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Jessy J Alexander, Jeyantt S Sankaran, Kenneth L Seldeen, Ramkumar Thiyagarajan, Alexander Jacob, Richard J Quigg, Bruce R Troen, Stefan Judex
Complement system is an important arm of the immune system that promotes inflammation. Complement Factor H (FH) is a critical regulator of the alternative complement pathway. Its absence causes pathology in different organs resulting in diseases such as age related macular degeneration and dense deposit disease. Recent studies suggest that the complement system plays a role in bone development and homeostasis. To determine the role of FH in bone architecture, we studied the FH knockout (fh-/-) mice. 3D reconstructions of femur from 16 week old fh-/- mice reveal significant changes, such as decreased BV/TV (4...
August 1, 2018: Immunobiology
Kelly A Jenkins, Martin J Fossat, Siwen Zhang, Durgesh K Rai, Sean Klein, Richard Gillilan, Zackary White, Grayson Gerlich, Scott A McCallum, Roland Winter, Sol M Gruner, Doug Barrick, Catherine A Royer
The effect of introducing internal cavities on protein native structure and global stability has been well documented, but the consequences of these packing defects on folding free-energy landscapes have received less attention. We investigated the effects of cavity creation on the folding landscape of the leucine-rich repeat protein pp32 by high-pressure (HP) and urea-dependent NMR and high-pressure small-angle X-ray scattering (HPSAXS). Despite a modest global energetic perturbation, cavity creation in the N-terminal capping motif (N-cap) resulted in very strong deviation from two-state unfolding behavior...
August 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J Winton
The intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage...
July 27, 2018: Cell Stem Cell
Vasila A Sulaymonova, Margret C Fuchs, Richard Gloaguen, Robert Möckel, Silke Merchel, Martin Rudolph, Matthias R Krbetschek
Cosmogenic nuclide (CN) dating relies on specific target minerals such as quartz as markers to identify geologic events, including the timing of landscape evolution. The presence of feldspar in sediment samples poses a challenge to the separation of quartz and affects the chemical procedures for extracting the radioactive CNs 10 Be and 26 Al. Additionally, feldspar contamination reduces the 26 Al/27 Al ratio, thus hinders the accurate determination of 26 Al by accelerator mass spectrometry (AMS). Using fluvial sediment samples from Central Asia, which contain 16-50 weight percent (wt...
2018: MethodsX
Edward B Garon, Jill M Siegfried, Laura P Stabile, Patricia A Young, Diana C Marquez-Garban, David J Park, Ravi Patel, Eddie H Hu, Saeed Sadeghi, Rupesh J Parikh, Karen L Reckamp, Brad Adams, Robert M Elashoff, David Elashoff, Tristan Grogan, He-Jing Wang, Sanja Dacic, Meghan Brennan, Yacgley Valdes, Simon Davenport, Steven M Dubinett, Michael F Press, Dennis J Slamon, Richard J Pietras
OBJECTIVES: This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily...
September 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Magda Bahcall, Mark M Awad, Lynette M Sholl, Frederick H Wilson, Man Xu, Stephen Wang, Sangeetha Palakurthi, Jihyun Choi, Elena Ivanova, Giulia C Leonardi, Bryan C Ulrich, Cloud P Paweletz, Paul T Kirschmeier, Masayuki Watanabe, Hideo Baba, Mizuki Nishino, Rebecca J Nagy, Richard B Lanman, Marzia Capelletti, Emily S Chambers, Amanda J Redig, Paul A VanderLaan, Daniel B Costa, Yu Imamura, Pasi A Janne
PURPOSE: MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14 mutant NSCLC and propose a combination therapy to target it. EXPERIMENTAL DESIGN: The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14 mutant patient tumor with massive focal amplification of WT KRAS...
August 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jessica L Kostick-Dunn, Jerilyn R Izac, John C Freedman, Lee T Szkotnicki, Lee D Oliver, Richard T Marconi
Cyclic-di-GMP (c-di-GMP) contributes to the regulation of processes required by the Lyme disease (LD) spirochetes to complete the tick-mammal enzootic cycle. Our understanding of the effector mechanisms of c-di-GMP in the Borrelia is evolving. While most LD spirochete isolates encode a single PilZ domain containing c-di-GMP receptor designated as PlzA, genome analyses have revealed that a subset encode a second PilZ domain protein (PlzB). The c-di-GMP binding potential of PlzB, and its role in LD spirochete biology, have not been investigated...
2018: Frontiers in Cellular and Infection Microbiology
Seok-Ho Yu, Peng Zhao, Pradeep K Prabhakar, Tiantian Sun, Aaron Beedle, Geert-Jan Boons, Kelley W Moremen, Lance Wells, Richard Steet
Deficiency in subunits of the conserved oligomeric Golgi (COG) complex results in pleiotropic defects in glycosylation and cause congenital disorders in humans. Insight regarding the functional consequences of this defective glycosylation and the identity of specific glycoproteins affected are lacking. A chemical glycobiology strategy was adopted to identify surface glycoproteins most sensitive to altered glycosylation in COG-deficient CHO cells. Following metabolic labeling, an unexpected increase in GalNAz incorporation into several glycoproteins, including alpha-dystroglycan (α-DG), was noted in cog1 -deficient ldlB cells...
July 26, 2018: Journal of Biological Chemistry
Bharadwaja S T Peddinti, Frank Scholle, Reza A Ghiladi, Richard J Spontak
To combat the global threat posed by surface-adhering pathogens that are becoming increasingly drug-resistant, we explore the anti-infective efficacy of bulk thermoplastic elastomer films containing ∼1 wt % zinc-tetra(4- N-methylpyridyl)porphine (ZnTMPyP4+ ), a photoactive antimicrobial that utilizes visible light to generate singlet oxygen. This photodynamic polymer is capable of inactivating five bacterial strains and two viruses with at least 99.89% and 99.95% success, respectively, after exposure to noncoherent light for 60 min...
August 8, 2018: ACS Applied Materials & Interfaces
Cindy C Shu, Margaret M Smith, Richard C Appleyard, Christopher B Little, James Melrose
The aim of this study was to determine the role of the perlecan (Hspg2) heparan sulphate (HS) side chains on cell and matrix homeostasis in tail and Achilles tendons in 3 and 12 week old Hspg2 exon 3 null HS deficient ( Hspg2 Δ3 - ∕Δ3 - ) and C57 BL/6 Wild Type (WT) mice. Perlecan has important cell regulatory and matrix organizational properties through HS mediated interactions with a range of growth factors and morphogens and with structural extracellular matrix glycoproteins which define tissue function and allow the resident cells to regulate tissue homeostasis...
2018: PeerJ
Maryam Rahmati Ishka, Elizabeth Brown, Chrystle Weigand, Richard L Tillett, Karen A Schlauch, Gad Miller, Jeffrey F Harper
BACKGROUND: In flowering plants, the male gametophyte (pollen) is one of the most vulnerable cells to temperature stress. In Arabidopsis thaliana, a pollen-specific Cyclic Nucleotide-Gated cation Channel 16 (cngc16), is required for plant reproduction under temperature-stress conditions. Plants harboring a cncg16 knockout are nearly sterile under conditions of hot days and cold nights. To understand the underlying cause, RNA-Seq was used to compare the pollen transcriptomes of wild type (WT) and cngc16 under normal and heat stress (HS) conditions...
July 24, 2018: BMC Genomics
Justyna Lisowska, Claudia Jasmin Rödel, Sandra Manet, Yekaterina A Miroshnikova, Cyril Boyault, Emmanuelle Planus, Richard De Mets, Hsiao-Hui Lee, Olivier Destaing, Hichem Mertani, Gwénola Boulday, Elisabeth Tournier-Lasserve, Martial Balland, Salim Abdelilah-Seyfried, Corinne Albiges-Rizo, Eva Faurobert
Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This cross-talk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in CCM genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. Our study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium...
July 20, 2018: Journal of Cell Science
Pradeep Kota, Martina Gentzsch, Yan L Dang, Richard C Boucher, M Jackson Stutts
Epithelial Na+ channels comprise three homologous subunits (α, β, and γ) that are regulated by alternative splicing and proteolytic cleavage. Here, we determine the basis of the reduced Na+ current (INa ) that results from expression of a previously identified, naturally occurring splice variant of the α subunit (α-ENaC), in which residues 34-82 are deleted (αΔ34-82 ). αΔ34-82 -ENaC expression with WT β and γ subunits in Xenopus oocytes produces reduced basal INa , which can largely be recovered by exogenous trypsin...
July 6, 2018: Journal of General Physiology
David Tyssen, Ying-Ying Wang, Joshua A Hayward, Paul A Agius, Kevin DeLong, Muriel Aldunate, Jacques Ravel, Thomas R Moench, Richard A Cone, Gilda Tachedjian
Women of reproductive age with a Lactobacillus- dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. While lactic acid has potent HIV virucidal activity in vitro , whether lactic acid present in the vaginal lumen inactivates HIV has not been investigated. Here we evaluated the anti-HIV-1 activity of native, minimally diluted cervicovaginal fluid obtained from women of reproductive age ( n = 20) with vaginal microbiota dominated by Lactobacillus spp...
July 5, 2018: MSphere
Alan J Weaver, Tami R Peters, Brian Tripet, Abigail Van Vuren, Rakesh, Richard E Lee, Valérie Copié, Martin Teintze
This study investigated resistance against trishexylaminomelamine trisphenylguanide (THAM-3ΦG), a novel antibacterial compound with selective microbicidal activity against Staphylococcus aureus. Resistance development was examined by culturing methicillin resistant S. aureus (MRSA) with sub-lethal doses of THAM-3ΦG. This quickly resulted in the formation of normal (WT) and small colonies (SC) of S. aureus exhibiting minimal inhibitory concentrations (MICs) 2× and 4× greater than the original MIC. Continuous cell passaging with increasing concentrations of THAM-3ΦG resulted in an exclusively SC phenotype with MIC >64 mg/L...
June 29, 2018: Scientific Reports
Antoine G Sreih, Rana Ezzedine, Lin Leng, Juan Fan, Jie Yao, Duncan Reid, Marta Piecychna, Simon Carette, David Cuthbertson, Paul Dellaripa, Gary S Hoffman, Nader A Khalidi, Curry L Koening, Carol A Langford, Alfred Mahr, Carol A McAlear, Kathleen Maksimowicz-Mckinnon, Paul A Monach, Philip Seo, Ulrich Specks, William St Clair, John H Stone, Steven R Ytterberg, Jeffrey Edberg, Peter A Merkel, Richard Bucala
OBJECTIVE: This study examined the association between Macrophage Migration Inhibitory Factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA), and MIF's role in a murine model of granulomatous vasculitis. METHODS: The human study involved 1077 patients with GPA and controls. Genotyping for the MIF -794 CATT5-8 promoter microsatellite (rs5844572) was performed by capillary electrophoresis. MIF promoter CATT-length dependent expression in response to β-glucan was assessed by gene reporter assays...
June 28, 2018: Arthritis & Rheumatology
William J Fitzsimmons, Robert J Woods, John T McCrone, Andrew Woodman, Jamie J Arnold, Madhumita Yennawar, Richard Evans, Craig E Cameron, Adam S Lauring
Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations...
June 2018: PLoS Biology
Pengfei Cheng, Qingwei Zhou, Xianbiao Hu, Shaoqiang Su, Xin Wang, Mingliang Jin, Lingling Shui, Xingsen Gao, Yanqing Guan, Richard Nözel, Guofu Zhou, Zhang Zhang, Junming Liu
Water disinfection is of great importance for human health and daily life. Photocatalysts with high efficiency, environmental protection, and narrow bandgaps are critical for practical water treatment. Here, a general approach is reported for the direct growth of pyramid-type MoS2 (pyramid MoS2 ) on transparent glass by chemical vapor deposition (CVD). The pyramid MoS2 exhibits a smaller bandgap and higher bactericidal activity than most TiO2 -based photocatalysts. The adjustable-bandgap nature of two-dimensional (2-D) MoS2 can harvest a wide spectrum of sunlight and provide more active sites with which to generate reactive oxygen species (ROS) for bacterial death in water...
July 18, 2018: ACS Applied Materials & Interfaces
Alice E Kane, Sooyoun Shin, Aimee A Wong, Emre Fertan, Natalia S Faustova, Susan E Howlett, Richard E Brown
Mouse models of Alzheimer's disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits...
2018: Frontiers in Aging Neuroscience
Jane A Lindborg, Jon P Niemi, Madeline A Howarth, Kevin W Liu, Christian Z Moore, Deepti Mahajan, Richard E Zigmond
BACKGROUND: Neuroinflammation accompanies neural trauma and most neurological diseases. Axotomy in the peripheral nervous system (PNS) leads to dramatic changes in the injured neuron: the cell body expresses a distinct set of genes known as regeneration-associated genes, the distal axonal segment degenerates and its debris is cleared, and the axons in the proximal segment form growth cones and extend neurites. These processes are orchestrated in part by immune and other non-neuronal cells...
June 26, 2018: Journal of Neuroinflammation
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