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Conservation and diversity of the eukaryotic SAGA coactivator complex across kingdoms.

Epigenetics Chromatin 2021 Jun 10;14(1):26. Epub 2021 Jun 10.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.

The SAGA complex is an evolutionarily conserved transcriptional coactivator that regulates gene expression through its histone acetyltransferase and deubiquitylase activities, recognition of specific histone modifications, and interactions with transcription factors. Multiple lines of evidence indicate the existence of distinct variants of SAGA among organisms as well as within a species, permitting diverse functions to dynamically regulate cellular pathways. Our co-expression analysis of genes encoding human SAGA components showed enrichment in reproductive organs, brain tissues and the skeletal muscle, which corresponds to their established roles in developmental programs, emerging roles in neurodegenerative diseases, and understudied functions in specific cell types. Read More

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More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation.

Channels (Austin) 2021 Dec;15(1):322-338

Functional Neurobiology, Johannes Gutenberg-University Mainz, Institute for Developmental Biology and Neurobiology, Mainz, Germany.

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. Read More

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December 2021

Controlled hierarchical self-assembly of networked coordination nanocapsules the use of molecular chaperones.

Chem Sci 2020 Oct 28;11(46):12547-12552. Epub 2020 Oct 28.

Department of Chemistry, University of Missouri-Columbia 601 S College Ave Columbia MO 65211 USA

Supramolecular chaperones play an important role in directing the assembly of multiple protein subunits and redox-active metal ions into precise, complex and functional quaternary structures. Here we report that hydroxyl tailed -alkylpyrogallol[4]arene ligands and redox-active Mn ions, with the assistance of proline chaperone molecules, can assemble into two-dimensional (2D) and/or three-dimensional (3D) networked nanocapsules. Dimensionality is controlled by coordination between the exterior of nanocapsule subunits, and endohedral functionalization within the 2D system is achieved chaperone guest encapsulation. Read More

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October 2020

Chameleonic layered metal-organic frameworks with variable charge-ordered states triggered by temperature and guest molecules.

Chem Sci 2020 Mar 5;11(14):3610-3618. Epub 2020 Mar 5.

Institute for Materials Research, Tohoku University 2-1-1 Katahira, Aoba-ku Sendai 980-8577 Japan

Molecular materials whose electronic states are multiply varied depending on external stimuli are among the most promising targets for the development of multiply accessible molecular switches. Here, we report a honeycomb layer composed of tetraoxolene-bridged iron (Fe) subunits whose charge-ordered states are multiply variable thermal treatments and solvation/desolvation with the crystallinity intact. The compound is (NPr)[Fe(ClAn)] (; NPr = tetra--propylammonium; ClAn = 2,5-dichloro-3,6-dihydroxo-1,4-benzoquinonate), which possesses three charge-ordered states: a low-temperature (LT) phase [(Fe)(ClAn)(ClAn˙)]; an intermediate (IM) phase [(Fe)(ClAn)(ClAn)]; and a high-temperature (HT) phase [(Fe)(ClAn)] that varies according to temperature. Read More

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Genetic manipulations of AMPA glutamate receptors in hippocampal synaptic plasticity.

Neuropharmacology 2021 Jun 2:108630. Epub 2021 Jun 2.

The Hospital for Sick Children, Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the principal mediators of fast excitatory synaptic transmission and they are required for various forms of synaptic plasticity, including long-term potentiation (LTP) and depression (LTD), which are key mechanisms of learning and memory. AMPARs are tetrameric complexes assembled from four subunits (GluA1-4), however, the lack of subunit-specific pharmacological tools has made the assessment of individual subunits difficult. The application of genetic techniques, particularly gene targeting, allows for precise manipulation and dissection of each subunit in the regulation of neuronal function and behaviour. Read More

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Predicting Paradise: Modeling future wildfire disasters in the western US.

Sci Total Environ 2021 Aug 13;784:147057. Epub 2021 Apr 13.

USDA Forest Service, Rocky Mountain Research Station, Missoula Fire Sciences Laboratory, Missoula, MT, USA.

The 2018 Camp fire destroyed the town of Paradise, California and resulted in 82 fatalities, the worst wildfire disaster in the US to date. Future disasters of similar or greater magnitude are inevitable given predicted climate change but remain highly uncertain in terms of location and timing. As with other natural disasters, simulation models are one of the primary tools to map risk and design prevention strategies. Read More

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Functional characterization of RebL1 highlights the evolutionary conservation of oncogenic activities of the RBBP4/7 orthologue in Tetrahymena thermophila.

Nucleic Acids Res 2021 Jun 4. Epub 2021 Jun 4.

Department of Chemistry and Biology, Ryerson University, 350 Victoria St., Toronto M5B 2K3, Canada.

Retinoblastoma-binding proteins 4 and 7 (RBBP4 and RBBP7) are two highly homologous human histone chaperones. They function in epigenetic regulation as subunits of multiple chromatin-related complexes and have been implicated in numerous cancers. Due to their overlapping functions, our understanding of RBBP4 and 7, particularly outside of Opisthokonts, has remained limited. Read More

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Use of Mitotic Protein Kinase Inhibitors and Phospho-Specific Antibodies to Monitor Protein Phosphorylation During the Cell Cycle.

Methods Mol Biol 2021 ;2329:205-221

Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Reversible protein phosphorylation regulates the transitions between different phases of the cell cycle ensuring proper segregation of the duplicated genome into two daughter cells. Protein kinases and protein phosphatases establish the appropriate phosphorylation stoichiometries in diverse substrates maintaining genomic stability as a cell undergoes this complex process. Along with regulating common substrates, these opposing enzymes regulate one another by fine-tuning each other's activity both spatially and temporally throughout mitosis. Read More

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January 2021

A conditionally replication-defective cytomegalovirus vaccine elicits potent and diverse functional monoclonal antibodies in a phase I clinical trial.

NPJ Vaccines 2021 Jun 2;6(1):79. Epub 2021 Jun 2.

Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.

A conditionally replication-defective human cytomegalovirus (HCMV) vaccine, V160, was shown to be safe and immunogenic in a two-part, double-blind, randomized, placebo-controlled phase I clinical trial (NCT01986010). However, the specificities and functional properties of V160-elicited antibodies remain undefined. Here, we characterized 272 monoclonal antibodies (mAbs) isolated from single memory B cells of six V160-vaccinated subjects. Read More

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PSMD9 ribosomal protein network maintains nucleolar architecture and WT p53 levels.

Biochem Biophys Res Commun 2021 Jul 30;563:105-112. Epub 2021 May 30.

Protein Interactome Lab for Structural and Functional Biology, Advanced Centre for Treatment, Research and Education in Cancer, Sector 22, Kharghar, Navi Mumbai, Maharashtra, 410210, India; Homi Bhabha National Institute, BARC Training School Complex, Anushaktinagar, Mumbai, Maharashtra, 400094, India. Electronic address:

Capitalizing on an unexpected observation that multiple free ribosomal proteins co-purify/pull-down with PSMD9, we report here for the first time that PSMD9 is necessary to maintain the morphology and integrity of the nucleolus. As seen by NPM1 immunofluorescence and electron microscopy, the nucleolar structure is clearly disrupted in PSMD9 null MCF7 breast cancer cells. The resultant stress is pronounced leading to the accumulation of WT p53 and slow growth. Read More

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Hotspot Coevolution Is a Key Identifier of Near-Native Protein Complexes.

J Phys Chem B 2021 Jun 2. Epub 2021 Jun 2.

Biosciences Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831-6038, United States.

Protein-protein interactions play a key role in mediating numerous biological functions, with more than half the proteins in living organisms existing as either homo- or hetero-oligomeric assemblies. Protein subunits that form oligomers minimize the free energy of the complex, but exhaustive computational search-based docking methods have not comprehensively addressed the challenge of distinguishing a natively bound complex from non-native forms. Current protein docking approaches address this problem by sampling multiple binding modes in proteins and scoring each mode, with the lowest-energy (or highest scoring) binding mode being regarded as a near-native complex. Read More

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Heterogeneity of G-protein activation by the calcium-sensing receptor.

J Mol Endocrinol 2021 Jun 1. Epub 2021 Jun 1.

C Gorvin, Institute of Metabolism and Systems Research and Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom of Great Britain and Northern Ireland.

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays a fundamental role in extracellular calcium (Ca2+e) homeostasis by regulating parathyroid hormone release and urinary calcium excretion. The CaSR has been described to activate all four G-protein subfamilies (Gαq/11, Gαi/o, Gα12/13, Gαs), and mutations in the receptor that cause hyper/hypocalcaemia, have been described to bias receptor signalling. However, many of these studies are based on measurements of second messenger proteins or gene transcription that occurs many steps downstream of receptor activation and can represent convergence points of several signalling pathways. Read More

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Studying Reaction Mechanisms in Solution Using a Distributed Electron Microscopy Method.

ACS Nano 2021 Jun 2. Epub 2021 Jun 2.

Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025, United States.

Electron microscopy (EM) of materials undergoing chemical reactions provides knowledge of the underlying mechanisms. However, the mechanisms are often complex and cannot be fully resolved using a single method. Here, we present a distributed electron microscopy method for studying complex reactions. Read More

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Deregulation of Ca-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes.

Int J Mol Sci 2021 May 12;22(10). Epub 2021 May 12.

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia.

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP-receptors (PLC/IPR) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)-dependent Ca signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. Read More

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An Inside Job: Molecular Determinants for Postsynaptic Localization of Nicotinic Acetylcholine Receptors.

Authors:
Michael Ferns

Molecules 2021 May 21;26(11). Epub 2021 May 21.

Departments of Anesthesiology & Pain Medicine, and Physiology & Membrane Biology, University of California Davis, Davis, CA 95616, USA.

Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission at neuromuscular and autonomic ganglionic synapses in the peripheral nervous system. The postsynaptic localization of muscle ((α1)β1γδ) and neuronal ((α3β4)β4) nicotinic receptors at these synapses is mediated by interactions between the nAChR intracellular domains and cytoplasmic scaffolding proteins. Recent high resolution structures and functional studies provide new insights into the molecular determinants that mediate these interactions. Read More

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RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis.

Nucleic Acids Res 2021 Jun 1. Epub 2021 Jun 1.

Department of Cell and Regenerative Biology, Wisconsin Blood Cancer Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.

Cellular differentiation requires vast remodeling of transcriptomes, and therefore machinery mediating remodeling controls differentiation. Relative to transcriptional mechanisms governing differentiation, post-transcriptional processes are less well understood. As an important post-transcriptional determinant of transcriptomes, the RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. Read More

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Infections in activated PI3K delta syndrome (APDS).

Curr Opin Immunol 2021 May 27;72:146-157. Epub 2021 May 27.

Department of Immunobiology, Yale University School of Medicine, 300 George Street 353G, New Haven, CT, 06511, USA. Electronic address:

Activated PI3K-delta Syndrome (APDS), also called PI3K-delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is an autosomal dominant disorder caused by inherited or de novo gain-of-function mutations in one of two genes encoding subunits of the phosphoinositide-3-kinase delta (PI3Kδ) complex. This largely leukocyte-restricted protein complex regulates cell growth, activation, proliferation, and survival. Patients who harbor these mutations have early onset immunodeficiency with recurrent infections, lymphadenopathy, and autoimmunity. Read More

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Experimental diagnostic of sequence-variant dynamic perturbations revealed by broadband dielectric spectroscopy.

Structure 2021 May 22. Epub 2021 May 22.

Univ Lyon, CNRS, INSA Lyon, Université Claude Bernard Lyon 1, Ecole Centrale de Lyon, Ampère, UMR5005, 69622 Villeurbanne, France; Institut Rhônalpin des systèmes complexes, IXXI-ENS-Lyon, 69007, Lyon, France. Electronic address:

Genetic diversity leads to protein robustness, adaptability, and failure. Some sequence variants are structurally robust but functionally disturbed because mutations bring the protein onto unfolding/refolding routes resulting in misfolding diseases (e.g. Read More

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Molecular recognition and deubiquitination of cyclic K48-linked ubiquitin chains by OTUB1.

Biochem Biophys Res Commun 2021 May 25;562:94-99. Epub 2021 May 25.

Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto, 615-8510, Japan.

Conjugation of K48-linked ubiquitin chains to intracellular proteins mainly functions as a signal for proteasomal degradation. The conjugating enzyme E2-25K synthesizes not only canonical (noncyclic) but also cyclic K48-linked ubiquitin chains. Although the cyclic conformation is expected to repress molecular recognition by ubiquitin binding proteins due to restricting the flexibility of the ubiquitin subunits in a chain, multiple proteins are reported to associate with cyclic ubiquitin chains similar to noncyclic chains. Read More

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GalaxyHeteromer: protein heterodimer structure prediction by template-based and ab initio docking.

Nucleic Acids Res 2021 May 28. Epub 2021 May 28.

Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.

Protein-protein interactions play crucial roles in diverse biological processes, including various disease progressions. Atomistic structural details of protein-protein interactions may provide important information that can facilitate the design of therapeutic agents. GalaxyHeteromer is a freely available automatic web server (http://galaxy. Read More

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IL-30 (IL-27A): a familiar stranger in immunity, inflammation, and cancer.

Exp Mol Med 2021 May 28;53(5):823-834. Epub 2021 May 28.

Department of Chemistry and Institute for Advanced Study, Technical University of Munich, 85748, Garching, Germany.

Over the years, interleukin (IL)-27 has received much attention because of its highly divergent, sometimes even opposing, functions in immunity. IL-30, the p28 subunit that forms IL-27 together with Ebi3 and is also known as IL-27p28 or IL-27A, has been considered a surrogate to represent IL-27. However, it was later discovered that IL-30 can form complexes with other protein subunits, potentially leading to overlapping or discrete functions. Read More

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Structures in G proteins important for subtype selective receptor binding and subsequent activation.

Commun Biol 2021 May 27;4(1):635. Epub 2021 May 27.

Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.

G protein-coupled receptors (GPCRs) selectively couple to specific heterotrimeric G proteins comprised of four subfamilies in order to induce appropriate physiological responses. However, structural determinants in Gα subunits responsible for selective recognition by approximately 800 human GPCRs have remained elusive. Here, we directly compare the influence of subtype-specific Gα structures on the stability of GPCR-G protein complexes and the activation by two Gq-coupled receptors. Read More

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Division of labor in epitranscriptomics: What have we learnt from the structures of eukaryotic and viral multimeric RNA methyltransferases?

Authors:
Marc Graille

Wiley Interdiscip Rev RNA 2021 May 27:e1673. Epub 2021 May 27.

Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole Polytechnique, IP Paris, Palaiseau Cedex, France.

The translation of an mRNA template into the corresponding protein is a highly complex and regulated choreography performed by ribosomes, tRNAs, and translation factors. Most RNAs involved in this process are decorated by multiple chemical modifications (known as epitranscriptomic marks) contributing to the efficiency, the fidelity, and the regulation of the mRNA translation process. Many of these epitranscriptomic marks are written by holoenzymes made of a catalytic subunit associated with an activating subunit. Read More

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Target-switchable Gd(III)-DOTA/protein cage nanoparticle conjugates with multiple targeting affibody molecules as target selective T contrast agents for high-field MRI.

J Control Release 2021 May 24;335:269-280. Epub 2021 May 24.

Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea. Electronic address:

Magnetic resonance imaging (MRI) is a non-invasive in vivo imaging tool, providing high enough spatial resolution to obtain both the anatomical and the physiological information of patients. However, MRI generally suffers from relatively low sensitivity often requiring the aid of contrast agents (CA) to enhance the contrast of vessels and/or the tissues of interest from the background. The targeted delivery of diagnostic probes to the specific lesion is a powerful approach for early diagnosis and signal enhancement leading to the effective treatment of various diseases. Read More

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Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens.

Diabetes 2021 May 24. Epub 2021 May 24.

Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA

The brain is now recognized as an insulin sensitive tissue, however, the role of changing insulin concentrations in the peripheral circulation on gene expression in the brain is largely unknown. Here we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 hours. We show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression in the brain compared with saline-infused controls. Read More

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Design principles of the ESCRT-III Vps24-Vps2 module.

Elife 2021 May 24;10. Epub 2021 May 24.

Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States.

ESCRT-III polymerization is required for all endosomal sorting complex required for transport (ESCRT)-dependent events in the cell. However, the relative contributions of the eight ESCRT-III subunits differ between each process. The minimal features of ESCRT-III proteins necessary for function and the role for the multiple ESCRT-III subunits remain unclear. Read More

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Structural Basis for a Dual Function ATP Grasp Ligase That Installs Single and Bicyclic ω-Ester Macrocycles in a New Multicore RiPP Natural Product.

J Am Chem Soc 2021 Jun 24;143(21):8056-8068. Epub 2021 May 24.

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.

Among the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, "graspetides" (formerly known as microviridins) contain macrocyclic esters and amides that are formed by ATP-grasp ligase tailoring enzymes using the side chains of Asp/Glu as acceptors and Thr/Ser/Lys as donors. Graspetides exhibit diverse patterns of macrocylization and connectivities exemplified by microviridins, that have a caged tricyclic core, and thuringin and plesiocin that feature a "hairpin topology" with cross-strand ω-ester bonds. Here, we characterize chryseoviridin, a new type of multicore RiPP encoded by DS19109 (Phylum Bacteroidetes) and solve a 2. Read More

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Plastid caseinolytic protease OsClpR1 regulates chloroplast development and chloroplast RNA editing in rice.

Rice (N Y) 2021 May 20;14(1):45. Epub 2021 May 20.

Key Laboratory of Eco-Agricultural Biotechnology around Hongze Lake, Regional Cooperative Innovation Center for Modern Agriculture and Environmental Protection, Huaiyin Normal University, Huai'an, 223300, China.

Background: Plant plastidic caseinolytic protease (Clp) is a central part of the plastid protease network and consists of multiple subunits. The molecular functions of many Clps in plants, especially in crops, are not well known.

Results: In this study, we identified an albino lethal mutant al3 in rice, which produces albino leaves and dies at the seedling stage. Read More

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Structural analysis of the OC43 coronavirus 2'-O-RNA methyltransferase.

J Virol 2021 May 19. Epub 2021 May 19.

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.

The OC43 coronavirus is a human pathogen that usually causes only the common cold. One of its key enzymes, similar to other coronaviruses, is the 2'-O-RNA methyltransferase (MTase) that is essential for viral RNA stability and expression. Here, we report the crystal structure of the 2'-O-RNA MTase in a complex with the pan-methyltransferase inhibitor sinefungin solved at 2. Read More

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Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia.

JAMA Psychiatry 2021 May 19. Epub 2021 May 19.

Department of Child and Adolescent Psychiatry and Behavioral Sciences, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Importance: Discovery of mechanisms that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders.

Objective: To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). Read More

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