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Mediator And Complex

Andrey Anikin, N Johansson
We report a series of 22 experiments in which the implicit associations test (IAT) was used to investigate cross-modal correspondences between visual (luminance, hue [R-G, B-Y], saturation) and acoustic (loudness, pitch, formants [F1, F2], spectral centroid, trill) dimensions. Colors were sampled from the perceptually accurate CIE-Lab space, and the complex, vowel-like sounds were created with a formant synthesizer capable of separately manipulating individual acoustic properties. In line with previous reports, the loudness and pitch of acoustic stimuli were associated with both luminance and saturation of the presented colors...
December 13, 2018: Attention, Perception & Psychophysics
Mingyan Huang, Huamin Wang, Xiang Hu, Xuetao Cao
Hepatocellular carcinoma (HCC) is one type of cancers whose carcinogenesis and progression are closely related to chronic inflammation. Identifying the molecular mechanisms for inflammation-related HCC progression will contribute to improve the efficacy of current therapeutics for HCC patients. Many kinds of epigenetic factors, including long non-coding RNAs (lncRNAs), have been discovered to be important in HCC growth and metastasis. However, how the lncRNAs promote HCC progression and what's the application of lncRNA silencing in vivo in suppressing HCC remain to be further investigated...
2019: Oncoimmunology
Joanna Walkowska, Thomas Kallemose, Göran Jönsson, Mats Jönsson, Ove Andersen, Mads Hald Andersen, Inge Marie Svane, Anne Langkilde, Mef Nilbert, Christina Therkildsen
Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors...
2019: Oncoimmunology
Antje Beling, Meike Kespohl
Viral myocarditis is an inflammation of the heart muscle triggered by direct virus-induced cytolysis and immune response mechanisms with most severe consequences during early childhood. Acute and long-term manifestation of damaged heart tissue and disturbances of cardiac performance involve virus-triggered adverse activation of the immune response and both immunopathology, as well as, autoimmunity account for such immune-destructive processes. It is a matter of ongoing debate to what extent subclinical virus infection contributes to the debilitating sequela of the acute disease...
2018: Frontiers in Immunology
Cesare Orlandi, Laurie P Sutton, Brian S Muntean, Chenghui Song, Kirill A Martemyanov
Affective disorders arise from abnormal responses of the brain to prolonged exposure to challenging environmental stimuli. Recent work identified the orphan receptor GPR158 as a molecular link between chronic stress and depression. Here we reveal a non-canonical mechanism by which GPR158 exerts its effects on stress-induced depression by the complex formation with Regulator of G protein Signaling 7 (RGS7). Chronic stress promotes membrane recruitment of RGS7 via GPR158 in the medial prefrontal cortex (mPFC)...
October 11, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Josie Libertucci, Vincent B Young
The human body is colonized by a diverse community of microorganisms collectively referred to as the microbiota. Here, we describe how the human microbiota influences susceptibility to infectious diseases using examples from the respiratory, gastrointestinal and female reproductive tract. We will discuss how interactions between the host, the indigenous microbiota and non-native microorganisms, including bacteria, viruses and fungi, can alter the outcome of infections. This Review Article will highlight the complex mechanisms by which the microbiota mediates colonization resistance, both directly and indirectly, against infectious agents...
January 2019: Nature Microbiology
Mark Z Kos, Jubao Duan, Alan R Sanders, Lucy Blondell, Eugene I Drigalenko, Melanie A Carless, Pablo V Gejman, Harald H H Göring
The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology...
December 13, 2018: Translational Psychiatry
Benny Zhitomirsky, Anna Yunaev, Roman Kreiserman, Ariel Kaplan, Michal Stark, Yehuda G Assaraf
Transcription factor EB (TFEB) is a master transcriptional regulator playing a key role in lysosomal biogenesis, autophagy and lysosomal exocytosis. TFEB activity is inhibited following its phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) on the surface of the lysosome. Phosphorylated TFEB is bound by 14-3-3 proteins, resulting in its cytoplasmic retention in an inactive state. It was suggested that the calcium-dependent phosphatase calcineurin is responsible for dephosphorylation and subsequent activation of TFEB under conditions of lysosomal stress...
December 13, 2018: Cell Death & Disease
Linh T Vuong, Carlo Iomini, Sophie Balmer, Davide Esposito, Stuart A Aaronson, Marek Mlodzik
Wnt/Wg-signalling is critical signalling in all metazoans. Recent studies suggest that IFT-A proteins and Kinesin-2 modulate canonical Wnt/Wg-signalling independently of their ciliary role. Whether they function together in Wnt-signalling and their mechanistic role in the pathway remained unresolved. Here we demonstrate that Kinesin-2 and IFT-A proteins act as a complex during Drosophila Wg-signalling, affecting pathway activity in the same manner, interacting genetically and physically, and co-localizing with β-catenin, the mediator of Wnt/Wg-signalling on microtubules...
December 13, 2018: Nature Communications
Sameer B Shah, David Parmiter, Christian Constantine, Paul Elizalde, Michael Naldrett, Tatiana S Karpova, John S Choy
The Dam1 complex is an essential component of the outer kinetochore that mediates attachments between spindle microtubules and chromosomes. Dam1p, a subunit of the Dam1 complex, binds to microtubules and is regulated by Aurora B/Ipl1p phosphorylation. We find that overexpression of cAMP-dependent protein kinase (PKA) catalytic subunits (i.e. TPK1 , TPK2 , TPK3 ) is lethal in DAM1 mutants and increases the rate of chromosome loss in wild-type cells. Replacing an evolutionarily conserved PKA site (S31) in Dam1p with a non-phosphorylatable alanine suppressed the high copy PKA dosage lethality in dam1-1 Consistent with Dam1p as a target of PKA we find that in vitro PKA can directly phosphorylate S31 in Dam1p and we observed phosphorylation of S31 in Dam1p purified from asynchronously growing yeast cells...
December 13, 2018: Genetics
Marco Fazzari, Dario A Vitturi, Steven R Woodcock, Sonia R Salvatore, Bruce A Freeman, Francisco J Schopfer
Electrophilic nitro-fatty acids (NO2-FA) showed beneficial signaling actions in preclinical studies, and safety in Phase 1 clinical trials. Detailed understanding of the pharmacokinetics (PK) of NO2-FA is complicated by the capability of electrophilic fatty acids to alkylate thiols reversibly, become esterified in various complex lipids, and the instability of the nitroalkene moiety during enzymatic and base hydrolysis. Herein, we report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously-detectable and prototypical NO2-FA 10-nitro-oleic acid (10-NO2-OA) in dogs after oral administration...
December 13, 2018: Journal of Lipid Research
Jing Zhi Anson Tan, Paul A Gleeson
Amyloid precursor protein (APP) is processed along the amyloidogenic pathway by the β-secretase, BACE1, generating amyloid-β (Aβ), or along the non-amyloidogenic pathway by α-secretase, precluding Aβ production. The plasma membrane is considered the major site for α-secretase-mediated APP cleavage, but other cellular locations have not been rigorously investigated. Here, we report that APP is processed by endogenous α-secretase at the trans -Golgi network (TGN) of both transfected HeLa cells and mouse primary neurons...
December 13, 2018: Journal of Biological Chemistry
Lin Yuan, Samuel J Kenny, Juliet Hemmati, Ke Xu, Randy Schekman
Large coat protein complex II (COPII)-coated vesicles serve to convey the large cargo procollagen I (PC1) from the endoplasmic reticulum (ER). The link between large cargo in the lumen of the ER and modulation of the COPII machinery remains unresolved. TANGO1 is required for PC secretion and interacts with PC and COPII on opposite sides of the ER membrane, but evidence suggests that TANGO1 is retained in the ER, and not included in normal size (<100 nm) COPII vesicles. Here we show that TANGO1 is exported out of the ER in large COPII-coated PC1 carriers, and retrieved back to the ER by the retrograde coat, COPI, mediated by the C-terminal RDEL retrieval sequence of HSP47...
December 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Tomohiro Uemura, Ryohei Thomas Nakano, Junpei Takagi, Yiming Wang, Katharina Kramer, Iris Finkemeier, Hirofumi Nakagami, Kenichi Tsuda, Takashi Ueda, Paul Schulze-Lefert, Akihiko Nakano
Spatiotemporal coordination of protein trafficking between organelles is essential for eukaryotic cells, and the post-Golgi interface, including the trans-Golgi network (TGN), is a pivotal hub for multiple trafficking pathways. The Golgi-released independent TGN (GI-TGN) is a compartment described only in plant cells, and its cellular and physiological roles remain elusive. In Arabidopsis thaliana, the SYP4 group Qa-SNARE (soluble N-ethyl-maleimide sensitive factor attachment protein receptor) membrane fusion proteins are shared components of TGN and GI-TGN and regulate secretory and vacuolar transport...
December 13, 2018: Plant Physiology
Logan Kistler, S Yoshi Maezumi, Jonas Gregorio de Souza, Natalia A S Przelomska, Flaviane Malaquias Costa, Oliver Smith, Hope Loiselle, Jazmín Ramos-Madrigal, Nathan Wales, Eduardo Rivail Ribeiro, Ryan R Morrison, Claudia Grimaldo, Andre P Prous, Bernardo Arriaza, M Thomas P Gilbert, Fabio de Oliveira Freitas, Robin G Allaby
Domesticated maize evolved from wild teosinte under human influences in Mexico beginning around 9000 years before the present (yr B.P.), traversed Central America by ~7500 yr B.P., and spread into South America by ~6500 yr B.P. Landrace and archaeological maize genomes from South America suggest that the ancestral population to South American maize was brought out of the domestication center in Mexico and became isolated from the wild teosinte gene pool before traits of domesticated maize were fixed. Deeply structured lineages then evolved within South America out of this partially domesticated progenitor population...
December 14, 2018: Science
Samuel Itskanov, Eunyong Park
The Sec61 protein-conducting channel mediates transport of many proteins, such as secretory proteins, across the endoplasmic reticulum (ER) membrane during or after translation. Posttranslational transport is enabled by two additional membrane proteins associated with the channel, Sec63 and Sec62, but its mechanism is poorly understood. We determined a structure of the Sec complex (Sec61-Sec63-Sec71-Sec72) from Saccharomyces cerevisiae by cryo-electron microscopy (cryo-EM). The structure shows that Sec63 tightly associates with Sec61 though interactions in cytosolic, transmembrane, and ER-luminal domains, prying open Sec61's lateral gate and translocation pore and thus activating the channel for substrate engagement...
December 13, 2018: Science
Mohamad-Reza Aghanoori, Darrell R Smith, Shiva Shariati-Ievari, Andrew Ajisebutu, Annee Nguyen, Fiona Desmond, Carlos H A Jesus, Xiajun Zhou, Nigel A Calcutt, Michel Aliani, Paul Fernyhough
OBJECTIVE: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN...
November 28, 2018: Molecular Metabolism
Yutao Yan, Lei Chang, Hongzhe Tian, Lu Wang, Yawei Zhang, Tao Yang, Guohao Li, Weifeng Hu, Kavita Shah, Gang Chen, Yonglian Guo
BACKGROUND: Tumor cell mediated immune-suppression remains a question of interest in tumor biology. In this study, we focused on the metabolites that are released by prostate cancer cells (PCC), which could potentially attenuate T cell immunity. METHODS: Prostate cancer cells (PCC) media (PCM) was used to treat T cells, and its impact on T cell signaling was evaluated. The molecular mechanism was further verified in vivo using mouse models. The clinical significance was determined using IHC in human clinical specimens...
December 13, 2018: Journal for Immunotherapy of Cancer
Bernhard Englinger, Sebastian Kallus, Julia Senkiv, Anna Laemmerer, Patrick Moser, Lisa Gabler, Diana Groza, Christian R Kowol, Petra Heffeter, Michael Grusch, Walter Berger
Knowledge of intracellular pharmacokinetics of anticancer agents is imperative for understanding drug efficacy as well as intrinsic and acquired cellular resistance mechanisms. However, the factors driving subcellular drug distribution are complex and poorly understood. Here, we describe for the first time the intrinsic fluorescence properties of the fibroblast growth factor receptor inhibitor PD1703074 as well as utilization of this physicochemical feature to investigate intracellular accumulation and compartmentalization of this compound in human lung cancer cells...
December 8, 2018: Cells
Can Wang, Zhuo Ma, Dong-Ying Yan, Chang Liu, Yu Deng, Wei Liu, Zhao-Fa Xu, Bin Xu
Synaptic vesicle fusion is mediated by an assembly of soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs), composed of syntaxin 1, soluble NSF-attachment protein (SNAP)-25, and synaptobrevin-2/VAMP-2. Previous studies have suggested that over-exposure to manganese (Mn) could disrupt synaptic vesicle fusion by influencing SNARE complex formation, both in vitro and in vivo. However, the mechanisms underlying this effect remain unclear. Here we employed calpeptin, an inhibitor of calpains, along with a lentivirus vector containing alpha-synuclein (α-Syn) shRNA, to examine whether specific SNAP-25 cleavage and the over-expression of α-Syn disturbed the formation of the SNARE complex in SH-SY5Y cells...
December 8, 2018: Cells
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