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https://www.readbyqxmd.com/read/28324594/polymers-in-the-delivery-of-sirna-for-the-treatment-of-virus-infections
#1
REVIEW
Nicholas Reynolds, Megan Dearnley, Tracey M Hinton
Viral diseases remain a major cause of death worldwide. Despite advances in vaccine and antiviral drug technology, each year over three million people die from a range of viral infections. Predominant viruses include human immunodeficiency virus, hepatitis viruses, and gastrointestinal and respiratory viruses. Now more than ever, robust, easily mobilised and cost-effective antiviral strategies are needed to combat both known and emerging disease threats. RNA interference and small interfering (si)RNAs were initially hailed as a "magic bullet", due to their ability to inhibit the synthesis of any protein via the degradation of its complementary messenger RNA sequence...
April 2017: Topics in Current Chemistry (Journal)
https://www.readbyqxmd.com/read/28324111/arap1-deficiency-causes-photoreceptor-degeneration-in-mice
#2
Ala Moshiri, Devin Humpal, Brian C Leonard, Denise M Imai, Addy Tham, Lynette Bower, Dave Clary, Thomas M Glaser, K C Kent Lloyd, Christopher J Murphy
Purpose: Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). Arap1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Methods: Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28323636/ultrasmall-water-dispersible-tween80-modified-yb-er-nagd-wo-sub-4-sub-sub-2-sub-nanoparticles-with-record-upconversion-ratiometric-thermal-sensitivity-and-their-internalization-by-mesenchymal-stem-cells
#3
Concepcion Cascales, Carlos Paino, Eulalia Bazán, Carlos Zaldo
This work presents the synthesis by coprecipitation of diamond shaped Yb:Er:NaGd(WO<sub>4</sub>)<sub>2</sub> crystalline nanoparticles (NPs) with diagonal dimensions in the 5-7 nm × 10-12 nm range which have been modified with TWEEN80 for their dispersion in water, and their interaction with mesenchymal stem cells (MSCs) proposed as cellular NP vehicles. These NPs belong to a large family of tetragonal Yb:Er:NaT(XO<sub>4</sub>)<sub>2</sub> (T=Y, La, Gd, Lu; X= Mo, W) compounds with green (<sup>2</sup>H<sub>11/2</sub>+<sup>4</sup>S<sub>3/2</sub>→<sup>4</sup>I<sub>15/2</sub>) Er-related upconversion (UC) efficiency comparable to that of Yb:Er:β-NaYF<sub>4</sub> reference compound, but with a ratiometric thermal sensitivity (S) 2...
March 21, 2017: Nanotechnology
https://www.readbyqxmd.com/read/28323513/transmembrane-tnf-dependent-uptake-of-anti-tnf-antibodies
#4
Arun Deora, Subramanya Hegde, Jacqueline Lee, Chee-Ho Choi, Qing Chang, Cheryl Lee, Lucia Eaton, Hua Tang, Dongdong Wang, David Lee, Mark Michalak, Medha Tomlinson, Qingfeng Tao, Nidhi Gaur, Bohdan Harvey, Shaun McLoughlin, Boris Labkovsky, Tariq Ghayur
TNF-alpha (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-alpha converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with two distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biological effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases...
March 21, 2017: MAbs
https://www.readbyqxmd.com/read/28319098/irap-endosomes-restrict-tlr9-activation-and-signaling
#5
Joel Babdor, Delphyne Descamps, Aimé Cézaire Adiko, Mira Tohmé, Sophia Maschalidi, Irini Evnouchidou, Luiz Ricardo Vasconcellos, Mariacristina De Luca, Francois-Xavier Mauvais, Meriem Garfa-Traore, Melanie M Brinkmann, Michel Chignard, Bénédicte Manoury, Loredana Saveanu
The retention of intracellular Toll-like receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal-lysosomal compartments. Here we identified IRAP(+) endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand, the dinucleotide CpG, were present as cargo in IRAP(+) endosomes. In the absence of the aminopeptidase IRAP, the trafficking of CpG and TLR9 to lysosomes and signaling via TLR9 were enhanced in DCs and in mice following bacterial infection...
March 20, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28318354/hs1bp3-inhibits-autophagy-by-regulation-of-pld1
#6
Kristiane Søreng, Helene Knævelsrud, Petter Holland, Anne Simonsen
Macroautophagy/autophagy is a membrane trafficking and intracellular degradation process involving the formation of double-membrane autophagosomes and their ultimate fusion with lysosomes. Much is yet to be learned about the regulation of this process, especially at the level of the membranes and lipids involved. We have recently found that the PX domain protein HS1BP3 (HCLS1 binding protein 3) is a negative regulator of autophagosome formation. HS1BP3 depletion increases the formation of LC3-positive autophagosomes both in human cells and zebrafish...
February 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28317932/bacterial-secretion-system-skews-the-fate-of-legionella-containing-vacuoles-towards-lc3-associated-phagocytosis
#7
Andree Hubber, Tomoko Kubori, Cevayir Coban, Takeshi Matsuzawa, Michinaga Ogawa, Tsuyoshi Kawabata, Tamotsu Yoshimori, Hiroki Nagai
The evolutionarily conserved processes of endosome-lysosome maturation and macroautophagy are established mechanisms that limit survival of intracellular bacteria. Similarly, another emerging mechanism is LC3-associated phagocytosis (LAP). Here we report that an intracellular vacuolar pathogen, Legionella dumoffii, is specifically targeted by LAP over classical endocytic maturation and macroautophagy pathways. Upon infection, the majority of L. dumoffii resides in ER-like vacuoles and replicate within this niche, which involves inhibition of classical endosomal maturation...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317021/the-bloc-1-subunit-pallidin-facilitates-activity-dependent-synaptic-vesicle-recycling
#8
Xun Chen, Wenpei Ma, Shixing Zhang, Jeremy Paluch, Wanlin Guo, Dion K Dickman
Membrane trafficking pathways must be exquisitely coordinated at synaptic terminals to maintain functionality, particularly during conditions of high activity. We have generated null mutations in the Drosophila homolog of pallidin, a central subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), to determine its role in synaptic development and physiology. We find that Pallidin localizes to presynaptic microtubules and cytoskeletal structures, and that the stability of Pallidin protein is highly dependent on the BLOC-1 components Dysbindin and Blos1...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28315462/implications-of-cerebrovascular-atp-binding-cassette-transporter-g1-abcg1-and-apolipoprotein-m-in-cholesterol-transport-at-the-blood-brain-barrier
#9
Alexandra Carmen Kober, Anil Paul Chirackal Manavalan, Carmen Tam-Amersdorfer, Andreas Holmér, Ahmed Saeed, Elham Fanaee Danesh, Martina Zandl, Nicole Maria Albrecher, Ingemar Björkhem, Gerhard M Kostner, Björn Dahlbäck, Ute Panzenboeck
Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28302910/new-insights-into-autophagosome-lysosome-fusion
#10
REVIEW
Shuhei Nakamura, Tamotsu Yoshimori
Macroautophagy (autophagy) is a highly conserved intracellular degradation system that is essential for homeostasis in eukaryotic cells. Due to the wide variety of the cytoplasmic targets of autophagy, its dysregulation is associated with many diseases in humans, such as neurodegenerative diseases, heart disease and cancer. During autophagy, cytoplasmic materials are sequestered by the autophagosome - a double-membraned structure - and transported to the lysosome for digestion. The specific stages of autophagy are induction, formation of the isolation membrane (phagophore), formation and maturation of the autophagosome and, finally, fusion with a late endosome or lysosome...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28302665/calpain-mobilizes-atg9-bif-1-vesicles-from-golgi-stacks-upon-autophagy-induction-by-thapsigargin
#11
Elena Marcassa, Marzia Raimondi, Tahira Anwar, Eeva-Liisa Eskelinen, Michael P Myers, Gianluca Triolo, Claudio Schneider, Francesca Demarchi
CAPNS1 is essential for stability and function of the ubiquitous calcium dependent proteases micro- and milli-calpain. Upon the inhibition of the endoplasmic reticulum Ca2+ ATPase by 100nM thapsigargin, both micro-calpain and autophagy are activated in human U2OS osteosarcoma cells in a CAPNS1 dependent manner. As reported for other autophagy triggers, thapsigargin treatment induces Golgi fragmentation and fusion of Atg9/Bif-1 containing vesicles with LC3 bodies in control cells. On the opposite, CAPNS1 depletion is coupled to an accumulation of LC3 bodies and Rab5 early endosomes...
March 16, 2017: Biology Open
https://www.readbyqxmd.com/read/28302654/palmitate-induced-vacuolar-type-h-atpase-inhibition-feeds-forward-into-insulin-resistance-and-contractile-dysfunction
#12
Yilin Liu, Laura K M Steinbusch, Miranda Nabben, Dimitris Kapsokalyvas, Marc van Zandvoort, Patrick Schönleitner, Gudrun Antoons, Peter J Simons, Will A Coumans, Amber Geomini, Dipanjan Chanda, Jan F C Glatz, Dietbert Neumann, Joost J F P Luiken
Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the sarcolemma as primary mechanism of excessive myocellular lipid import. Here, we show that increased CD36 translocation is caused by alkalinization of endosomes due to inhibition of proton pumping activity of vacuolar-type H(+)-ATPase (v-ATPase). Endosomal alkalinization was observed in hearts from rats fed a lard-based high fat-diet and in rodent and human cardiomyocytes upon palmitate overexposure, and appeared as early lipid-induced event preceding the onset of insulin resistance...
March 16, 2017: Diabetes
https://www.readbyqxmd.com/read/28301372/news-on-the-molecular-regulation-and-function-of-hepatic-low-density-lipoprotein-receptor-and-ldlr-related-protein-1
#13
Bart van de Sluis, Melinde Wijers, Joachim Herz
PURPOSE OF REVIEW: Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. RECENT FINDINGS: Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface...
March 15, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28300561/nucleolin-is-a-nuclear-target-of-heparan-sulfate-derived-from-glypican-1
#14
Fang Cheng, Mattias Belting, Lars-Åke Fransson, Katrin Mani
The recycling, S-nitrosylated heparan sulfate (HS) proteoglycan glypican-1 releases anhydromannose (anMan)-containing HS chains by a nitrosothiol-catalyzed cleavage in endosomes that can be constitutive or induced by ascorbate. The HS-anMan chains are then transported to the nucleus. A specific nuclear target for HS-anMan has not been identified. We have monitored endosome-to-nucleus trafficking of HS-anMan by deconvolution and confocal immunofluorescence microscopy using an anMan-specific monoclonal antibody in non-growing, ascorbate-treated, and growing, untreated, wild-type mouse embryonic fibroblasts and hypoxia-exposed Alzheimer mouse Tg2576 fibroblasts and human U87 glioblastoma cells...
March 12, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28300075/a-human-antibody-against-zika-virus-crosslinks-the-e-protein-to-prevent-infection
#15
S Saif Hasan, Andrew Miller, Gopal Sapparapu, Estefania Fernandez, Thomas Klose, Feng Long, Andrei Fokine, Jason C Porta, Wen Jiang, Michael S Diamond, James E Crowe, Richard J Kuhn, Michael G Rossmann
The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117...
March 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28300057/combined-toll-like-receptor-3-7-9-deficiency-on-host-cells-results-in-t-cell-dependent-control-of-tumour-growth
#16
Johanna C Klein, Katrin Moses, Gennadiy Zelinskyy, Simon Sody, Jan Buer, Stephan Lang, Iris Helfrich, Ulf Dittmer, Carsten J Kirschning, Sven Brandau
Toll-like receptors (TLRs) are located either on the cell surface or intracellularly in endosomes and their activation normally contributes to the induction of protective immune responses. However, in cancer their activation by endogenous ligands can modulate tumour progression. It is currently unknown how endosomal TLRs regulate endogenous anti-tumour immunity. Here we show that TLR3, 7 and 9 deficiencies on host cells, after initial tumour growth, result in complete tumour regression and induction of anti-tumour immunity...
March 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28299779/the-related-neuronal-endosomal-proteins-neep21-nsg1-and-p19-nsg2-have-divergent-expression-profiles-in-vivo
#17
Kelly Barford, Chan Choo Yap, Noelle D Dwyer, Bettina Winckler
Endosomal maturation and transport constitutes a complex trafficking system present in all cell types. Neurons have adapted their endosomal system to meet their unique and complex needs. These adaptations include repurposing existing proteins to diversify endocytosis and trafficking, as well as preferential expression of certain regulators more highly in neurons than other cell types. These neuronal regulators include the family of Neuron-Specific Gene family members (Nsg), NEEP21 (Nsg1), and P19 (Nsg2). NEEP21/Nsg1 plays a role in the trafficking of multiple receptors, including the cell adhesion molecule L1/NgCAM, the neurotransmitter receptor GluA2, and β-APP...
March 15, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28299521/dynamic-of-contribution-of-ubpy-sorted-cargo-to-acrosome-biogenesis-effects-of-its-derailment-in-a-mouse-model-of-globozoospermia-the-infertile-vps54-l967q-mutant
#18
Mariarosa Gioria, Maria Enrica Pasini, Giovanna Berruti
The sperm acrosome is a specialized vacuole, a member of the family of cell-specific lysosome-related organelles. Its exocytosis, the acrosome reaction, is a crucial event during fertilization. The released acrosomal contents promote sperm penetration through the investments of the oocyte, whereas the membranous components of the acrosome are involved in sperm-oocyte interaction/fusion and oocyte activation. The way that these functionally distinct acrosomal costituents reach the vacuole during its biogenesis remains poorly understood...
March 15, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28299505/changes-in-membrane-lipids-drive-increased-endocytosis-following-fas-ligation
#19
Mauro Degli Esposti, Paola Matarrese, Antonella Tinari, Agostina Longo, Serena Recalchi, Roya Khosravi-Far, Walter Malorni, Roberta Misasi, Tina Garofalo, Maurizio Sorice
Once activated, some surface receptors promote membrane movements that open new portals of endocytosis, in part to facilitate the internalization of their activated complexes. The prototypic death receptor Fas (CD95/Apo1) promotes a wave of enhanced endocytosis that induces a transient intermixing of endosomes with mitochondria in cells that require mitochondria to amplify death signaling. This initiates a global alteration in membrane traffic that originates from changes in key membrane lipids occurring in the endoplasmic reticulum (ER)...
March 15, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28298598/proteolytic-cleavage-of-bovine-adenovirus-3-encoded-pviii
#20
Amit Gaba, Lisanework Ayalew, Niraj Makadiya, Suresh Tikoo
Proteolytic maturation involving cleavage of one non-structural and six structural precursor proteins including pVIII by adenovirus protease is an important aspect of adenovirus life cycle. The pVIII encoded by BAdV-3 is a protein of 216 amino acids, which contains two potential protease cleavage sites. Here, we report that BAdV-3 pVIII is cleaved by adenovirus protease at both potential consensus protease cleavage sites. Usage of at least one cleavage site appears essential for the production of progeny BAdV-3 virions as glycine to alanine mutation of both protease cleavage sites appears lethal for the production of progeny virions...
March 15, 2017: Journal of Virology
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