Featured
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Transmembrane anion transport mediated by halogen-bond donors
The transport of anions across bilayer membranes is achieved by ion channel proteins, but some small molecules are also able to mediate transmembrane movement of anions. In this study, the halogen bonding of small perfluorinated molecules is shown to allow the transmembrane movement of anions.
- Andreas Vargas Jentzsch
- , Daniel Emery
- & Stefan Matile
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TEMPRANILLO genes link photoperiod and gibberellin pathways to control flowering in Arabidopsis
InArabidopsis the photoperiod pathway promotes flowering in response to longer days, but during short days flowering depends on gibberellin accumulation. This study shows that TEMPRANILLO downregulation is required to induce flowering, as TEMPRANILLOgenes repress floral induction in the photoperiod and gibberellin pathways.
- Michela Osnato
- , Cristina Castillejo
- & Soraya Pelaz
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Article
| Open AccessCombinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells
Phage display screening can unravel protein–protein interactions, but its application has been mainly restricted to the cell surface. Here, a phage-based reagent is introduced that allows the targeting of combinatorial peptides to cell organelles, providing a tool for the discovery of intracellular ligand-receptors.
- Roberto Rangel
- , Liliana Guzman-Rojas
- & Wadih Arap
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Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release
Accumulation of lysosomal lipids is a feature of Niemann'-Picks (NP) disease, but how these lipids contribute to the disease is unclear. In this study, calcium released via the lysosomal TRPML1 channel is shown to be reduced in NP-type C cells, and sphingomyelins are found to inhibit the channel's activity.
- Dongbiao Shen
- , Xiang Wang
- & Haoxing Xu
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Article
| Open AccessStructure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine
The pentameric ligand gated ion channel fromErwinia chrysanthemi(ELIC) is similar in structure to the nicotinic acetylcholine receptor, a member of the Cys-loop receptor family. This study reports the crystal structure of ELIC bound to acetylcholine and shows that acetylcholine is a competitive antagonist of ELIC.
- Jianjun Pan
- , Qiang Chen
- & Pei Tang
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Article
| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz
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Article
| Open AccessDraft genome sequence and genetic transformation of the oleaginous alga Nannochloropsis gaditana
Algae show much promise in the production of biofuels owing to their high photoautotrophic biomass and lipid production rates. In this study, the draft genome ofNannochloropsis gaditanaCCMP526 and a method for the transformation of this alga are reported, facilitating the investigation of lipid synthesis and biofuel production.
- Randor Radakovits
- , Robert E. Jinkerson
- & Matthew C. Posewitz
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Article
| Open AccessPPARγ contributes to PKM2 and HK2 expression in fatty liver
Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuket al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
- Ganna Panasyuk
- , Catherine Espeillac
- & Mario Pende
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Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds
Multivalent display of integrin antagonists enhances their efficacy, but current synthetic scaffolds used to display ligands are limited in range and precision. Englundet al. develop a new scaffold to study the multivalent effects of integrin antagonists across wide ranges of ligand number, density, and 3D arrangement.
- Ethan A. Englund
- , Deyun Wang
- & Daniel H. Appella
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| Open AccessPKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades
G-protein-coupled receptors sense extracellular cues and transmit the signal to distinct trimeric G-proteins. Stefanet al.show that in response to cAMP, a central and conserved component of the Gαs-coupled receptor cascade, the RII subunit of PKA, specifically binds to and participates in Gαi signaling.
- Eduard Stefan
- , Mohan K. Malleshaiah
- & Stephen W. Michnick
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| Open AccessGlobal kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum
New approaches are required to combatPlasmodium falciparuminfection. In this proteome-wide study, 1305 phosphorylation sites are identified and 36 kinases are shown to have crucial roles in parasite survival, providing new insights into parasite biology and potential new drug targets for anti-malarial chemotherapy.
- Lev Solyakov
- , Jean Halbert
- & Christian Doerig
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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol
TRPA1 is a key ion channel in pain signalling. This study shows that activation of TRPA1 in the spinal cord by acetaminophen metabolites and a non-electrophilic cannabinoid produces antinociception that is lost in mice lacking TRPA1, providing an explanation for the analgesic activity of acetaminophen.
- David A Andersson
- , Clive Gentry
- & Peter M Zygmunt
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Metabolomic high-content nuclear magnetic resonance-based drug screening of a kinase inhibitor library
Metabolism is altered in many diseases, and monitoring metabolic changes during treatment could facilitate investigations into treatment efficacy and cellular responses. This study reports an NMR-based method to screen the metabolic responses of mammalian cells to drugs.
- Stefano Tiziani
- , Yunyi Kang
- & Giovanni Paternostro
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Article
| Open AccessA gustatory receptor involved in host plant recognition for oviposition of a swallowtail butterfly
Female Swallowtail butterflies will only lay their eggs on a small number of plants, which they choose by detecting specific chemicals on the leaf surface. Here, a gustatory receptor,PxutGr1, is identified in Papilio xuthus, which is used by the butterfly to detect synephrine when selecting a host plant.
- Katsuhisa Ozaki
- , Masasuke Ryuda
- & Hiroshi Yoshikawa
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Epithelial organisation revealed by a network of cellular contacts
Differences in the arrangement of cells is a fundamental precursor to the establishment of different organs. In this study, network theory is applied at the level of individual cells to map patterns in cell-to-cell contacts, creating a new approach to objectively characterise epithelia.
- Luis M. Escudero
- , Luciano da F. Costa
- & M. Madan Babu
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Synapse microarray identification of small molecules that enhance synaptogenesis
Large scale synapse assays can facilitate identification of drug leads. Shiet al. develop a 'synapse microarray' technology that enables sensitive, high-throughput, quantitative screening of synaptogenic events, and use it to identify novel histone deacetylase inhibitors that enhance synaptogenesis.
- Peng Shi
- , Mark A. Scott
- & Mehmet Fatih Yanik
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Bottom-up synthesis of finite models of helical (n,m)-single-wall carbon nanotubes
Hoop-shaped aromatic hydrocarbons can be considered as finite models of single-wall carbon nanotubes. Hitosugiet al. describe the bottom-up synthesis of a macrocyclic tetramer of chrysene, and show that its persistent rotational isomers are finite models of chiral nanotubes.
- Shunpei Hitosugi
- , Waka Nakanishi
- & Hiroyuki Isobe
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Selective fluorescent probes for live-cell monitoring of sulphide
Molecular probes that can detect aqueous sulphides could help to elucidate their roles in biological signalling. Qianet al. develop two sulphide-selective fluorescent probes and demonstrate their ability to image free sulphide in living cells.
- Yong Qian
- , Jason Karpus
- & Chuan He
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A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death
Radiomitigating compounds could be used to protect against ionizing radiation. In this study, mitochondria-targeted oleic and stearic acid derivatives are shown to inhibit pro-apoptotic oxidative events, prevent cell death, and protect mice against lethal doses of radiation.
- Jeffrey Atkinson
- , Alexandr A. Kapralov
- & Valerian E. Kagan
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| Open AccessIdentification and microbial production of a terpene-based advanced biofuel
Advanced biofuels with comparable properties to petroleum-based fuels could be microbially produced from lignocellulosic biomass. In this study,Escherichia coliis engineered to produce bisabolene, the immediate precursor of bisabolane, a biosynthetic alternative to D2 diesel.
- Pamela P. Peralta-Yahya
- , Mario Ouellet
- & Taek Soon Lee
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Article
| Open AccessBackbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides
Cell-penetrating peptides can deliver molecular cargoes into living cells, and cross biological membranes by transduction—a non-endocytic mechanism. Here, the transduction efficiency of cyclic arginine-rich peptides is shown to be higher than that of more flexible linear peptides.
- Gisela Lättig-Tünnemann
- , Manuel Prinz
- & M. Cristina Cardoso
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| Open AccessBlimp1 regulates the transition of neonatal to adult intestinal epithelium
Many mammals are born with an immature intestinal epithelium, which adapts to a changing diet during the weaning period. Muncanet al. show that the transcriptional repressor Blimp1is expressed in the intestine of mice at birth, and that expression is lost at the transition to the weaning stage.
- Vanesa Muncan
- , Jarom Heijmans
- & Gijs R. van den Brink
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| Open AccessFreely orbiting magnetic tweezers to directly monitor changes in the twist of nucleic acids
Rotational motion and torsional strain affects DNA replication, transcription and repair. Lipfertet al. have developed a new technique that uses freely orbiting magnetic tweezers to measure equilibrium fluctuations and determine the twist of tethered nucleic acid molecules.
- Jan Lipfert
- , Matthew Wiggin
- & Nynke H. Dekker
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Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site
The sigma-2 receptor is used as a biomarker for tumour cell proliferation but its identity is unknown. Using a novel radiolabelled probe, the authors identify progesterone receptor membrane component 1, which is overexpressed in several tumour types, as the putative sigma-2 receptor.
- Jinbin Xu
- , Chenbo Zeng
- & Robert H. Mach
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Article
| Open AccessMicroorganisms from aphid honeydew attract and enhance the efficacy of natural enemies
In this study, a bacterium is identified in the honeydew of aphids, which produces volatile chemicals and attracts hoverflies. The findings could aid the development of pest control systems for aphids.
- Pascal D. Leroy
- , Ahmed Sabri
- & Eric Haubruge
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Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Class I anti-arrhythmic drugs act at cardiac sodium channels and are subdivided into classes Ia-c based on their effects on the electrocardiogram. Here, class Ib drugs are found to rely on cation–pi interactions for their activity, whereas class Ib and Ic drugs rely significantly less on this interaction.
- Stephan A. Pless
- , Jason D. Galpin
- & Christopher A. Ahern
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A synthetic icosahedral DNA-based host–cargo complex for functional in vivo imaging
Encapsulating molecules within supramolecular frameworks for potential biological application is challenging. Bhatiaet al. incorporate a fluorescent polymer within an icosahedral DNA nanocapsule, and show that it can be used to target specific cells in vivoand map pH spatially and temporally.
- Dhiraj Bhatia
- , Sunaina Surana
- & Yamuna Krishnan
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An autonomous DNA nanomachine maps spatiotemporal pH changes in a multicellular living organism
Many synthetic DNA nanomachines have been developed and demonstratedin vitro, but their use in living organisms has not been reported. Now, a DNA nanomachine, the I-switch, is used to map spatiotemporal pH changes associated with endosomal maturation within coelomocytes of Caenorhabditis elegans.
- Sunaina Surana
- , Jaffar M. Bhat
- & Yamuna Krishnan
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Article
| Open AccessA bacterial platform for fermentative production of plant alkaloids
Secondary metabolites are widely used in human health and nutrition, but extraction yields from plants are often low. Nakagawaet al. have engineered the metabolism of Escherichia colito develop a fermentation system that produces plant alkaloids from simple carbon sources.
- Akira Nakagawa
- , Hiromichi Minami
- & Hidehiko Kumagai
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Article
| Open AccessChemical treatment enhances skipping of a mutated exon in the dystrophin gene
Duchenne muscular dystrophy is caused by a loss of thedystrophin gene, and control of dystrophin mRNA splicing could aid treatment of the disease. Nishida et al. show that a small molecule promotes skipping of exon 31 and increases production of a functional dystrophin protein in a patient.
- Atsushi Nishida
- , Naoyuki Kataoka
- & Masafumi Matsuo
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Article
| Open AccessConvergent evolution in biosynthesis of cyanogenic defence compounds in plants and insects
Cyanide-releasing defence systems in plants and animals are important to the evolution of plant–herbivore interactions. The authors identify the enzymes responsible for biosynthesis of cyanogenic glucosides by Six-spot Burnet moth caterpillars, which have evolved independently from the known plant pathway.
- Niels Bjerg Jensen
- , Mika Zagrobelny
- & Søren Bak
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Ionic polypeptides with unusual helical stability
Water-soluble peptides with stable α-helical conformations are desirable for a range of applications, but incorporating charged residues to improve solubility usually leads to reduced helical stability. Here, polypeptides produced from amino acids with elongated charged side chains are found to be water soluble and exhibit very high helical stability.
- Hua Lu
- , Jing Wang
- & Jianjun Cheng
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Article
| Open AccessSubstrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
γ-Secretase modulators have promise in the treatment of Alzheimer's disease, but their molecular target is uncertain. Here, fluorescence resonance energy transfer is used to determine that the γ-secretase allosteric site is within the γ-secretase complex and that substrate docking is required for modulators to access the site.
- Kengo Uemura
- , Katherine C. Farner
- & Oksana Berezovska
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| Open AccessDrug export and allosteric coupling in a multidrug transporter revealed by molecular simulations
The drug transporter AcrB is a component of the tripartite efflux system AcrB–AcrA–TolC, which is important in multidrug-resistantEscherichia coli. Takada and co-workers used molecular simulations to further reveal the mechanism of drug export.
- Xin-Qiu Yao
- , Hiroo Kenzaki
- & Shoji Takada
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| Open AccessNovel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
The influenza virus life cycle relies on sialidases, which are classified as group-1 or group-2, depending on the flexibility of the '150-loop'. In this study, chemical compounds are developed, which lock open the '150-loop', selectively inhibiting the activity of group-1 sialidases.
- Santosh Rudrawar
- , Jeffrey C. Dyason
- & Mark von Itzstein
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| Open AccessStructural bases for the interaction of frataxin with the central components of iron–sulphur cluster assembly
Frataxin is an essential protein that has been linked to iron–sulphur cluster assembly, and reduced levels are associated with Friedrich's ataxia. In this study, a combination of techniques is used to probe the interactions of the bacterial frataxin orthologue CyaY with the iron–sulphur cluster assembly machinery.
- Filippo Prischi
- , Petr V. Konarev
- & Annalisa Pastore
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Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A
The kinase Dyrk1A is essential for brain function and development, and its excessive activity has been implicated in Down syndrome. In this study, a selective inhibitor of Dyrk1A is developed, which may help to elucidate the molecular mechanisms of normal and diseased brain.
- Yasushi Ogawa
- , Yosuke Nonaka
- & Masatoshi Hagiwara
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A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors
NMDA receptors are complexes of NR1 and NR2 subunits that mediate excitatory synaptic transmission and have roles in neurological disorders. Here, a subunit-selective potentiator of NMDA receptors is identified, which may allow the evaluation of the functional roles of individual NMDA receptor subunits.
- Praseeda Mullasseril
- , Kasper B. Hansen
- & Stephen F. Traynelis
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Review Article |
Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules
Biologically active molecules can be identified through the screening of small-molecule libraries, but compound collections typically consist of large numbers of structurally similar compounds. Gallowayet al. review how diversity-oriented synthesis can efficiently generate structurally diverse compound libraries.
- Warren R.J.D. Galloway
- , Albert Isidro-Llobet
- & David R. Spring
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Article |
Ice as a protocellular medium for RNA replication
A crucial transition in the origin of life was the emergence of self-replicating RNA and its compartmentalization within protocellular structures. Here it is shown that the physicochemical properties of ice, a simple medium widespread on a temperate early earth, could have mediated this transition.
- James Attwater
- , Aniela Wochner
- & Philipp Holliger
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Article
| Open AccessA chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy
Candidate anti-tuberculosis drugs are often identified in whole-cell screens. Here, Petheet al. show that inappropriate carbon-source selection can lead to the identification of compounds devoid of efficacy in vivo, underlining the importance of developing predictive in vitroscreens.
- Kevin Pethe
- , Patricia C. Sequeira
- & Thomas Dick
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Article |
Phase diagram of bismuth in the extreme quantum limit
Electrons in metals at extremely high magnetic fields show interesting quantum structures. The authors measure the angle-dependent Nernst effect with high precision and show that, for bismuth, Coulomb interactions between the electrons become important in this ultraquantum regime.
- Huan Yang
- , Benoît Fauqué
- & Kamran Behnia
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