in vivo in ascites, we show that IRF4 and MAFB were critical regulators of monocyte differentiation into mo-DCs and mo-Macs, respectively...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28930535/leader-sequences-of-coronavirus-are-altered-during-infection
#8
Li Liu, Wei Chen
The life cycle of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) involves a unique process called discontinuous transcription by which a set of 3' coterminal subgenomic mRNAs (sgmRNA) with identical 5' leader sequences can be generated. The current study demonstrates that the replication intermediates of minus strand of subgenomic RNA (sgRNA) can be readily recovered from SARS-CoV infected cells. A novel sgmRNA (M-1) was identified as a short version of membrane (M) gene. Transcriptional regulatory sequences (TRS) of SARS-CoV and Mouse Hepatitis Virus (MHV) sgmRNAs contain a species specific core element (CE)...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28929923/rethinking-brain-cancer-therapy-tumor-enzyme-activatable-theranostic-nanoparticles
#9
Heike E Daldrup-Link
This invited commentary discusses a recent article by Mohanty et al in Molecular Cancer Therapeutics about significant therapeutic efficacies of novel theranostic nanoparticles (TNPs) for the treatment of human brain cancers in mouse models. The TNPs were cleaved by enzymes in the tumor tissue, matrix metalloproteinase (MMP-14), which lead to release of a highly potent therapeutic drug, azademethylcolchicine. Data showed that the TNPs caused selective toxic effects in MMP-14-expressing glioblastoma and not normal brain...
January 2017: Molecular Imaging
https://www.readbyqxmd.com/read/28929735/heart-repair-using-nanogel-encapsulated-human-cardiac-stem-cells-in-mice-and-pigs-with-myocardial-infarction
#10
Junnan Tang, Xiaolin Cui, Thomas G Caranasos, M Taylor Hensley, Adam C Vandergriff, Yusak Hartanto, Deliang Shen, Hu Zhang, Jinying Zhang, Ke Cheng
Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice...
September 20, 2017: ACS Nano
https://www.readbyqxmd.com/read/28929191/overview-of-lag-3-expressing-il-10-producing-regulatory-t-cells
#11
Keishi Fujio, Kazuhiko Yamamoto, Tomohisa Okamura
Regulatory T cells (Treg cells) play crucial roles in the induction of peripheral tolerance to self- and foreign-antigens. IL-10-producing regulatory T cells (IL-10-producing Treg cells) constitute a Treg cell subset characterized by the production of high amounts of IL-10, cytokine-mediated immunosuppressive capabilities, and independence of Foxp3 expression for their suppressive activity. In the past decade, identifying naturally occurring IL-10-producing Treg cells was difficult due to the lack of suitable surface markers...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28928736/selective-igm-deficiency-an-underestimated-primary-immunodeficiency
#12
REVIEW
Sudhir Gupta, Ankmalika Gupta
Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28928465/endothelial-adenosine-a2a-receptor-mediated-glycolysis-is-essential-for-pathological-retinal-angiogenesis
#13
Zhiping Liu, Siyuan Yan, Jiaojiao Wang, Yiming Xu, Yong Wang, Shuya Zhang, Xizhen Xu, Qiuhua Yang, Xianqiu Zeng, Yaqi Zhou, Xuejiao Gu, Sarah Lu, Zhongjie Fu, David J Fulton, Neal L Weintraub, Ruth B Caldwell, Wenbo Zhang, Chaodong Wu, Xiao-Ling Liu, Jiang-Fan Chen, Aftab Ahmad, Ismail Kaddour-Djebbar, Mohamed Al-Shabrawey, Qinkai Li, Xuejun Jiang, Ye Sun, Akrit Sodhi, Lois Smith, Mei Hong, Yuqing Huo
Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28928458/agonist-immunotherapy-restores-t-cell-function-following-mek-inhibition-improving-efficacy-in-breast-cancer
#14
Sathana Dushyanthen, Zhi Ling Teo, Franco Caramia, Peter Savas, Christopher P Mintoff, Balaji Virassamy, Melissa A Henderson, Stephen J Luen, Mariam Mansour, Michael H Kershaw, Joseph A Trapani, Paul J Neeson, Roberto Salgado, Grant A McArthur, Justin M Balko, Paul A Beavis, Phillip K Darcy, Sherene Loi
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28928238/talk-1-channels-control-%C3%AE-cell-endoplasmic-reticulum-ca-2-homeostasis
#15
Nicholas C Vierra, Prasanna K Dadi, Sarah C Milian, Matthew T Dickerson, Kelli L Jordan, Patrick Gilon, David A Jacobson
Ca(2+) handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca(2+) homeostasis is determined by ion movements across the ER membrane, including K(+) flux through K(+) channels. We demonstrated that K(+) flux through ER-localized TALK-1 channels facilitated Ca(2+) release from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca(2+) and increased ER Ca(2+) concentrations, suggesting reduced ER Ca(2+) leak...
September 19, 2017: Science Signaling
https://www.readbyqxmd.com/read/28928232/sdhd-ablation-promotes-thyroid-tumorigenesis-by-inducing-a-stem-like-phenotype
#16
Amruta Ashtekar, Danielle Huk, Alexa Magner, Krista La Perle, Xiaoli Zhang, Jose Piruat, Jose Lopez-Barneo, Sissy Jhiang, Lawrence Kirschner
Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas, and pheochromocytomas. In recent studies, missense mutations in the Succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (SDHD) in the thyroid...
September 19, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28928215/influenza-virus-hemagglutinin-stalk-specific-antibodies-in-human-serum-are-a-surrogate-marker-for-in-vivo-protection-in-a-serum-transfer-mouse-challenge-model
#17
Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A Brokstad, Rebecca J Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant, it has been shown that hemagglutination inhibition titers do not always accurately predict protection from disease. In addition, several novel influenza virus vaccines that are currently under development do not target the hemagglutinin head domain, but rather more conserved sites, including the hemagglutinin stalk...
September 19, 2017: MBio
https://www.readbyqxmd.com/read/28928204/bone-morphogenetic-protein-and-retinoic-acid-synergistically-specify-female-germ-cell-fate-in-mice
#18
Hidetaka Miyauchi, Hiroshi Ohta, So Nagaoka, Fumio Nakaki, Kotaro Sasaki, Katsuhiko Hayashi, Yukihiro Yabuta, Tomonori Nakamura, Takuya Yamamoto, Mitinori Saitou
The mechanism for sex determination in mammalian germ cells remains unclear. Here, we reconstitute the female sex determination in mouse germ cells in vitro under a defined condition without the use of gonadal somatic cells. We show that retinoic acid (RA) and its key effector, STRA8, are not sufficient to induce the female germ-cell fate. In contrast, bone morphogenetic protein (BMP) and RA synergistically induce primordial germ cells (PGCs)/PGC-like cells (PGCLCs) derived from embryonic stem cells (ESCs) into fetal primary oocytes...
September 19, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28928151/comparative-analysis-reveals-genomic-features-of-stress-induced-transcriptional-readthrough
#19
Anna Vilborg, Niv Sabath, Yuval Wiesel, Jenny Nathans, Flonia Levy-Adam, Therese A Yario, Joan A Steitz, Reut Shalgi
Transcription is a highly regulated process, and stress-induced changes in gene transcription have been shown to play a major role in stress responses and adaptation. Genome-wide studies reveal prevalent transcription beyond known protein-coding gene loci, generating a variety of RNA classes, most of unknown function. One such class, termed downstream of gene-containing transcripts (DoGs), was reported to result from transcriptional readthrough upon osmotic stress in human cells. However, how widespread the readthrough phenomenon is, and what its causes and consequences are, remain elusive...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28928145/structure-insight-of-gsdmd-reveals-the-basis-of-gsdmd-autoinhibition-in-cell-pyroptosis
#20
Siyun Kuang, Jun Zheng, Hui Yang, Suhua Li, Shuyan Duan, Yanfang Shen, Chaoneng Ji, Jianhua Gan, Xue-Wei Xu, Jixi Li
Recent findings have revealed that the protein gasdermin D (GSDMD) plays key roles in cell pyroptosis. GSDMD binds lipids and forms pore structures to induce pyroptosis upon microbial infection and associated danger signals. However, detailed structural information for GSDMD remains unknown. Here, we report the crystal structure of the C-terminal domain of human GSDMD (GSDMD-C) at 2.64-Å resolution. The first loop on GSDMD-C inserts into the N-terminal domain (GSDMD-N), which helps stabilize the conformation of the full-length GSDMD...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
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