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Kendra A Turk-Kubo, Paige Connell, David Caron, Mary E Hogan, Hanna M Farnelid, Jonathan P Zehr
Major advances in understanding the diversity, distribution, and activity of marine N2 -fixing microorganisms (diazotrophs) have been made in the past decades, however, large gaps in knowledge remain about the environmental controls on growth and mortality rates. In order to measure diazotroph net growth rates and microzooplankton grazing rates on diazotrophs, nutrient perturbation experiments and dilution grazing experiments were conducted using free-floating in situ incubation arrays in the vicinity of Station ALOHA in March 2016...
2018: Frontiers in Microbiology
Jesse H Erasmus, Amit P Khandhar, Jeff Guderian, Brian Granger, Jacob Archer, Michelle Archer, Emily Gage, Jasmine Fuerte-Stone, Elise Larson, Susan Lin, Ryan Kramer, Rhea N Coler, Christopher B Fox, Dan T Stinchcomb, Steven G Reed, Neal Van Hoeven
Since the first demonstration of in vivo gene expression from an injected RNA molecule almost two decades ago,1 the field of RNA-based therapeutics is now taking significant strides, with many cancer and infectious disease targets entering clinical trials.2 Critical to this success has been advances in the knowledge and application of delivery formulations. Currently, various lipid nanoparticle (LNP) platforms are at the forefront,3 but the encapsulation approach underpinning LNP formulations offsets the synthetic and rapid-response nature of RNA vaccines...
August 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sam Chen, Josh Zaifman, Jayesh A Kulkarni, Igor V Zhigaltsev, Ying K Tam, Marco A Ciufolini, Yuen Yi C Tam, Pieter R Cullis
Lipid nanoparticles (LNPs) are playing a leading role in enabling clinical applications of gene therapies based on DNA or RNA polymers. One factor impeding clinical acceptance of LNP therapeutics is that LNP formulations of nucleic acid polymers can be immunostimulatory, necessitating co-administration of potent corticosteroid immunosuppressive agents. Here, we describe the development of hydrophobic prodrugs of a potent corticosteroid, dexamethasone, that can be readily incorporated into LNP systems. We show that the presence of the dexamethasone prodrug LD003 effectively suppresses production of cytokines such as KC-GRO, TNFα, IL-1β and IL-6 following intravenous administration of LNP loaded with immune stimulatory oligodeoxynucleotides containing cytosine-guanine dinucleotide motifs...
July 17, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Kalina Paunovska, Carmen J Gil, Melissa P Lokugamage, Cory D Sago, Manaka Sato, Gwyn N Lando, Marielena Gamboa Castro, Anton V Bryksin, James E Dahlman
Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs-which can be structurally similar to LDL and VLDL-would alter nanoparticle targeting in vivo. To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR-/- , and VLDLR-/- mice that were both age-matched and female...
July 20, 2018: ACS Nano
Haruko Ueda, Natsumi Ohta, Yoshitaka Kimori, Teruka Uchida, Tomoo Shimada, Kentaro Tamura, Ikuko Hara-Nishimura
The endoplasmic reticulum (ER) is a large network made of the membranous cisternae and tubules, which accounts for a large proportion of the total lipid-bilayer endomembrane of the cell. In mammals and yeast, Lunapark proteins are preferentially localized at the three-way junctions of the ER network, stabilizing the junctions and establishing the ER architecture. We identified two Arabidopsis homologues and designated them LNPA and LNPB. Subcellular localization analysis with a non-dimerizable type of GFP revealed that both LNPA and LNPB are predominantly distributed throughout the ER, but not preferentially localized at the three-way junctions...
July 14, 2018: Plant & Cell Physiology
Yueping Jiang, Wen Zi, Zhifang Pei, Shao Liu
Two novel polysaccharides, Plumula nelumbinis (P. nelumbinis) polysaccharide I (LNP I) and P. nelumbinis polysaccharide II (LNP II), were extracted and purified from P. nelumbinis , and a sulfated polysaccharide, P. nelumbinis polysaccharide III (LNP III), with a substitution degree of 0.62 was prepared from LNPI. The structures of the LNPs were preliminarily characterized using high performance size exclusion chromatography (HPSEC), gas chromatography-mass spectrometry (GC-MS), Fourier transformed infrared spectrometry (FT-IR), and nuclear magnetic resonance (NMR) spectrometry...
July 2018: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Piotr S Kowalski, Umberto Capasso Palmiero, Yuxuan Huang, Arnab Rudra, Robert Langer, Daniel G Anderson
The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI...
July 5, 2018: Advanced Materials
Jian Zhang, Joseph R Lakowicz
Background: Near-field fluorescence (NFF) effects were employed to develop a novel near-infrared (NIR) luminescent nanoparticle (LNP) with superior brightness. The LNP is used as imaging contrast agent for cellular and small animal imaging and furthermore suggested to use for detecting voltage-sensitive calcium in living cells and animals with high sensitivity. Results: NIR Indocyanine green (ICG) dye was conjugated with human serum albumin (HSA) followed by covalently binding to gold nanorod (AuNR)...
2018: Cell & Bioscience
Ann E Almazar, Joseph Y Chang, Joseph J Larson, Elizabeth J Atkinson, G Richard Locke, Nicholas J Talley, Yuri A Saito
GOALS: To evaluate agreement of MCM6-13910 with self-report of dairy sensitivity (DS) and lactose hydrogen methane breath test (LHMBT) results in subjects with irritable bowel syndrome (IBS). BACKGROUND: IBS is a functional gastrointestinal disorder with symptoms including abdominal pain, variable bowel habits, and bloating. Adult patients with lactose malabsorption may present with similar symptoms. Patients with lactose malabsorption have a lactase nonpersistent (LNP) phenotype...
June 16, 2018: Journal of Clinical Gastroenterology
Ema Robinson, Kelvin D MacDonald, Kai Slaughter, Madison McKinney, Siddharth Patel, Conroy Sun, Gaurav Sahay
The promise of gene therapy for the treatment of cystic fibrosis has yet to be fully clinically realized despite years of effort toward correcting the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR). mRNA therapy via nanoparticle delivery represents a powerful technology for the transfer of genetic material to cells with large, widespread populations, such as airway epithelia. We deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and rescue of its primary function as a chloride channel...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
D K Nishad, H S Rawat, T Singh, A Bhatnagar, G Mittal
INTRODUCTION: This study examined the decorporation potential of lansoprazole (LNP) as radioactivity decorporation agent for radiothallium (201 Tl) in internally contaminated BALB/c mice and New Zealand White rabbits using radiometry and gamma scintigraphy. METHODS: Animals were divided into three groups, that is, control, pretreatment-1 (1X LNP), and pretreatment-2 (2X LNP). Mice received LNP intraperitoneally, while in rabbits LNP was given through oral route 0...
January 1, 2018: Human & Experimental Toxicology
Naftali R Smith, Baruch Meerson
We determine the exact short-time distribution -lnP_{f}(H,t)=S_{f}(H)/sqrt[t] of the one-point height H=h(x=0,t) of an evolving 1+1 Kardar-Parisi-Zhang (KPZ) interface for flat initial condition. This is achieved by combining (i) the optimal fluctuation method, (ii) a time-reversal symmetry of the KPZ equation in 1+1 dimension, and (iii) the recently determined exact short-time height distribution -lnP_{st}(H,t)=S_{st}(H)/sqrt[t] for stationary initial condition. In studying the large-deviation function S_{st}(H) of the latter, one encounters two branches: an analytic and a nonanalytic...
May 2018: Physical Review. E
Kristian Alsbjerg Skipper, Mathias Gaarde Nielsen, Sofie Andersen, Laura Barrett Ryø, Rasmus O Bak, Jacob Giehm Mikkelsen
Continuous innovation of revolutionizing genome engineering technologies calls for an intensified focus on new delivery technologies that not only match the inventiveness of genome editors but also enable the combination of potent delivery and time-restricted action of genome-modifying bits and tools. We have previously demonstrated the use of lentivirus-derived nanoparticles (LNPs) as a protein delivery vehicle, incorporating and transferring DNA transposases, designer nucleases, or RNA-guided endonucleases fused to the N terminus of the Gag/GagPol polypeptide...
June 1, 2018: Molecular Therapy. Nucleic Acids
Verena Kriechbaumer, Emily Breeze, Charlotte Pain, Frances Tolmie, Lorenzo Frigerio, Chris Hawes
The plant endoplasmic reticulum (ER) is crucial to the maintenance of cellular homeostasis. The ER consists of a dynamic and continuously remodelling network of tubules and cisternae. Several conserved membrane proteins have been implicated in formation and maintenance of the ER network in plants, such as RHD3 and the reticulon proteins. Despite the recent work in mammalian and yeast cells, the detailed molecular mechanisms of ER network organization in plants remain largely unknown. Recently, novel ER network-shaping proteins called Lunapark (LNP) have been identified in yeast and mammalian cells...
August 2018: New Phytologist
Franziska G Leifer, Donna M Konicek, Kuan-Ju Chen, Adam J Plaunt, Dany Salvail, Charles E Laurent, Michel R Corboz, Zhili Li, Richard W Chapman, Walter R Perkins, Vladimir S Malinin
Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]...
May 23, 2018: Drug Research
Naftali R Smith, Alex Kamenev, Baruch Meerson
We study the short-time distribution P(H,L,t) of the two-point two-time height difference H=h(L,t)-h(0,0) of a stationary Kardar-Parisi-Zhang interface in 1+1 dimension. Employing the optimal-fluctuation method, we develop an effective Landau theory for the second-order dynamical phase transition found previously for L=0 at a critical value H=H_{c}. We show that |H| and L play the roles of inverse temperature and external magnetic field, respectively. In particular, we find a first-order dynamical phase transition when L changes sign, at supercritical H...
April 2018: Physical Review. E
Norbert Pardi, Michael J Hogan, Martin S Naradikian, Kaela Parkhouse, Derek W Cain, Letitia Jones, M Anthony Moody, Hans P Verkerke, Arpita Myles, Elinor Willis, Celia C LaBranche, David C Montefiori, Jenna L Lobby, Kevin O Saunders, Hua-Xin Liao, Bette T Korber, Laura L Sutherland, Richard M Scearce, Peter T Hraber, István Tombácz, Hiromi Muramatsu, Houping Ni, Daniel A Balikov, Charles Li, Barbara L Mui, Ying K Tam, Florian Krammer, Katalin Karikó, Patricia Polacino, Laurence C Eisenlohr, Thomas D Madden, Michael J Hope, Mark G Lewis, Kelly K Lee, Shiu-Lok Hu, Scott E Hensley, Michael P Cancro, Barton F Haynes, Drew Weissman
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates...
June 4, 2018: Journal of Experimental Medicine
Alida F Hasiniaina, Marina Scheumann, Mamy Rina Evasoa, Diane Braud, Solofonirina Rasoloharijaona, Blanchard Randrianambinina, Elke Zimmermann
The critically endangered Claire's mouse lemur, only found in the evergreen rain forest of the National Park Lokobe (LNP) and a few lowland evergreen rain forest fragments of northern Madagascar, was described recently. The present study provides the first quantified information on vocal acoustics of calls, sound associated behavioral context, acoustic niche, and vocal activity of this species. We recorded vocal and social behavior of six male-female and six male-male dyads in a standardized social-encounter paradigm in June and July 2016 at the LNP, Nosy Bé island...
June 2018: American Journal of Primatology
Rebecca L Ball, Khalid A Hajj, Jamie Vizelman, Palak Bajaj, Kathryn A Whitehead
Although mRNA and siRNA have significant therapeutic potential, their simultaneous delivery has not been previously explored. To facilitate the treatment of diseases associated with aberrant gene upregulation and downregulation, we sought to co-formulate siRNA and mRNA in a single lipidoid nanoparticle (LNP) formulation. We accommodated the distinct molecular characteristics of mRNA and siRNA in a formulation consisting of an ionizable and biodegradable amine-containing lipidoid, cholesterol, DSPC, DOPE, and PEG-lipid...
June 13, 2018: Nano Letters
Yasunori Uemura, Tomoyuki Naoi, Yasumasa Kanai, Katsuya Kobayashi
Small interfering of RNA (siRNA) technology has the potential to be a next-generation therapy. However, naked siRNA does not have high transfection efficiency and is rapidly degraded after systemic injection, so an appropriate drug delivery system (DDS) is required for clinical use. Several potential systems have been assessed, clinically focusing on hepatocyte or cancer tissue using siRNA. However, targeting immune cells using siRNA is still challenging, and a new DDS is required. In this study, we prepared lipid nanoparticles (LNP) composed of original cationic lipid, neutral lipid of DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and PEG2000-DMPE (N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, sodium salt)...
May 8, 2018: Pharmaceutical Development and Technology
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