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| Open AccessA nonspecific defensive compound evolves into a competition avoidance cue and a female sex pheromone
Chemical communication can evolve from compounds used for other purposes, but experimental evidence is scarce. Here, Weiss et al.show a gradual evolution of a defensive compound into a competition avoidance mediator and a sex pheromone, which was accompanied by diversification of chemical messengers to obtain the required specificity.
- Ingmar Weiss
- , Thomas Rössler
- & Johannes Stökl
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The N-terminal domains of spider silk proteins assemble ultrafast and protected from charge screening
Web spiders synthesize silk fibres at high speed, assisted by a self-associating protein domain, but the molecular details are not yet understood. Here, the authors use an engineered fluorescence probe in combination with mutagenesis to reveal the underlying kinetics and side chain contributions.
- Simone Schwarze
- , Fabian U. Zwettler
- & Hannes Neuweiler
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Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen
As drug-resistant strains of Mycobacterium tuberculosis continue to emerge, antitubercular drugs with novel mechanisms of action are in high demand. Here, the authors show that ebselen is an inhibitor of M. tuberculosisantigen 85 and reveal the mechanism of inhibition.
- Lorenza Favrot
- , Anna E. Grzegorzewicz
- & Donald R. Ronning
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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Article |
Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease that is resistant to many forms of treatment. Tanake et al.screen compounds from a library of medicines and find that mepenzolate bromide reduces inflammatory responses and improves respiration in a mouse model of COPD.
- Ken-Ichiro Tanaka
- , Tomoaki Ishihara
- & Tohru Mizushima
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Article |
Probing water micro-solvation in proteins by water catalysed proton-transfer tautomerism
Detailed knowledge of the water environment within proteins may lead to an increased understanding of protein folding and function. Here the authors present a tryptophan analogue with remarkable water catalysed proton-transfer properties that may be exploited for site-specific water sensing.
- Jiun-Yi Shen
- , Wei-Chih Chao
- & Pi-Tai Chou
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Unexpected reactivity and mechanism of carboxamide activation in bacterial N-linked protein glycosylation
Oligosaccharyltransferases catalyse the transfer of lipid-anchored glycans onto acceptor asparagine residues in substrate proteins. By assaying chemically modified peptide substrate analogues, Lizak et al. rule out all but one of the currently postulated catalytic mechanisms for this enzyme.
- Christian Lizak
- , Sabina Gerber
- & Kaspar P. Locher
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Article
| Open AccessSuper liquid-repellent gas membranes for carbon dioxide capture and heart–lung machines
Membranes allowing transfer of a gas between a liquid and gas layer have applications in areas such as blood oxygenation and carbon dioxide capture. Here, a super liquid repellent membrane is fabricated, allowing high gas transfer and also avoiding wetting and clogging of the membrane pores.
- Maxime Paven
- , Periklis Papadopoulos
- & Hans-Jürgen Butt
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Trinuclear zinc complexes for biologically relevant μ3-oxoanion binding and carbon dioxide fixation
Molecular models of the biologically relevant oxoanion-bridged trinuclear zinc cluster found in numerous enzymatic active sites are desirable. Cao et al. report the synthesis of a trinuclear zinc scaffold, pre-organized to capture oxoanions, and its ability to catalytically convert CO2to carbonates in solution.
- Xiao Liu
- , Pingwu Du
- & Rui Cao
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Article |
Dynamic optimization identifies optimal programmes for pathway regulation in prokaryotes
The ability to induce metabolic pathways in response to a changing environment is an important component of bacterial fitness. Bartl et al. identify optimal programmes for metabolic pathway activation depending on protein synthesis capacity constraints, and demonstrate their impact on operonic organization.
- Martin Bartl
- , Martin Kötzing
- & Christoph Kaleta
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Root-derived CLE glycopeptides control nodulation by direct binding to HAR1 receptor kinase
Symbiotic bacteria form nodules with plant roots and this is controlled by CLE-RS genes found in the plant. In this study, the CLE-RS2gene product is shown to be a glycopeptide that can travel from the roots to the shoot of plants and binds to the receptor kinase HAR1.
- Satoru Okamoto
- , Hidefumi Shinohara
- & Masayoshi Kawaguchi
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Disrupting malaria parasite AMA1–RON2 interaction with a small molecule prevents erythrocyte invasion
Invasion of host erythrocytes is an essential step in the life cycle of P. falciparum. Srinivasan et al.demonstrate that small-molecule inhibitors can block the entry of the parasite into erythrocytes, highlighting the potential of invasion inhibitors as antimalarials.
- Prakash Srinivasan
- , Adam Yasgar
- & Louis H. Miller
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Synthetic polyamines promote rapid lamellipodial growth by regulating actin dynamics
While small molecules that destabilize actin filaments are readily available, artificially stimulating actin polymerization in cells typically involves genetic manipulation. Here, the authors design cell-permeable branched polyamines that promote lamellipodium formation by stimulating actin polymerization.
- Iliana Nedeva
- , Girish Koripelly
- & Daniel Riveline
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Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons
Human non-neuronal somatic cells can be converted into neurons; however, this is a low-efficiency process and the resulting neuronal subtypes are of low purity. Here the authors show that two small molecules enable NGN2 to efficiently convert human fibroblasts into pure cholinergic neurons.
- Meng-Lu Liu
- , Tong Zang
- & Chun-Li Zhang
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Far-red light photoactivatable near-infrared fluorescent proteins engineered from a bacterial phytochrome
Near-infrared fluorescent proteins have applications in deep-tissue and whole-body imaging. Here, the authors report photoactivatable near-infrared proteins engineered from bacteria, with substantial contrast enhancement, which may be advantageous for in vivoimaging in high autofluorescence conditions.
- Kiryl D. Piatkevich
- , Fedor V. Subach
- & Vladislav V. Verkhusha
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Article
| Open AccessTetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies
Heparin-like oligosaccharides are implicated in various diseases. Hansen et al. report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach to synthesize a structurally defined heparin dodecasaccharide with a latent aldehyde tag for labelling and conjugation.
- Steen U. Hansen
- , Gavin J. Miller
- & John M. Gardiner
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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules
Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.
- Jessica L. Childs-Disney
- , Ewa Stepniak-Konieczna
- & Matthew D. Disney
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Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1
The peptide hormone relaxin has potential in the treatment of acute heart failure, but it must be intravenously injected and has a short half-life after administration. Now, small-molecule alternatives to relaxin are reported with similar efficacies to the natural hormone in functional assays.
- Jingbo Xiao
- , Zaohua Huang
- & Juan J. Marugan
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Article
| Open AccessComparative cross-linking and mass spectrometry of an intact F-type ATPase suggest a role for phosphorylation
Rotary ATPases are membrane-embedded motors that produce or consume ATP and control pH within cells. Schmidt et al.use mass spectrometry to characterize the intact chloroplast ATPase from spinach and, using comparative cross-linking, show that phosphorylation affects stability and nucleotide occupancy.
- Carla Schmidt
- , Min Zhou
- & Carol V. Robinson
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Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer
Androgen receptor signalling plays an important role in driving prostate cancer progression. Here the authors design a peptidomimetic that blocks the interaction between the androgen receptor and its coactivator PELP1, and show that the drug slows prostate cancer cell growth in a xenograft model.
- Preethi Ravindranathan
- , Tae-Kyung Lee
- & Ganesh V. Raj
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Stimuli-responsive selection of target DNA sequences by synthetic bZIP peptides
The expression of specific genes can be controlled by the combination of DNA-binding proteins, which determines their binding site selectivity. Here, simplified synthetic basic region leucine zipper-based peptides are induced to dimerize either through their C- or N-terminus, and thus are targeted to different DNA sequences.
- Jesús Mosquera
- , Adrián Jiménez-Balsa
- & José L Mascareñas
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Article
| Open AccessAssembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein
AChBP is used as a structurally accessible prototype for studying ligand binding to nicotinic acetylcholine receptors. Stornaiuolo et al. report that a small molecule binds AChBP in an ordered p–p stack of three molecules per binding site, which may lead to new approaches in drug design.
- Mariano Stornaiuolo
- , Gerdien E. De Kloe
- & Titia K. Sixma
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Article
| Open AccessDendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties
It has been hypothesized that the steroidal alkaloid dendrogenin A (DDA) is a natural metabolite. de Medina et al.show that DDA is produced in mammalian tissues from 5,6α-epoxy-cholesterol and histamine metabolism, and that the compound displays cell differentiation and anti-tumour activities.
- Philippe de Medina
- , Michael R. Paillasse
- & Marc Poirot
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Interspecific bacterial sensing through airborne signals modulates locomotion and drug resistance
Microbes use small molecules to sense and communicate with other cells and species. Kim et al. now demonstrate that volatile compounds emitted by Bacillus subtilis can affect Escherichia colimotility and antibiotic resistance through activation of a conserved regulatory mechanism.
- Kwang-sun Kim
- , Soohyun Lee
- & Choong-Min Ryu
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FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA
Internal modifications in mRNA and non-coding RNA are necessary for modulating various intracellular signalling pathways. In this study, the authors report novel modifications resulting from oxidative RNA demethylation, which regulate RNA–protein interactions affecting gene expression.
- Ye Fu
- , Guifang Jia
- & Chuan He
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Article |
An engineered dimeric protein pore that spans adjacent lipid bilayers
An important challenge in the bottom-up fabrication of artificial tissues is communication between compartments bounded by lipid bilayers. Mantri et al. engineer a dimeric transmembrane pore that, like eukaryotic gap junctions, can form a conductive pathway between adjacent bilayers.
- Shiksha Mantri
- , K. Tanuj Sapra
- & Hagan Bayley
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Article
| Open AccessArginine clustering on calix[4]arene macrocycles for improved cell penetration and DNA delivery
Arginine-rich peptides act as delivery systems for the internalization of cargoes in cells. Here, the clustering of arginine units in a parallel array on a macrocyclic scaffold produces a vector with high efficiency in DNA delivery and transfection.
- Valentina Bagnacani
- , Valentina Franceschi
- & Rocco Ungaro
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Highly sensitive sulphide mapping in live cells by kinetic spectral analysis of single Au-Ag core-shell nanoparticles
H2S is an important gasotransmitter in many physiological processes but its concentrations are difficult to measure in vivo. Xiong et al. demonstrate that local variations in H2S levels in live cells can be mapped in real time via spectral shift rates of Au-Ag core-shell plasmonic nanoprobes.
- Bin Xiong
- , Rui Zhou
- & Edward S. Yeung
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Aldara activates TLR7-independent immune defence
The skin cancer treatment Aldara generates psoriasis-like symptoms in mice, which are thought to be due to stimulation of TLR7 by the active ingredient imiquimod. The authors show that some of these inflammatory effects are independent of both imiquimod and TLR7, implicating an unexpected role for the vehicle.
- Anne Walter
- , Matthias Schäfer
- & Maries van den Broek
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Tet-mediated covalent labelling of 5-methylcytosine for its genome-wide detection and sequencing
A number of methylome sequencing technologies depend on affinity purification of methylated DNA. Zhang et al. demonstrate a click-chemistry-based protocol for covalently labelling 5-methylcytosine residues with biotin, providing enhanced sensitivity and specificity compared with antibody-based enrichment.
- Liang Zhang
- , Keith E. Szulwach
- & Chuan He
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Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo
Current pharmacokinetic models describe the distribution of drugs within tissues but usually lack single-cell resolution. Here Weissleder and colleagues visualize the subcellular distribution of an anticancer drug in real time in living animals and develop a model to extrapolate these findings to humans.
- Greg M. Thurber
- , Katy S. Yang
- & Ralph Weissleder
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Cleavage-based signal amplification of RNA
RNA detection is important in biomedical research and largely relies on the reverse transcription–PCR reaction. Zhao et al.report an isothermal reaction, which involves cleavage by a DNAzyme and signal amplification, to simultaneously amplify and detect RNA.
- Yongyun Zhao
- , Li Zhou
- & Zhuo Tang
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Article |
Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors
New influenza neuramidase inhibitors may increase preparedness against influenza outbreaks. Vavricka et al.confirm the catalytic mechanism of neuramidase and show that it can be inhibited irreversibly with covalent inhibitors.
- Christopher J. Vavricka
- , Yue Liu
- & George F. Gao
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Article |
Synthetic RNA devices to expedite the evolution of metabolite-producing microbes
Genome-wide variation in the directed evolution of metabolite-overproducing microbes requires high-throughput screening platforms. Yang et al.show that synthetic RNA devices can sense target metabolites, enrich pathway optimisation, and expedite the evolution of metabolite-producing microbes.
- Jina Yang
- , Sang Woo Seo
- & Gyoo Yeol Jung
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Article
| Open AccessA thermoresponsive and chemically defined hydrogel for long-term culture of human embryonic stem cells
To transfer cultured human embryonic stem cells (hESCs) between culture dishes, cells need to be released using mechanical, enzymatic or chemical means, which can damage cells. Zhanget al. describe a thermomodulatable hydrogel that allows gentle, reagent-free cell passaging for the long-term culture of hESCs.
- Rong Zhang
- , Heidi K. Mjoseng
- & Mark Bradley
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Article |
A safe lithium mimetic for bipolar disorder
Lithium is commonly used to treat bipolar disorder, but it exerts side effects at doses close to the therapeutic range. Singh and colleagues screen a collection of clinical compounds and find that ebselen induces lithium-like effects on mouse models of bipolar disorder by inhibiting inositol monophosphatase.
- Nisha Singh
- , Amy C. Halliday
- & Grant C. Churchill
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Article |
Activity of the mitochondrial calcium uniporter varies greatly between tissues
The flow of calcium into the mitochondrial matrix is mediated by the mitochondrial calcium uniporter. Fieniet al. apply patch-clamp techniques to mitoplasts isolated from different mouse and Drosophilatissues and find that the mitochondrial calcium uniporter activity varies depending on the tissue studied.
- Francesca Fieni
- , Sung Bae Lee
- & Yuriy Kirichok
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Article
| Open AccessVirus-like glycodendrinanoparticles displaying quasi-equivalent nested polyvalency upon glycoprotein platforms potently block viral infection
Host–pathogen relationships can be mediated by polyvalent glycan ligand–protein interactions. Here well-defined highly valent glycodendrimeric constructs are synthesized that can mimic pathogens, and can inhibit a model of infection by the Ebola virus.
- Renato Ribeiro-Viana
- , Macarena Sánchez-Navarro
- & Benjamin G. Davis
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Article
| Open AccessRapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex
Tuberous sclerosis complex is an autosomal dominant cognitive disorder caused by mutations affecting TSCgenes. Sato and colleagues examine tuberous sclerosis complex mutant mice and find that the behavioural and anatomical abnormalities can be reversed by inhibiting rapamycin-sensitive signalling pathways, even in adulthood.
- Atsushi Sato
- , Shinya Kasai
- & Masashi Mizuguchi
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Article |
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
Mice that cannot produce the hormone Klotho show various aging-related phenotypes. Here, Xie and colleagues reveal that Klotho protects the heart of mice from stress-induced remodelling by inhibiting exocytosis of the TRPC6 ion channel in cardiomyocytes.
- Jian Xie
- , Seung-Kuy Cha
- & Chou-Long Huang
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Article |
The metastasis-promoting S100A4 protein confers neuroprotection in brain injury
Multifunctional S100 proteins are upregulated in brain injury, but their role in neurodegeneration is not clear. Dmytriyeva and colleagues study in vivomodels of brain trauma and find that the S100A4 protein and its peptide mimetics protect neurons via the interleukin-10 receptor and the Janus kinase (JAK)/STAT pathway.
- Oksana Dmytriyeva
- , Stanislava Pankratova
- & Darya Kiryushko
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Article
| Open AccessLocalizing internal friction along the reaction coordinate of protein folding by combining ensemble and single-molecule fluorescence spectroscopy
Internal friction affects the kinetics of protein folding. Borgiaet al. investigate how this friction affects the folding dynamics of the protein spectrin, revealing a potential role in the rate-limiting conformational changes.
- Alessandro Borgia
- , Beth G. Wensley
- & Benjamin Schuler
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Article |
Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Mutations of the NaV1.7 voltage-gated sodium channel are implicated in abnormal pain signal transduction. Yang and colleagues perform structural modeling, mutant cycle analysis and electrophysiology on specific mutants and find that they can accurately predict their response profiles to channel blockers.
- Yang Yang
- , Sulayman D. Dib-Hajj
- & Stephen G. Waxman
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Article |
Spectroscopic observation of iodosylarene metalloporphyrin adducts and manganese(V)-oxo porphyrin species in a cytochrome P450 analogue
Metalloporphyrin compounds are studied as models of cytochrome P450, which is capable of catalysing oxidative reactions. Here, reaction conditions are varied to allow spectroscopic observation of oxidant-metalloporphyrin adducts and metal-oxo intermediates, which may elucidate reaction mechanisms.
- Mian Guo
- , Hang Dong
- & Aiwen Lei
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Article
| Open AccessSimilarities between protein folding and granular jamming
Granular matter is rigid when jammed, and flows under external loads. Here temperature- and force-unfolding molecular dynamics stimulations are used to demonstrate that proteins display features of jamming, characterized by a force distribution peak on folding and a slowdown of stress relaxation.
- Prasanth P Jose
- & Ioan Andricioaei
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CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease
L-type calcium channels comprising the CaV1.3 subunit have been linked to the generation of mitochondrial oxidant stress in Parkinson’s disease. Kang et al. identify pyrimidine-2,4,6-triones as a potential molecular scaffold, which they modify to develop a potent and highly selective CaV1.3 antagonist.
- Soosung Kang
- , Garry Cooper
- & Richard B. Silverman
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Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations
Identifying molecules that bind to RNA is difficult because information about RNA–ligand interactions is limited. Tran and Disney report a solution-based screening method that can probe large numbers of RNA motif-small molecule interactions to identify privileged RNA structures and chemical spaces that interact.
- Tuan Tran
- & Matthew D. Disney
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Article
| Open AccessSn-Beta zeolites with borate salts catalyse the epimerization of carbohydrates via an intramolecular carbon shift
Epimerization of carbohydrates to rare sugars yields products that have potential applications as anti-viral drugs or chiral building blocks. Here, Sn-Beta zeolite in the presence of sodium tetraborate is shown to catalyze the selective epimerization of aldoses in aqueous media.
- William R. Gunther
- , Yuran Wang
- & Yuriy Román-Leshkov
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Article |
Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue
The design of chemical photoswitches could potentially lead to the development of novel therapeutics that regulates neurotransmission. In this study, a light-sensitive modified derivative of propofol is shown to activate GABAA receptors in Xenopusoocytes, rat ganglion cells and mouse cerebellar slices.
- Lan Yue
- , Michal Pawlowski
- & David R. Pepperberg
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