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Xin Zhou, Yu He, Xiaofang Huang, Yuting Guo, Dong Li, Junjie Hu
Three-way junctions are characteristic structures of the tubular endoplasmic reticulum (ER) network. Junctions are formed through atlastin (ATL)-mediated membrane fusion and stabilized by lunapark (Lnp). However, how Lnp is preferentially enriched at three-way junctions remains elusive. Here, we showed that Lnp loses its junction localization when ATLs are deleted. Reintroduction of ATL1 R77A and ATL3, which have been shown to cluster at the junctions, but not wild-type ATL1, relocates Lnp to the junctions...
November 29, 2018: Protein & Cell
Puneet Tyagi, Sergei Pechenov, Jonathan RiosDoria, Luke Masterson, Niall J Dickinson, Philip Howard, Shenlan Mao, Jay Harper, Leslie Wetzel, Kwok Yo, J Anand Subramony
We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly(DL-lactide-co-glycolide) (PLGA) and lipid (LNP) nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug...
November 22, 2018: Journal of Pharmaceutical Sciences
Ian Lai, Srividya Swaminathan, Virginie Baylot, Adriane Mosley, Renumathy Dhanasekaran, Meital Gabay, Dean W Felsher
Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity...
November 20, 2018: Journal for Immunotherapy of Cancer
Songyu Wang, Robert E Powers, Vicki Am Gold, Tom A Rapoport
Lunapark (Lnp) is a conserved membrane protein that localizes to and stabilizes three-way junctions of the tubular ER network. In higher eukaryotes, phosphorylation of Lnp may contribute to the conversion of the ER from tubules to sheets during mitosis. Here, we report on the reconstitution of purified Lnp with phospholipids. Surprisingly, Lnp induces the formation of stacked membrane discs. Each disc is a bicelle, with Lnp sitting in the bilayer facing both directions. The interaction between bicelles is mediated by the cytosolic domains of Lnp, resulting in a constant distance between the discs...
January 2018: Life science alliance
Xin Ye, Chise Tateno, Emily P Thi, Masakazu Kakuni, Nicholas M Snead, Yuji Ishida, Trisha R Barnard, Michael J Sofia, Takashi Shimada, Amy C H Lee
Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice...
November 20, 2018: ACS Infectious Diseases
Claire Desfrançois, Rachel Auzély, Isabelle Texier
Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in the last twenty years. However, for some of them (especially dermal, transdermal, mucosal), the LNP aqueous dispersions display unsuitable rheological properties. They therefore need to be processed as semi-solid formulations such as LNP-hydrogel composites to turn into versatile drug delivery systems able to provide precise spatial and temporal control of active ingredient release...
November 1, 2018: Pharmaceuticals
Drew M P Peltier, Kiona Ogle
While we often assume tree growth-climate relationships are time-invariant, impacts of climate phenomena such as the El Niño Southern Oscillation (ENSO) and the North American Monsoon (NAM) may challenge this assumption. To test this assumption, we grouped ring-widths (1900-present) in three southwestern US conifers into La Niña periods (LNP) and other years (OY). The four years following each La Niña year are included in LNP, and despite 1-2 year growth declines, compensatory adjustments in tree growth responses result in essentially equal mean growth in LNP and OY, as average growth exceeds OY means 2-4 years after La Niña events...
October 22, 2018: Global Change Biology
Hamideh Parhiz, Vladimir V Shuvaev, Norbert Pardi, Makan Khoshnejad, Raisa Yu Kiseleva, Jacob S Brenner, Thomas Uhler, Steven Tuyishime, Barbara L Mui, Ying K Tam, Thomas D Madden, Michael J Hope, Drew Weissman, Vladimir R Muzykantov
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts...
December 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Patrick N Lawlor, Matthew G Perich, Lee E Miller, Konrad P Kording
Prominent models of spike trains assume only one source of variability - stochastic (Poisson) spiking - when stimuli and behavior are fixed. However, spike trains may also reflect variability due to internal processes such as planning. For example, we can plan a movement at one point in time and execute it at some arbitrary later time. Neurons involved in planning may thus share an underlying time course that is not precisely locked to the actual movement. Here we combine the standard Linear-Nonlinear-Poisson (LNP) model with Dynamic Time Warping (DTW) to account for shared temporal variability...
October 8, 2018: Journal of Computational Neuroscience
Pablo Hervella, Johan Hygum Dam, Helge Thisgaard, Christina Baun, Birgitte Brinkmann Olsen, Poul Flemming Høilund-Carlsen, David Needham
BACKGROUND AND MOTIVATION: While small molecules can be used in cancer diagnosis there is a need for imageable diagnostic NanoParticles (NPs) that act as surrogates for the therapeutic NPs. Many NPs are composed of hydrophobic materials so the challenge is to formulate hydrophobic imaging agents. To develop individualized medical treatments based on NP, a first step should be the selection of patients who are likely responders to the treatment as judged by imaging tumor accumulation of NPs...
December 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Harvinder Saggi, Dhiman Maitra, An Jiang, Rong Zhang, Pengcheng Wang, Pamela Cornuet, Sucha Singh, Joseph Locker, Xiaochao Ma, Harry Dailey, Marc Abrams, M Bishr Omary, Satdarshan P Monga, Kari Nejak-Bowen
BACKGROUND & AIMS: Porphyrias occur from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet, which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury...
October 1, 2018: Journal of Hepatology
Mika H Sipponen, Heiko Lange, Mariko Ago, Claudia Crestini
The mechanism of lignin nanoprecipitation and subsequent self-assembly was elucidated by studying generation of lignin nanoparticles (LNPs) from aqueous ethanol. LNP formation was found to follow a kinetically controlled nucleation-growth mechanism in which large lignin molecules formed the initial critical nuclei. Using this information, we demonstrate entrapment of budesonide in LNPs and subsequent pH-triggered and surfactant-responsive release of this synthetic anti-inflammatory corticosteroid. Overall, our results not only provide a promising intestinal delivery system for budesonide but also deliver fundamental mechanistic understanding for the entrapment of actives in LNPs with controlled size and release properties...
July 2, 2018: ACS Sustainable Chemistry & Engineering
Zhiyu He, Yizong Hu, Tianqi Nie, Haoyu Tang, Jinchang Zhu, Kuntao Chen, Lixin Liu, Kam W Leong, Yongming Chen, Hai-Quan Mao
Lipid-based nanoparticles (LNPs) have been developed to address the transport and uptake barriers to enhance the delivery efficiency of plasmid DNA therapeutics. In these systems, plasmid DNA can be encapsulated through condensation by a cationic lipid to form lipo-complexes, or polycation following complexation into cationic liposomes to form lipo-polyplexes. Conventional methods for achieving these two DNA-delivering LNP vehicles suffer from significant batch-to-batch variation, poor scalability and complicated multi-step preparation procedures...
September 27, 2018: Acta Biomaterialia
Cory D Sago, Melissa P Lokugamage, Gwyneth N Lando, Naima Djeddar, Nirav N Shah, Chris Syed, Anton V Bryksin, James E Dahlman
Nanoparticles are often targeted to receptors expressed on specific cells, but few receptors are (i) highly expressed on one cell type and (ii) involved in endocytosis. One unexplored alternative is manipulating an endocytic gene expressed on multiple cell types; an ideal gene would inhibit delivery to cell type A more than cell type B, promoting delivery to cell type B. This would require a commonly expressed endocytic gene to alter nanoparticle delivery in a cell type-dependent manner in vivo; whether this can occur is unknown...
September 20, 2018: Nano Letters
Minori Kawai, Takashi Nakamura, Naoya Miura, Mio Maeta, Hiroki Tanaka, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Kota Tange, Yuta Nakai, Hiroki Yoshioka, Hideyoshi Harashima, Hidetaka Akita
Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE)...
November 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
Kyuri Lee, Bora Jang, You-Ri Lee, Eun-Young Suh, Ji-Seon Yoo, Mi-Jin Lee, Joo-Young Lee, Hyukjin Lee
siRNA therapeutics allows precise regulation of disease specific gene expression to treat various diseases. Although gene silencing approaches using siRNA therapeutics shows some promising results in the treatment of gene-related diseases, the practical applications has been limited by problems such as inefficient in vivo delivery to target cells and nonspecific immune responses after systemic or local administration. To overcome these issues, various in vivo delivery platforms have been introduced. Here we provide an overview for three different platform technologies for the in vivo delivery of therapeutic siRNAs (siRNA-GalNAc conjugate, SAMiRNA technology, and LNP-based delivery method) and their applications in the treatment of various diseases...
September 2018: Archives of Pharmacal Research
Owen S Fenton, Kevin J Kauffman, Rebecca L McClellan, James C Kaczmarek, Manhao D Zeng, Jason L Andresen, Luke H Rhym, Michael W Heartlein, Frank DeRosa, Daniel G Anderson
RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs...
October 8, 2018: Angewandte Chemie
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...
October 3, 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...
September 28, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
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