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Daniel Sauter, Frank Kirchhoff
HIV-1, the main causative agent of AIDS, and related primate lentiviruses show a striking ability to efficiently replicate throughout the lifetime of an infected host. In addition to their high variability, the acquisition of several accessory genes has enabled these viruses to efficiently evade or counteract seemingly strong antiviral immune responses. The respective viral proteins, i.e. Vif, Vpr, Vpu, Vpx and Nef, show a stunning functional diversity, acting by various mechanisms and targeting a large variety of cellular factors involved in innate and adaptive immunity...
February 23, 2018: Cytokine & Growth Factor Reviews
Zine-Eddine Kherraf, Beatrice Conne, Amir Amiri-Yekta, Marie Christou Kent, Charles Coutton, Jessica Escoffier, Serge Nef, Christophe Arnoult, Pierre F Ray
High throughput sequencing (HTS) and CRISPR/Cas9 are two recent technologies that are currently revolutionizing biological and clinical research. Both techniques are complementary as HTS permits to identify new genetic variants and genes involved in various pathologies and CRISPR/Cas9 permits to create animals or cell models to validate the effect of the identified variants, to characterize the pathogeny of the identified variants and the function of the genes of interest and ultimately to provide ways of correcting the molecular defects...
March 6, 2018: Molecular and Cellular Endocrinology
Xiang-Yong Liu, Hai-Xiao Xu, Jian-Kui Li, Dong Zhang, Xiao-Hong Ma, Li-Na Huang, Jun-Hong Lü, Xiao-Zhi Wang
Damage to the endothelial glycocalyx is a critical factor in increased pulmonary vascular permeability, which is the basic pathological feature of acute respiratory distress syndrome (ARDS). Neferine (Nef), a bisbenzylisoquinoline alkaloid isolated from green seed embryos of Nelumbo nucifera Gaertn , has extensive pharmacological activity. In this study, we showed that Nef reduced lung-capillary permeability, down-regulated the production of cytokines (IL-1β, IL-6, TNF-α, and IL-10) and inhibited the activation of the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced ARDS...
2018: Frontiers in Physiology
Maia Kavanagh Williamson, Naomi Coombes, Florian Juszczak, Marios Athanasopoulos, Mariam B Khan, Thomas R Eykyn, Ushani Srenathan, Leonie S Taams, Julianna Dias Zeidler, Andrea T Da Poian, Hendrik Huthoff
Infection of primary CD4+ T cells with HIV-1 coincides with an increase in glycolysis. We investigated the expression of glucose transporters (GLUT) and glycolytic enzymes in human CD4+ T cells in response to infection with HIV-1. We demonstrate the co-expression of GLUT1, GLUT3, GLUT4, and GLUT6 in human CD4+ T cells after activation, and their concerted overexpression in HIV-1 infected cells. The investigation of glycolytic enzymes demonstrated activation-dependent expression of hexokinases HK1 and HK2 in human CD4+ T cells, and a highly significant increase in cellular hexokinase enzyme activity in response to infection with HIV-1...
March 7, 2018: Viruses
Jing Shi, Ran Xiong, Tao Zhou, Peiyi Su, Xihe Zhang, Xusheng Qiu, Hongmei Li, Sunan Li, Changqing Yu, Bin Wang, Chan Ding, Thomas E Smithgall, Yong-Hui Zheng
The primate lentiviral accessory protein Nef downregulates CD4 and MHC-I from the cell surface via independent endosomal trafficking pathways to promote viral pathogenesis. In addition, Nef antagonizes a novel restriction factor, SERINC5 (Ser5), to increase viral infectivity. To explore the molecular mechanism of Ser5 antagonism by Nef, we determined how Nef affects Ser5 expression and intracellular trafficking in comparison with CD4 and MHC-I. We confirm that Nef excludes Ser5 from HIV-1 virions by downregulating its cell surface expression via similar functional motifs required for CD4-downregulation...
March 7, 2018: Journal of Virology
Holger Nef, Jens Wiebe, Niklas Boeder, Oliver Dörr, Timm Bauer, Karl-Eugen Hauptmann, Azeem Latib, Antonio Colombo, Dieter Fischer, Tanja Rudolph, Nicolas Foin, Gert Richardt, Christian Hamm
OBJECTIVES: To date, experience with bioresorbable scaffolds (BRS) that elute agents other than everolimus is limited. Thus, a post-marketing clinical follow-up study was conducted to evaluate the continued safety and effectiveness of the DESolve® NOVOLIMUS™ Eluting BRS as treatment for patients with stable coronary artery disease. BACKGROUND: The DESolve BRS combines a poly-l-lactide-based backbone with a biodegradable polylactide-based polymer and Novolimus, a macrocyclic lactone mTOR inhibitor...
March 6, 2018: Catheterization and Cardiovascular Interventions
Farouk Chrif, Tobias Nef, Kenneth J Hunt
Background: Leg-press machines are widely employed for musculoskeletal conditioning of the lower-limbs and they provide cardiovascular benefits for resistance training in cardiac patients. The aim of this study was to assess the feasibility of a dynamic leg press (DLP) for incremental cardiopulmonary exercise testing (CPET) and to compare the results with those obtained using a cycle ergometer (CE). Methods: Twelve healthy participants aged 27±4 years (mean ± standard deviation) performed incremental cardiopulmonary exercise tests on a DLP and on a CE...
2018: BMC Sports Science, Medicine and Rehabilitation
Brigitte Raynaud-Messina, Lucie Bracq, Maeva Dupont, Shanti Souriant, Shariq M Usmani, Amsha Proag, Karine Pingris, Vanessa Soldan, Christophe Thibault, Florence Capilla, Talal Al Saati, Isabelle Gennero, Pierre Jurdic, Paul Jolicoeur, Jean-Luc Davignon, Thorsten R Mempel, Serge Benichou, Isabelle Maridonneau-Parini, Christel Vérollet
Bone deficits are frequent in HIV-1-infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Charles Coutton, Alexandra S Vargas, Amir Amiri-Yekta, Zine-Eddine Kherraf, Selima Fourati Ben Mustapha, Pauline Le Tanno, Clémentine Wambergue-Legrand, Thomas Karaouzène, Guillaume Martinez, Serge Crouzy, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Valérie Mitchell, Lazhar Halouani, Ouafi Marrakchi, Mounir Makni, Habib Latrous, Mahmoud Kharouf, Jean-François Deleuze, Anne Boland, Sylviane Hennebicq, Véronique Satre, Pierre-Simon Jouk, Nicolas Thierry-Mieg, Beatrice Conne, Denis Dacheux, Nicolas Landrein, Alain Schmitt, Laurence Stouvenel, Patrick Lorès, Elma El Khouri, Serge P Bottari, Julien Fauré, Jean-Philippe Wolf, Karin Pernet-Gallay, Jessica Escoffier, Hamid Gourabi, Derrick R Robinson, Serge Nef, Emmanuel Dulioust, Raoudha Zouari, Mélanie Bonhivers, Aminata Touré, Christophe Arnoult, Pierre F Ray
Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 (n = 6), CFAP43 (n = 10), and CFAP44 (n = 6). CRISPR/Cas9 created homozygous CFAP43/44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results...
February 15, 2018: Nature Communications
Ryan P McNamara, Lindsey M Costantini, T Alix Myers, Blake Schouest, Nicholas J Maness, Jack D Griffith, Blossom A Damania, Andrew G MacLean, Dirk P Dittmer
Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques...
February 6, 2018: MBio
Suisheng Shang, Andreas V Willems, Satendra S Chauhan
Diastereoselective addition of nitromethane to Boc-D-Phe-H in the presence of sodium hydride in diethyl ether/hexane containing 15-crown-5 and subsequent N,O-protection with 2,2-dimethoxypropane gave trans-oxazolidine in a diastereomeric ratio of >16:1. The oxazolidine was easily separated by column chromatography, which after Nef reaction was coupled to H-Leu-OtBu. The 8-step synthesis afforded (-)-bestatin in an overall yield of 24.7% after deprotection and ion exchange.
February 12, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Isabelle Stévant, Yasmine Neirijnck, Christelle Borel, Jessica Escoffier, Lee B Smith, Stylianos E Antonarakis, Emmanouil T Dermitzakis, Serge Nef
The gonad is a unique biological system for studying cell-fate decisions. However, major questions remain regarding the identity of somatic progenitor cells and the transcriptional events driving cell differentiation. Using time-series single-cell RNA sequencing on XY mouse gonads during sex determination, we identified a single population of somatic progenitor cells prior to sex determination. A subset of these progenitors differentiates into Sertoli cells, a process characterized by a highly dynamic genetic program consisting of sequential waves of gene expression...
February 6, 2018: Cell Reports
Suresh Kumar, Ashish Jain, Farzin Farzam, Jingyue Jia, Yuexi Gu, Seong Won Choi, Michal H Mudd, Aurore Claude-Taupin, Michael J Wester, Keith A Lidke, Tor-Erik Rusten, Vojo Deretic
Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM...
February 2, 2018: Journal of Cell Biology
Mousheng Wu, John J Alvarado, Corinne E Augelli-Szafran, Roger G Ptak, Thomas E Smithgall
The HIV-1 Nef accessory protein is essential for viral pathogenicity and AIDS progression. Nef forms complexes with multiple host cell factors to facilitate viral replication and promote immune escape of HIV-infected cells. Previous X-ray crystal structures demonstrate that Nef forms homodimers, the orientation of which are influenced by host cell binding partners. In cell-based fluorescence complementation assays, Nef forms homodimers at the plasma membrane. However, recombinant Nef proteins often exist as monomers in solution, suggesting that membrane interaction may also trigger monomer to dimer transitions...
2018: PloS One
Reshu Saxena, Umesh Kumar Vekariya, Pradeep Kumar, Amit Kumar Tripathi, Jimut Kanti Ghosh, Raj Kamal Tripathi
HIV-1 transmission and spread involves significant host-virus interaction. Possible targets for obstacle of HIV-1 lie at the site of mucosal barriers. Thus a better understanding of how HIV-1 infects target cells at such sites and leads their invasion is required, with prime focus on the host determinants regulating HIV-1 spread. For the viral infectivity and pathogenicity, HIV-1 Nef facilitates immune evasion through protein-protein interactions within host cell. HIV-1 Nef is significant for viral infectivity and pathogenicity...
February 5, 2018: Molecular and Cellular Biochemistry
Yasmine Neirijnck, Pierre Calvel, Karen R Kilcoyne, Françoise Kühne, Isabelle Stévant, Richard J Griffeth, Jean-Luc Pitetti, Silvana A Andric, Meng-Chun Hu, François Pralong, Lee B Smith, Serge Nef
The insulin family of growth factors (insulin, IGF1, and IGF2) are critical in sex determination, adrenal differentiation, and testicular function. Notably, the IGF system has been reported to mediate the proliferation of steroidogenic cells. However, the precise role and contribution of the membrane receptors mediating those effects, namely, insulin receptor (INSR) and type-I insulin-like growth factor receptor (IGF1R), have not, to our knowledge, been investigated. We show here that specific deletion of both Insr and Igf1r in steroidogenic cells in mice leads to severe alterations of adrenocortical and testicular development...
January 24, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Gonzalo Yebra, Dan Frampton, Tiziano Gallo Cassarino, Jade Raffle, Jonathan Hubb, R Bridget Ferns, Laura Waters, C Y William Tong, Zisis Kozlakidis, Andrew Hayward, Paul Kellam, Deenan Pillay, Duncan Clark, Eleni Nastouli, Andrew J Leigh Brown
BACKGROUND & METHODS: The ICONIC project has developed an automated high-throughput pipeline to generate HIV nearly full-length genomes (NFLG, i.e. from gag to nef) from next-generation sequencing (NGS) data. The pipeline was applied to 420 HIV samples collected at University College London Hospitals NHS Trust and Barts Health NHS Trust (London) and sequenced using an Illumina MiSeq at the Wellcome Trust Sanger Institute (Cambridge). Consensus genomes were generated and subtyped using COMET, and unique recombinants were studied with jpHMM and SimPlot...
2018: PloS One
Weiwei Dai, Yoshiko Usami, Yuanfei Wu, Heinrich Göttlinger
We recently identified the multipass transmembrane protein SERINC5 as an antiviral protein that can potently inhibit HIV-1 infectivity and is counteracted by HIV-1 Nef. We now report that the anti-HIV-1 activity, but not the sensitivity to Nef, is conserved among vertebrate SERINC5 proteins. However, a Nef-resistant SERINC5 became Nef sensitive when its intracellular loop 4 (ICL4) was replaced by that of Nef-sensitive human SERINC5. Conversely, human SERINC5 became resistant to Nef when its ICL4 was replaced by that of a Nef-resistant SERINC5...
January 23, 2018: Cell Reports
J Aalders, E Hartman, G Nefs, A Nieuwesteeg, C Hendrieckx, H-J Aanstoot, P Winterdijk, E van Mil, J Speight, F Pouwer
AIMS: To identify the sociodemographic and clinical correlates of fear of hypoglycaemia among parents of children (aged 4-18 years) with Type 1 diabetes and to examine the relationships between parental fear of hypoglycaemia, mindfulness and mindful parenting. METHODS: Sociodemographic, self-reported clinical and psychological data were extracted from the cross-sectional Diabetes MILES Youth - The Netherlands dataset. Questionnaires included the Hypoglycaemia Fear Survey - Parent Worry (parental fear of hypoglycaemia), the Freiburg Mindfulness Inventory - Short version (mindfulness) and the Interpersonal Mindfulness in Parenting Scale (mindful parenting)...
January 31, 2018: Diabetic Medicine: a Journal of the British Diabetic Association
Jia Yao, Xiaoshuang Zhou, Ming Kong, Lu Li, Xin Hua, Yaping Zhao, Shuqing Yu, Yu Chen, Zhongping Duan
BACKGROUND AND OBJECTIVES: Respiratory quotient (RQ) is a good marker of substrate oxidation. Low RQ is fre-quently found in patients with liver cirrhosis and is associated with poor outcome. The purpose of this study was to demonstrate the effects of eating frequency on RQ in patients with cirrhosis. METHODS AND STUDY DESIGN: We performed a randomized controlled trial to assess the effects of eating frequency on RQ in patients with cirrhosis. Seventy patients and 30 healthy controls were enrolled, and patients were further randomized to receive either normal eating frequency (NEF) meals at 08:00, 12:00 and 18:00 h, or high eating frequency (HEF) meals at 08:00, 10:00, 12:00, 15:00, 18:00 and 20:00 h...
2018: Asia Pacific Journal of Clinical Nutrition
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