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https://www.readbyqxmd.com/read/29213119/electrostatic-map-of-proteasome-%C3%AE-rings-encodes-the-design-of-allosteric-porphyrin-based-inhibitors-able-to-affect-20s-conformation-by-cooperative-binding
#1
Antonio Di Dato, Alessandra Cunsolo, Marco Persico, Anna Maria Santoro, Alessandro D'Urso, Danilo Milardi, Roberto Purrello, Manuela Stefanelli, Roberto Paolesse, Grazia R Tundo, Diego Sbardella, Caterina Fattorusso, Massimo Coletta
The importance of allosteric proteasome inhibition in the treatment of cancer is becoming increasingly evident. Motivated by this urgent therapeutic need, we have recently identified cationic porphyrins as a highly versatile class of molecules able to regulate proteasome activity by interfering with gating mechanisms. In the present study, the mapping of electrostatic contacts bridging the regulatory particles with the α-rings of the human 20S proteasome led us to the identification of (meso-tetrakis(4-N-methylphenyl pyridyl)-porphyrin (pTMPyPP4) as a novel non-competitive inhibitor of human 20S proteasome...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212814/structural-basis-for-assembly-of-the-cbf3-kinetochore-complex
#2
Vera Leber, Andrea Nans, Martin R Singleton
Eukaryotic chromosomes contain a specialised region known as the centromere, which forms the platform for kinetochore assembly and microtubule attachment. The centromere is distinguished by the presence of nucleosomes containing the histone H3 variant, CENP-A. In budding yeast, centromere establishment begins with the recognition of a specific DNA sequence by the CBF3 complex. This in turn facilitates CENP-ACse4 nucleosome deposition and kinetochore assembly. Here, we describe a 3.6 Å single-particle cryo-EM reconstruction of the core CBF3 complex, incorporating the sequence-specific DNA-binding protein Cep3 together with regulatory subunits Ctf13 and Skp1...
December 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29208747/proposed-role-for-kaic-like-atpases-as-major-signal-transduction-hubs-in-archaea
#3
Kira S Makarova, Michael Y Galperin, Eugene V Koonin
All organisms must adapt to ever-changing environmental conditions and accordingly have evolved diverse signal transduction systems. In bacteria, the most abundant networks are built around the two-component signal transduction systems that include histidine kinases and receiver domains. In contrast, eukaryotic signal transduction is dominated by serine/threonine/tyrosine protein kinases. Both of these systems are also found in archaea, but they are not as common and diversified as their bacterial and eukaryotic counterparts, suggesting the possibility that archaea have evolved other, still uncharacterized signal transduction networks...
December 5, 2017: MBio
https://www.readbyqxmd.com/read/29204900/molecular-design-for-recombinant-adeno-associated-virus-raav-vector-production
#4
REVIEW
Juan Jose Aponte-Ubillus, Daniel Barajas, Joseph Peltier, Cameron Bardliving, Parviz Shamlou, Daniel Gold
Recombinant adeno-associated virus (rAAV) vectors are increasingly popular tools for gene therapy applications. Their non-pathogenic status, low inflammatory potential, availability of viral serotypes with different tissue tropisms, and prospective long-lasting gene expression are important attributes that make rAAVs safe and efficient therapeutic options. Over the last three decades, several groups have engineered recombinant AAV-producing platforms, yielding high titers of transducing vector particles. Current specific productivity yields from different platforms range from 103 to 105 vector genomes (vg) per cell, and there is an ongoing effort to improve vector yields in order to satisfy high product demands required for clinical trials and future commercialization...
December 4, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29199039/the-coronavirus-nucleocapsid-protein-is-adp-ribosylated
#5
Matthew E Grunewald, Anthony R Fehr, Jeremiah Athmer, Stanley Perlman
ADP-ribosylation is a common post-translational modification, although how it modulates RNA virus infection is not well understood. While screening for ADP-ribosylated proteins during coronavirus (CoV) infection, we detected a ~55kDa ADP-ribosylated protein in mouse hepatitis virus (MHV)-infected cells and in virions, which we identified as the viral nucleocapsid (N) protein. The N proteins of porcine epidemic diarrhea virus (PEDV), severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV were also ADP-ribosylated...
November 30, 2017: Virology
https://www.readbyqxmd.com/read/29193231/using-mri-cell-tracking-to-monitor-immune-cell-recruitment-in-response-to-a-peptide-based-cancer-vaccine
#6
Marie-Laurence Tremblay, Christa Davis, Chris V Bowen, Olivia Stanley, Cathryn Parsons, Genevieve Weir, Mohan Karkada, Marianne M Stanford, Kimberly D Brewer
PURPOSE: MRI cell tracking can be used to monitor immune cells involved in the immunotherapy response, providing insight into the mechanism of action, temporal progression of tumor growth, and individual potency of therapies. To evaluate whether MRI could be used to track immune cell populations in response to immunotherapy, CD8+ cytotoxic T cells, CD4+ CD25+ FoxP3+ regulatory T cells, and myeloid-derived suppressor cells were labeled with superparamagnetic iron oxide particles. METHODS: Superparamagnetic iron oxide-labeled cells were injected into mice (one cell type/mouse) implanted with a human papillomavirus-based cervical cancer model...
November 29, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/29192094/over-production-of-growth-differentiation-factor-15-gdf15-promotes-human-rhinovirus-infection-and-virus-induced-inflammation-in-the-lung
#7
Qun Wu, Di Jiang, Niccolette R Schaefer, Laura Harmacek, Brian P O'Connor, Thomas Eling, Oliver Eickelberg, Hong Wei Chu
Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year-round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. Therefore, in the current study, we investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation...
November 30, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29186624/local-and-systemic-inflammation-may-mediate-diesel-engine-exhaust-induced-lung-function-impairment-in-a-chinese-occupational-cohort
#8
Haitao Wang, Huawei Duan, Tao Meng, Mo Yang, Lianhua Cui, Ping Bin, Yufei Dai, Yong Niu, Meili Shen, Liping Zhang, Yuxin Zheng, Shuguang Leng
Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (e.g., the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (e.g., serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE induced lung function impairment using a unique cohort of diesel engine testers (DET, n = 137) and non-DETs (n = 127), made up of current and non-current smokers...
November 23, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29184623/neutral-sphingomyelinases-control-extracellular-vesicles-budding-from-the-plasma-membrane
#9
Kerstin Menck, Can Sönmezer, Thomas Stefan Worst, Matthias Schulz, Gry Helene Dihazi, Frank Streit, Gerrit Erdmann, Simon Kling, Michael Boutros, Claudia Binder, Julia Christina Gross
Extracellular vesicles (EVs) are membrane particles secreted from cells into all body fluids. Several EV populations exist differing in size and cellular origin. Using differential centrifugation EVs pelleting at 14,000 g ("microvesicles" (MV)) and 100,000 g ("exosomes") are distinguishable by protein markers. Neutral sphingomyelinase (nSMase) inhibition has been shown to inhibit exosome release from cells and has since been used to study their functional implications. How nSMases (also known as SMPD2 and SMPD3) affect the basal secretion of MVs is unclear...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/29180451/molecular-mimicking-of-c-terminal-phosphorylation-tunes-the-surface-dynamics-of-cav1-2-calcium-channels-in-hippocampal-neurons
#10
Alessandra Folci, Angela Steinberger, Boram Lee, Ruslan Stanika, Susanne Scheruebel, Marta Campiglio, Claudia Ramprecht, Brigitte Pelzmann, Johannes W Hell, Gerald J Obermair, Martin Heine, Valentina Di Biase
L-type voltage gated CaV1.2 calcium channels (CaV1.2) are key regulators of neuronal excitability, synaptic plasticity, and excitation-transcription coupling. Surface exposed CaV1.2 distributes in clusters along the dendrites of hippocampal neurons. A permanent exchange between stably clustered and laterally diffusive extra-clustered channels maintains steady-state levels of CaV1.2 at dendritic signaling domains. A dynamic equilibrium between anchored and diffusive receptors is a common feature among ion channels and is crucial to modulate signaling transduction...
November 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29178844/boolfilter-an-r-package-for-estimation-and-identification-of-partially-observed-boolean-dynamical-systems
#11
Levi D Mcclenny, Mahdi Imani, Ulisses M Braga-Neto
BACKGROUND: Gene regulatory networks govern the function of key cellular processes, such as control of the cell cycle, response to stress, DNA repair mechanisms, and more. Boolean networks have been used successfully in modeling gene regulatory networks. In the Boolean network model, the transcriptional state of each gene is represented by 0 (inactive) or 1 (active), and the relationship among genes is represented by logical gates updated at discrete time points. However, the Boolean gene states are never observed directly, but only indirectly and incompletely through noisy measurements based on expression technologies such as cDNA microarrays, RNA-Seq, and cell imaging-based assays...
November 25, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/29175006/predicted-cumulative-dose-to-firefighters-and-the-offsite-public-from-natural-and-anthropogenic-radionuclides-in-smoke-from-wildland-fires-at-the-savannah-river-site-south-carolina-usa
#12
Brian J Viner, Tim Jannik, Allan Hepworth, Olorunfemi Adetona, Luke Naeher, Teresa Eddy, Eric Doman, John Blake
The contaminated ground surface at Savannah River Site (SRS) is a result of the decades of work that has been performed maintaining the country's nuclear stockpile and performing research and development on nuclear materials. The volatilization of radionuclides during wildfire results in airborne particles that are dispersed within the smoke plume and may result in doses to downwind firefighters and the public. To better understand the risk that these smoke plumes present, we have characterized four regions at SRS in terms of their fuel characteristics and radiological contamination on the ground...
November 21, 2017: Journal of Environmental Radioactivity
https://www.readbyqxmd.com/read/29162052/chloroplast-petd-protein-evidence-for-srp-alb3-dependent-insertion-into-the-thylakoid-membrane
#13
Jarosław Króliczewski, Rafał Bartoszewski, Bożena Króliczewska
BACKGROUND: In thylakoid membrane, each monomer of the dimeric complex of cytochrome b 6 f is comprised of eight subunits that are both nucleus- and plastid-encoded. Proper cytochrome b 6 f complex integration into the thylakoid membrane requires numerous regulatory factors for coordinated transport, insertion and assembly of the subunits. Although, the chloroplast-encoded cytochrome b 6 f subunit IV (PetD) consists of three transmembrane helices, the signal and the mechanism of protein integration into the thylakoid membrane have not been identified...
November 21, 2017: BMC Plant Biology
https://www.readbyqxmd.com/read/29149742/stability-of-heavy-metals-in-soil-washing-residue-with-and-without-biochar-addition-under-accelerated-ageing
#14
Zhengtao Shen, Deyi Hou, Bin Zhao, Wendi Xu, Yong Sik Ok, Nanthi S Bolan, Daniel S Alessi
Soil washing residue (SWR), which typically concentrates the washed toxic metals and is comprised of high contents of clay particles, may pose risks to the surrounding environment. This study aims to simulate accelerated ageing to assess the stability of selected metals (Cd(2+) (132mg/kg), Cu(2+) (248mg/kg) and Pb(2+) (3470mg/kg)) in a SWR (89.68% of clay) with and without biochar treatment. The soil was incubated under constant moisture and wet-dry cycles (accelerated ageing), respectively, and the mobility and fractions of heavy metals in the soils with and without biochar treatment were examined...
November 14, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/29148731/conjugation-of-transforming-growth-factor-beta-to-antigen-loaded-poly-lactide-co-glycolide-nanoparticles-enhances-efficiency-of-antigen-specific-tolerance
#15
Liam M Casey, Ryan M Pearson, Kevin Hughes, Jeffrey Liu, Justin Rose, Madeleine G North, Leon Wang, Lei Mei, Stephen D Miller, Lonnie D Shea
Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide-co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen(Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that co-delivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-β), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction...
November 17, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29145996/-comparative-profile-of-the-use-of-filter-needles-in-quebec-and-france-in-healthcare-facility
#16
L Painchart, P Odou, J-F Bussières
OBJECTIVES: The manipulation of drugs from glass ampules can generate particles when the ampule is broken. Several authors recommend the use of filter needle to withdraw the drug content. The main objective is to establish an inventory of the use of filter needles and the perception of pharmacists in Quebec and in France. METHODS: This is a cross-sectional descriptive study. A questionnaire was sent to all health facilities in Quebec (n=30) and a selection of hospitals in France (n=100)...
November 13, 2017: Annales Pharmaceutiques Françaises
https://www.readbyqxmd.com/read/29141908/two-distinct-regulatory-mechanisms-of-transcriptional-initiation-in-response-to-nutrient-signaling
#17
Jannatul Ferdoush, Rwik Sen, Amala Kaja, Priyanka Barman, Sukesh R Bhaumik
SAGA (Spt-Ada-Gcn5-Acetyltransferase) and TFIID (transcription factor IID) have been previously shown to facilitate the PIC (pre-initiation complex) formation at the promoters of two distinct sets of genes. Here, we demonstrate that TFIID and SAGA differentially participate in stimulation of the PIC formation (and hence transcriptional initiation) at the promoter of PHO84, a gene for high affinity inorganic phosphate (Pi) transporter for crucial cellular functions, in response to nutrient signaling. We show that transcriptional initiation of PHO84 occurs predominantly in the TFIID-dependent manner in the absence of Pi in the growth medium...
November 15, 2017: Genetics
https://www.readbyqxmd.com/read/29138400/accessibility-of-the-histone-h3-tail-in-the-nucleosome-for-binding-of-paired-readers
#18
Jovylyn Gatchalian, Xiaodong Wang, Jinzen Ikebe, Khan L Cox, Adam H Tencer, Yi Zhang, Nathaniel L Burge, Luo Di, Matthew D Gibson, Catherine A Musselman, Michael G Poirier, Hidetoshi Kono, Jeffrey J Hayes, Tatiana G Kutateladze
Combinatorial polyvalent contacts of histone-binding domains or readers commonly mediate localization and activities of chromatin-associated proteins. A pair of readers, the PHD fingers of the protein CHD4, has been shown to bivalently recognize histone H3 tails. Here we describe a mechanism by which these linked but independent readers bind to the intact nucleosome core particle (NCP). Comprehensive NMR, chemical reactivity, molecular dynamics, and fluorescence analyses point to the critical roles of intra-nucleosomal histone-DNA interactions that reduce the accessibility of H3 tails in NCP, the nucleosomal DNA, and the linker between readers in modulating nucleosome- and/or histone-binding activities of the readers...
November 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29128752/the-roles-of-five-conserved-lentiviral-rna-structures-in-hiv-1-replication
#19
Yang Liu, Jianbo Chen, Olga A Nikolaitchik, Belete A Desimmie, Steven Busan, Vinay K Pathak, Kevin M Weeks, Wei-Shau Hu
The HIV-1 RNA genome contains complex structures with many structural elements playing regulatory roles during viral replication. A recent study has identified multiple RNA structures with unknown functions that are conserved among HIV-1 and two simian immunodeficiency viruses. To explore the roles of these conserved RNA structures, we introduced synonymous mutations into the HIV-1 genome to disrupt each structure. These mutants exhibited similar particle production, viral infectivity, and replication kinetics relative to the parent NL4-3 virus...
November 9, 2017: Virology
https://www.readbyqxmd.com/read/29109089/the-trappiii-complex-activates-the-gtpase-ypt1-rab1-in-the-secretory-pathway
#20
Laura L Thomas, Aaron M N Joiner, J Christopher Fromme
Rab GTPases serve as molecular switches to regulate eukaryotic membrane trafficking pathways. The transport protein particle (TRAPP) complexes activate Rab GTPases by catalyzing GDP/GTP nucleotide exchange. In mammalian cells, there are two distinct TRAPP complexes, yet in budding yeast, four distinct TRAPP complexes have been reported. The apparent differences between the compositions of yeast and mammalian TRAPP complexes have prevented a clear understanding of the specific functions of TRAPP complexes in all cell types...
November 6, 2017: Journal of Cell Biology
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