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  • 1
    Publication Date: 2018-10-19
    Description: Animal toxins that modulate the activity of voltage-gated sodium (Na v ) channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Na v channel Na v PaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSD II and the pore of Na v PaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na + access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Na v channel drugs.
    Keywords: Biochemistry, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-03-09
    Description: Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Publication Date: 2018-05-25
    Description: RNA promotes liquid-liquid phase separation (LLPS) to build membraneless compartments in cells. How distinct molecular compositions are established and maintained in these liquid compartments is unknown. Here, we report that secondary structure allows messenger RNAs (mRNAs) to self-associate and determines whether an mRNA is recruited to or excluded from liquid compartments. The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence. These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity. Thus, the shape of RNA can promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell.
    Keywords: Cell Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2018-08-02
    Description: It has become exceedingly important to understand the precise molecular profiles of the nearly 40 trillion cells in an adult human because of their role in determining health, disease, and therapeutic outcome. The National Institutes of Health (NIH) Common Fund–supported Single Cell Analysis Program (SCAP) was designed to address this challenge. In this review, we outline the original program goals and provide a perspective on the impact of the program as a catalyst for exploration of heterogeneity of human tissues at the cellular level. We believe that the technological advances in single-cell RNA sequencing and multiplexed imaging combined with computational methods made by this program will undoubtedly have an impact on broad and robust applications of single-cell analyses in both health and disease research.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    Publication Date: 2011-02-05
    Description: If they could be easily exfoliated, layered materials would become a diverse source of two-dimensional crystals whose properties would be useful in applications ranging from electronics to energy storage. We show that layered compounds such as MoS(2), WS(2), MoSe(2), MoTe(2), TaSe(2), NbSe(2), NiTe(2), BN, and Bi(2)Te(3) can be efficiently dispersed in common solvents and can be deposited as individual flakes or formed into films. Electron microscopy strongly suggests that the material is exfoliated into individual layers. By blending this material with suspensions of other nanomaterials or polymer solutions, we can prepare hybrid dispersions or composites, which can be cast into films. We show that WS(2) and MoS(2) effectively reinforce polymers, whereas WS(2)/carbon nanotube hybrid films have high conductivity, leading to promising thermoelectric properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Coleman, Jonathan N -- Lotya, Mustafa -- O'Neill, Arlene -- Bergin, Shane D -- King, Paul J -- Khan, Umar -- Young, Karen -- Gaucher, Alexandre -- De, Sukanta -- Smith, Ronan J -- Shvets, Igor V -- Arora, Sunil K -- Stanton, George -- Kim, Hye-Young -- Lee, Kangho -- Kim, Gyu Tae -- Duesberg, Georg S -- Hallam, Toby -- Boland, John J -- Wang, Jing Jing -- Donegan, John F -- Grunlan, Jaime C -- Moriarty, Gregory -- Shmeliov, Aleksey -- Nicholls, Rebecca J -- Perkins, James M -- Grieveson, Eleanor M -- Theuwissen, Koenraad -- McComb, David W -- Nellist, Peter D -- Nicolosi, Valeria -- New York, N.Y. -- Science. 2011 Feb 4;331(6017):568-71. doi: 10.1126/science.1194975.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Physics and Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, D2, Ireland. colemaj@tcd.ie〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21292974" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-08-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fouchier, Ron A M -- Kawaoka, Yoshihiro -- Cardona, Carol -- Compans, Richard W -- Garcia-Sastre, Adolfo -- Govorkova, Elena A -- Guan, Yi -- Herfst, Sander -- Orenstein, Walter A -- Peiris, J S Malik -- Perez, Daniel R -- Richt, Juergen A -- Russell, Charles -- Schultz-Cherry, Stacey L -- Smith, Derek J -- Steel, John -- Tompkins, S Mark -- Topham, David J -- Treanor, John J -- Tripp, Ralph A -- Webby, Richard J -- Webster, Robert G -- New York, N.Y. -- Science. 2013 Aug 9;341(6146):612-3. doi: 10.1126/science.341.6146.612.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23929965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Drug Resistance, Multiple, Viral/*genetics ; Humans ; Influenza A virus/*genetics/*pathogenicity ; Influenza Vaccines/genetics/immunology ; Influenza in Birds/*transmission/*virology ; Influenza, Human/*prevention & control/transmission/virology ; Pandemics/*prevention & control ; Poultry ; Security Measures
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-08-09
    Description: Since the end of March 2013, avian a influenza viruses of the H7N9 subtype have caused more than 130 human cases of infection in China, many of which were severe, resulting in 43 fatalities. Although this A(H7N9) virus outbreak is now under control, the virus (or one with similar properties) could reemerge as winter approaches. To better assess the pandemic threat posed by A(H7N9) viruses, NIAID/NIH Centers of Excellence in Influenza Research and Surveillance (CEIRS) investigators and other expert laboratories in China and elsewhere have characterized the wild-type avian A(H7N9) viruses in terms of host range, virulence, and transmission, and are evaluating the effectiveness of antiviral drugs and vaccine candidates. However, to fully assess the potential risk associated with these novel viruses, there is a need for additional research including experiments that may be classified as "gain-of-function" (GOF). Here, we outline the aspects of the current situation that most urgently require additional research, our proposed studies, and risk-mitigation strategies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fouchier, Ron A M -- Kawaoka, Yoshihiro -- Cardona, Carol -- Compans, Richard W -- Garcia-Sastre, Adolfo -- Govorkova, Elena A -- Guan, Yi -- Herfst, Sander -- Orenstein, Walter A -- Peiris, J S Malik -- Perez, Daniel R -- Richt, Juergen A -- Russell, Charles -- Schultz-Cherry, Stacey L -- Smith, Derek J -- Steel, John -- Tompkins, S Mark -- Topham, David J -- Treanor, John J -- Tripp, Ralph A -- Webby, Richard J -- Webster, Robert G -- New York, N.Y. -- Science. 2013 Aug 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Viroscience, Erasmus Medical Center, 3015GE, Rotterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23926190" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2011-10-25
    Description: Ultrafast two-dimensional infrared (2D IR) vibrational echo spectroscopy has proven broadly useful for studying molecular dynamics in solutions. Here, we extend the technique to probing the interfacial dynamics and structure of a silica surface-tethered transition metal carbonyl complex--tricarbonyl (1,10-phenanthroline)rhenium chloride--of interest as a photoreduction catalyst. We interpret the data using a theoretical framework devised to separate the roles of structural evolution and excitation transfer in inducing spectral diffusion. The structural dynamics, as reported on by a carbonyl stretch vibration of the surface-bound complex, have a characteristic time of ~150 picoseconds in the absence of solvent, decrease in duration by a factor of three upon addition of chloroform, and decrease another order of magnitude for the bulk solution. Conversely, solvent-complex interactions increase the lifetime of the probed vibration by 160% when solvent is applied to the monolayer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosenfeld, Daniel E -- Gengeliczki, Zsolt -- Smith, Brian J -- Stack, T D P -- Fayer, M D -- GM50730/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2011 Nov 4;334(6056):634-9. doi: 10.1126/science.1211350. Epub 2011 Oct 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22021674" target="_blank"〉PubMed〈/a〉
    Keywords: Carbon/chemistry ; Catalysis ; Oxygen/chemistry ; Silicon Dioxide ; Spectrophotometry, Infrared/*methods
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-01-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nachman, Keeve E -- Smith, Tyler J S -- Martin, Robert P -- New York, N.Y. -- Science. 2014 Jan 10;343(6167):136. doi: 10.1126/science.343.6167.136-a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24408415" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/*adverse effects ; Antibiotic Prophylaxis/*adverse effects/*veterinary ; *Drug Resistance, Bacterial ; *Guidelines as Topic ; Humans ; *Legislation, Veterinary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2014-11-22
    Description: We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246172/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fonville, J M -- Wilks, S H -- James, S L -- Fox, A -- Ventresca, M -- Aban, M -- Xue, L -- Jones, T C -- Le, N M H -- Pham, Q T -- Tran, N D -- Wong, Y -- Mosterin, A -- Katzelnick, L C -- Labonte, D -- Le, T T -- van der Net, G -- Skepner, E -- Russell, C A -- Kaplan, T D -- Rimmelzwaan, G F -- Masurel, N -- de Jong, J C -- Palache, A -- Beyer, W E P -- Le, Q M -- Nguyen, T H -- Wertheim, H F L -- Hurt, A C -- Osterhaus, A D M E -- Barr, I G -- Fouchier, R A M -- Horby, P W -- Smith, D J -- 087982/Wellcome Trust/United Kingdom -- 089276/Wellcome Trust/United Kingdom -- DP1-OD000490-01/OD/NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272201400008C/PHS HHS/ -- MR/K021885/1/Medical Research Council/United Kingdom -- WT087982MA/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):996-1000. doi: 10.1126/science.1256427.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. World Health Organization (WHO) Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge CB2 3EJ, UK. Department of Viroscience, Erasmus Medical Center, Rotterdam 3015 CE, Netherlands. ; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. World Health Organization (WHO) Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge CB2 3EJ, UK. ; Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Hanoi, Vietnam. ; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. ; WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, Melbourne VIC 3000, Australia. ; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam. ; Oxford University Museum of Natural History, Oxford OX1 3PW, UK. ; Insect Biomechanics Group, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. ; Department of Viroscience, Erasmus Medical Center, Rotterdam 3015 CE, Netherlands. ; World Health Organization (WHO) Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge CB2 3EJ, UK. Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. ; bobblewire.com, Saint Louis, MO 63112, USA. ; Abbott Laboratories, Weesp 1380 DA, Netherlands. ; Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Hanoi, Vietnam. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford OX3 7BN, UK. ; WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, Melbourne VIC 3000, Australia. Melbourne School of Population and Global Health, University of Melbourne, Parkville VIC 3010, Australia. ; Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. World Health Organization (WHO) Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge CB2 3EJ, UK. Department of Viroscience, Erasmus Medical Center, Rotterdam 3015 CE, Netherlands. dsmith@zoo.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414313" target="_blank"〉PubMed〈/a〉
    Keywords: Antibodies, Viral/blood/*immunology ; Antigenic Variation/genetics/immunology ; Evolution, Molecular ; Humans ; Influenza A Virus, H3N2 Subtype/genetics/*immunology ; Influenza Vaccines/*immunology ; Influenza, Human/blood/*immunology/prevention & control ; *Vaccination
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    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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