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Mediator And Complex

Erika L Pearson, Joel H Graber, Susan D Lee, Kristoph S Naggert, Claire L Moore
The yeast protein Ipa1 was recently discovered to interact with the Ysh1 endonuclease of the pre-mRNA cleavage and polyadenylation (C/P) machinery, and Ipa1 mutation impairs 3'end processing. We report that Ipa1 globally promotes proper transcription termination and poly(A) site selection, but with variable effects on genes depending upon the specific configurations of polyadenylation signals. Our findings suggest that the role of Ipa1 in termination is mediated through interaction with Ysh1, since Ipa1 mutation leads to decrease in Ysh1 and poor recruitment of the C/P complex to a transcribed gene...
February 12, 2019: Cell Reports
Kyoko Shimamoto, Jessica D Gipson
Maternal and newborn mortality remain unacceptably high in sub-Saharan Africa where use of a skilled birth attendant (SBA) at delivery has remained low. Despite the recognized importance of women's empowerment as a key determinant of maternal and newborn health, evidence from sub-Saharan Africa is more limited. Using data from the 2010 Tanzania Demographic and Health Survey (n = 4,340), this study employs a robust method-structural equation modeling (SEM)-to investigate the complex and multidimensional pathways through which women's empowerment affects SBA use...
2019: PloS One
Yunbo Ke, Pratap Karki, Chenou Zhang, Yue Li, Trang Nguyen, Konstantin G Birukov, Anna A Birukova
Mechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)-induced endothelial (EC) barrier dysfunction. However, cellular mechanotransduction complexes remain to be characterized. This study tested a hypothesis that recovery of vascular EC barrier after pathologic mechanical stress may be accelerated by cell exposure to physiologic CS levels and involves Rap1-dependent rearrangement of endothelial cell junctions...
February 13, 2019: Molecular Biology of the Cell
Curic Stjepan, Leicht Gregor, Thiebes Stephanie, Andreou Christina, Polomac Nenad, Eichler Iris-Carola, Eichler Lars, Zöllner Christian, Gallinat Jürgen, Steinmann Saskia, Mulert Christoph
Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior...
February 6, 2019: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Xue Yuan Pei, Tom Dendooven, Elisabeth Sonnleitner, Shaoxia Chen, Udo Blasi, Ben F Luisi
In diverse bacterial species, the global regulator Hfq contributes to post-transcriptional networks that control expression of numerous genes. Hfq of the opportunistic pathogen Pseudomonas aeruginosa inhibits translation of target transcripts by forming a regulatory complex with the catabolite repression protein Crc. This repressive complex acts part of an intricate mechanism of preferred nutrient utilisation. We describe high-resolution cryo-EM structures of the assembly of Hfq and Crc bound to the translation initiation site of a target mRNA...
February 13, 2019: ELife
Elizabeth G Gibson, Ben Bax, Pan F Chan, Neil Osheroff
Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential...
February 13, 2019: ACS Infectious Diseases
Xiangying Mao, Jeong Im Kim, Mitchell T Wheeler, Anne K Heintzelman, Vikki M Weake, Clint Chapple
The Mediator complex functions as a hub for transcriptional regulation. MED5, an Arabidopsis Mediator tail subunit, is required for maintaining phenylpropanoid homeostasis. A semi-dominant mutation (ref4-3) that causes a single amino acid substitution in MED5b functions as a strong suppressor of the pathway, leading to decreased soluble phenylpropanoid accumulation, reduced lignin content and dwarfism. By contrast, loss of MED5 results in increased levels of phenylpropanoids. We used a reverse genetic approach to identify suppressors of ref4-3 and found that ref4-3 requires CDK8, a kinase module subunit of Mediator, to repress plant growth...
February 12, 2019: New Phytologist
Ki Sa Sung, Sun-Jick Kim, Sang Woo Cho, Ye-Jin Park, Kun Tae, Cheol Yong Choi
Covalent conjugations of the SUMO-1 moiety on a target protein play important roles in the regulation of cellular protein function. SUMO-conjugation of PML is a regulatory step for PML nuclear body (PML-NB) formation, and HIPK2 is SUMO-conjugated and recruited into the PML-NBs. Although HIPK2 mutations (R861W and N951I) were found in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients, little is known about the underlying mechanisms by which HIPK2 mutations are associated with the pathogenesis of leukemia...
2019: American Journal of Cancer Research
Ines Block, Carolin Müller, Daniel Sdogati, Henriette Pedersen, Markus List, Aleksandra M Jaskot, Silje Damkjær Syse, Pernille Lund Hansen, Steffen Schmidt, Helle Christiansen, Cinzia Casella, Sidsel Bering Olsen, Monica M Blomstrøm, Angela Riedel, Mads Thomassen, Torben A Kruse, Søren W Karlskov Hansen, Petra Kioschis, Jan Mollenhauer
Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines...
February 12, 2019: Oncogene
Chan-Hun Jung, Eun Mi Kim, Jie-Young Song, Jong Kuk Park, Hong-Duck Um
Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), β-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL . Given that Bcl-XL can increase O2 •- production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I...
February 12, 2019: Experimental & Molecular Medicine
Nicolas Lucas, Romain Legrand, Christine Bôle-Feysot, Jonathan Breton, Moïse Coëffier, Kirsti Akkermann, Anu Järv, Jaanus Harro, Pierre Déchelotte, Sergueï O Fetissov
Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls...
February 12, 2019: Translational Psychiatry
Pei-Suen Tsou, Phillip Campbell, M Asif Amin, Patrick Coit, Shaylynn Miller, David A Fox, Dinesh Khanna, Amr H Sawalha
Scleroderma (SSc) is a complex disease that involves activation of the immune system, vascular complications, and tissue fibrosis. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) mediates trimethylation of lysine 27 of histone 3 (H3K27me3), which acts as a repressive epigenetic mark. Both EZH2 and H3K27me3 were elevated in SSc dermal fibroblasts and endothelial cells compared with healthy controls. EZH2 inhibitor DZNep halted fibrosis both in vitro and in vivo. In SSc fibroblasts, DZNep dose-dependently reduced the expression of profibrotic genes and inhibited migratory activity of SSc fibroblasts...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Matthew G Ondeck, Aditya Kumar, Jesse K Placone, Christopher M Plunkett, Bibiana F Matte, Kirsten C Wong, Laurent Fattet, Jing Yang, Adam J Engler
Breast cancer development is associated with increasing tissue stiffness over years. To more accurately mimic the onset of gradual matrix stiffening, which is not feasible with conventional static hydrogels, mammary epithelial cells (MECs) were cultured on methacrylated hyaluronic acid hydrogels whose stiffness can be dynamically modulated from "normal" (<150 Pascals) to "malignant" (>3,000 Pascals) via two-stage polymerization. MECs form and remain as spheroids, but begin to lose epithelial characteristics and gain mesenchymal morphology upon matrix stiffening...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Andrew L Chang, Yiming Kang, Tamara L Doering
Cryptococcus neoformans kills 200,000 people worldwide each year. After inhalation, this environmental yeast proliferates either extracellularly or within host macrophages. Under conditions of immunocompromise, cryptococci disseminate from the lungs to the brain, causing a deadly meningoencephalitis that is difficult and expensive to treat. Cryptococcal adaptation to the harsh lung environment is a critical first step in its pathogenesis, and consequently a compelling topic of study. This adaptation is mediated by a complex transcriptional program that integrates cellular responses to environmental stimuli...
February 12, 2019: MBio
Pengbo Cao, Xueming Wei, Ram Prasad Awal, Rolf Müller, Daniel Wall
Self-recognition underlies sociality in many group-living organisms. In bacteria, cells use various strategies to recognize kin to form social groups and, in some cases, to transition into multicellular life. One strategy relies on a single genetic locus that encodes a variable phenotypic tag ("greenbeard") for recognizing other tag bearers. Previously, we discovered a polymorphic cell surface receptor called TraA that directs self-identification through homotypic interactions in the social bacterium Myxococcus xanthus Recognition by TraA leads to cellular resource sharing in a process called outer membrane exchange (OME)...
February 12, 2019: MBio
Felicitas Bossler, Bianca J Kuhn, Thomas Günther, Stephen J Kraemer, Prajakta Khalkar, Svenja Adrian, Claudia Lohrey, Angela Holzer, Mitsugu Shimobayashi, Matthias Dürst, Arnulf Mayer, Frank Rösl, Adam Grundhoff, Jeroen Krijgsveld, Karin Hoppe-Seyler, Felix Hoppe-Seyler
Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia...
February 12, 2019: MBio
David M Hershey, Aretha Fiebig, Sean Crosson
Due to their intimate physical interactions with the environment, surface polysaccharides are critical determinants of fitness for bacteria. Caulobacter crescentus produces a specialized structure at one of its cell poles called the holdfast that enables attachment to surfaces. Previous studies have shown that the holdfast is composed of carbohydrate-based material and identified a number of genes required for holdfast development. However, incomplete information about its chemical structure, biosynthetic genes, and regulatory principles has limited progress in understanding the mechanism of holdfast synthesis...
February 12, 2019: MBio
Tzu-Chun Tang, Pascal Kienlen-Campard, Yi Hu, Florian Perrin, Rémi Opsomer, Jean-Noël Octave, Stefan N Constantinescu, Steven O Smith
Extracellular deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease (AD). Upon β-secretase-mediated cleavage of the β C-terminal fragment (β-CTF) from the Aβ precursor protein, the γ-secretase complex produces the amyloid β (Aβ) peptides associated with AD. The familial T43I mutation within the transmembrane domain of the β-CTF (also referred to as C99) increases the ratio between the Aβ42 and Aβ40 peptides largely due to a decrease in Aβ40 formation. Aβ42 is the principal component of amyloid deposits within the brain parenchyma, and an increase in the Aβ42:Aβ40 ratio is correlated with early-onset AD...
February 12, 2019: Journal of Biological Chemistry
Bouchra Kitab, Masaaki Satoh, Yusuke Ohmori, Tsubasa Munakata, Masayuki Sudoh, Michinori Kohara, Kyoko Tsukiyama-Kohara
Hepatitis C virus (HCV) establishes a chronic infection that can lead to cirrhosis and hepatocellular carcinoma. The HCV life cycle is closely associated with host factors that promote or restrict viral replication, the characterization of which could help to identify potential therapeutic targets. To this end, here we performed a genome-wide microarray analysis andidentified ribonucleotide reductase M2 (RRM2) as a cellular factor essential for HCV replication. We found that RRM2 is up-regulated in response to HCV infection in quiescent hepatocytes from humanized chimeric mouse livers...
February 12, 2019: Journal of Biological Chemistry
Marc Herb, Alexander Gluschko, Katja Wiegmann, Alina Farid, Anne Wolf, Olaf Utermöhlen, Oleg Krut, Martin Krönke, Michael Schramm
A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in Listeria monocytogenes- infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS)...
February 12, 2019: Science Signaling
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