Featured
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| Open AccessPhytohormone profiling in an evolutionary framework
Genomic evidence dates the origins of most phytohormones to terrestrialization or later. Here, the authors show that the biosynthesis of many compounds in green algae preceded their recruitment in phytohormone signaling and metabolism in land plants.
- Vojtěch Schmidt
- , Roman Skokan
- & Jan Petrášek
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Article
| Open AccessA structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.
- Xiuxiu Lu
- , Monika Chandravanshi
- & Kylie J. Walters
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Article
| Open AccessSubstrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity
InsP3 3-kinase phosphorylates 1,4,5-trisphosphate (InsP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Here, the authors used a combination of methods to survey InsP3 3-kinase ligand specificity and determined that IP3K specificity surpasses that of its natural substrate, allowing it to bind diverse ligands with a primary hydroxyl in the reactive position and based on a carbohydrate moiety.
- María Ángeles Márquez-Moñino
- , Raquel Ortega-García
- & Beatriz González
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Article
| Open AccessA universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle
Succinate dehydrogenase converts malate to enoloxaloacetate, a metabolically inactive and inhibitory side product of the TCA cycle. Here, Zmuda et al. describe a conserved metabolite damage repair enzyme that can remove enol-oxaloacetate and is critical for efficient aerobic respiration.
- Anthony J. Zmuda
- , Xiaojun Kang
- & Thomas D. Niehaus
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Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
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Article
| Open AccessStructure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.
- Sheng Wang
- , Sebastian O. Klein
- & Roland Schüle
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Article
| Open AccessChemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Deregulation of BCL-2 proteins ensures resistance to apoptosis. Here, the authors describe cytosolic BAX dimers, which in cancer cells inhibit BAX activation and they develop a strategy to modulate BAX dimers to potentiate BAX-mediated apoptosis.
- Nadege Gitego
- , Bogos Agianian
- & Evripidis Gavathiotis
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Article
| Open AccessAn inorganic mineral-based protocell with prebiotic radiation fitness
Protocell’s survival and fitness under prebiotic radiations are elusive. Here, the authors present a radioresistant protocell model based on the assembly of two types of coacervate droplets, formed through interactions of inorganic polyphosphate with manganese and cationic tripeptide, respectively, and show that nonenzymatic Mn antioxidants are essential for its resistance to radiation.
- Shang Dai
- , Zhenming Xie
- & Bing Tian
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Article
| Open AccessA simeprevir-inducible molecular switch for the control of cell and gene therapies
Chemical inducer of dimerization (CID) modules can be used to effectively control biological processes; however, CID modules have been explored primarily in engineering cells for in vitro applications using inducers that have limited clinical utility. Here, the authors identify a CID module with favorable properties to enable rapid translation from in vitro applications to potential use in humans.
- Stacey E. Chin
- , Christina Schindler
- & Natalie J. Tigue
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Article
| Open AccessCLOOME: contrastive learning unlocks bioimaging databases for queries with chemical structures
Artificial intelligence can assist in obtaining knowledge from bioimaging data, but need human annotation. Here the authors use multimodal contrastive learning to link chemical structures and cell phenotypes, which can lead to foundation models for microscopy images.
- Ana Sanchez-Fernandez
- , Elisabeth Rumetshofer
- & Günter Klambauer
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Article
| Open AccessStructure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.
- Sarath Ramachandran
- , Nikolai Makukhin
- & Alessio Ciulli
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Article
| Open AccessPharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Article
| Open AccessMolecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome
Here the authors use fast kinetics, X-ray crystallography, and cryo-EM to uncover the mechanism of ribosome inhibition by amikacin and kanamycin. They find that amikacin binds near the P-site tRNA, offering new strategies to fight antibiotic resistance.
- Savannah M. Seely
- , Narayan P. Parajuli
- & Matthieu G. Gagnon
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Article
| Open AccessTargeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
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Article
| Open AccessRapid and reversible optical switching of cell membrane area by an amphiphilic azobenzene
The surface area of living cells is tightly regulated. Here, authors show that the surface area and shape of cells can be reversibly manipulated with light using amphiphilic molecular photoswitches that enter and leave the membrane.
- Fabian Höglsperger
- , Bart E. Vos
- & Bart Jan Ravoo
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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Article
| Open AccessN-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics
Cysteine is a popular target of covalent drugs and can undergo redox modifications. Here, the authors developed cysteine probes, N-acryloylindole-alkynes, for imaging and chemoproteomics to study cysteine oxidation and to identify targetable hotspots by small molecule compounds.
- Tin-Yan Koo
- , Hinyuk Lai
- & Clive Yik-Sham Chung
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Article
| Open AccessNERNST: a genetically-encoded ratiometric non-destructive sensing tool to estimate NADP(H) redox status in bacterial, plant and animal systems
NADP(H) is a crucial cofactor, acting as a reducing agent in numerous pathways in living organisms. Here the authors report a ratiometric biosensor named NERNST, which can be used to estimate the NADP(H) redox status in bacterial, plant and animal cells and organelles.
- Pamela E. Molinari
- , Adriana R. Krapp
- & Matias D. Zurbriggen
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Article
| Open AccessCo-crystal structures of the fluorogenic aptamer Beetroot show that close homology may not predict similar RNA architecture
The recently discovered aptamer Beetroot is a homodimeric RNA that binds and activates DFAME, a conditional, red-shifted fluorophore derived from GFP. Here the authors determine the Beetroot-DFAME co-crystal structure, which is distinctively different from that of similar RNA aptamer Corn.
- Luiz F. M. Passalacqua
- , Mary R. Starich
- & Adrian R. Ferré-D’Amaré
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Article
| Open AccessChemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development
Chemical imaging of maize roots reveals differential patterns of TCA cycle metabolites along the axis of development. Root growth is affected in distinct ways by exogenous treatments and tissue-specific genetic manipulation of TCA metabolites.
- Tao Zhang
- , Sarah E. Noll
- & Alexandra J. Dickinson
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Article
| Open AccessConstrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics
Constrained catecholamines gain β2AR selectivity. Although the orthosteric pockets are identical in β1AR and β2AR, surrounding residues allosterically modify the pockets and contribute to the β2AR selectivity of the constrained catecholamines.
- Xinyu Xu
- , Jeremy Shonberg
- & Peter Gmeiner
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Article
| Open AccessStructural basis of selective cannabinoid CB2 receptor activation
Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB2R activation.
- Xiaoting Li
- , Hao Chang
- & Tian Hua
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Article
| Open AccessA general highly efficient synthesis of biocompatible rhodamine dyes and probes for live-cell multicolor nanoscopy
Rhodamines are privileged fluorescent dyes for labelling intracellular structures in living cells. Here, the authors present a facile protecting-group-free synthesis permitting generation of a wide range of symmetrical and unsymmetrical 4-carboxyrhodamines covering the whole visible spectrum.
- Jonas Bucevičius
- , Rūta Gerasimaitė
- & Gražvydas Lukinavičius
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Article
| Open AccessStructural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins
Asymmetric reduction of prochiral ketones is challenging. Here, the authors identify and solve the structure of anthrol reductase CbAR, whose variant H162F can convert 1,3-cyclodiketones and α-haloacetophenones to the corresponding chiral alcohols.
- Xiaodong Hou
- , Huibin Xu
- & Yijian Rao
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Article
| Open AccessBiomolecular condensate phase diagrams with a combinatorial microdroplet platform
A central concept for characterising phase-separating systems is the phase diagram but generation of such diagrams for biomolecular systems is typically slow and low-throughput. Here the authors describe PhaseScan, a combinatorial droplet microfluidic platform for high-resolution acquisition of multidimensional biomolecular phase diagrams.
- William E. Arter
- , Runzhang Qi
- & Tuomas P. J. Knowles
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Article
| Open AccessAnti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
The development of selective ClpP activators targeting only the MRSA isolates without interfering with the human variant is currently challenging. Here, the authors report on the structure-based design of enantiomers of ZG197 and identify the discriminator factor between the proteins.
- Bingyan Wei
- , Tao Zhang
- & Cai-Guang Yang
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Article
| Open AccessHemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity
The development of photochromic systems is an important and growing area of research, in particular for bioactive molecular photoswitches. Here, the authors report on photopharmacological antimitotic agents, operational under visible light, based on a peptide-derived hemipiperazine photochrome.
- Susanne Kirchner
- , Anna-Lena Leistner
- & Zbigniew Pianowski
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Article
| Open AccessVisualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target
Studying the specific roles of macrophage subsets has been hampered by a lack of subset-specific probes. Here the authors report an M1 selective fluorescent probe named CDr17, and demonstrate the suitability of this probe for tracking M1 macrophages in vivo.
- Heewon Cho
- , Haw-Young Kwon
- & Young-Tae Chang
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Article
| Open AccessOrthogonally-tunable and ER-targeting fluorophores detect avian influenza virus early infection
Methods to detect and distinguish the early stage of viral infection often involve complicated and time-consuming protocols. Here, the authors disclose a class of fluorescent molecules that enable fast detection of avian influenza virus infection by selectively localizing at the endoplasmic reticulum in the cell.
- Taewon Kang
- , Md Mamunul Haque
- & Dongwhan Lee
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Article
| Open AccessA small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II.
- Yanli Liu
- , Aman Iqbal
- & Jinrong Min
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Article
| Open AccessElucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands.
- Mark A. Tye
- , N. Connor Payne
- & Ralph Mazitschek
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Article
| Open AccessCryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae
The Na+-pumping NADH-ubiquinone oxidoreductase (Na+-NQR) is a unique respiratory enzyme found in many pathogenic bacteria. Here, the authors present high-resolution cryo-EM structures of Na+-NQR from V. cholerae with or without a bound inhibitor.
- Jun-ichi Kishikawa
- , Moe Ishikawa
- & Hideto Miyoshi
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Perspective
| Open AccessWater as the often neglected medium at the interface between materials and biology
Key to life, water is an often overlooked or over-simplified factor in materials and biology. In this perspective the importance of water in biomaterials is discussed as well as the need to more carefully consider water’s role in every aspect of a biomaterial’s function.
- B. L. Dargaville
- & D. W. Hutmacher
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Article
| Open AccessProbing strigolactone perception mechanisms with rationally designed small-molecule agonists stimulating germination of root parasitic weeds
Strigolactone agonists could potentially help control noxious weeds by promoting suicidal germination. Here the authors describe a series of small molecule agonists that stimulate germination via the Striga ShHTL7 receptor and show that stereochemistry and hydrolysis-independent signalling mediate potency.
- Dawei Wang
- , Zhili Pang
- & Zhen Xi
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Article
| Open AccessModulating mitofusins to control mitochondrial function and signaling
Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins’ activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage.
- Emmanouil Zacharioudakis
- , Bogos Agianian
- & Evripidis Gavathiotis
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Matters Arising
| Open AccessReply to: Pitfalls in using phenanthroline to study the causal relationship between promoter nucleosome acetylation and transcription
- Benjamin J. E. Martin
- & LeAnn J. Howe
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Article
| Open AccessPeripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects
The current peripherally acting mu-opioid receptor antagonists present limited permeability and pharmacokinetic properties. Here, the authors develop a drug delivery approach based on AG10, which demonstrates the impact of mu-opioid receptors in the central nervous system in precipitating opioid-induced constipation.
- Md Tariqul Haque Tuhin
- , Dengpan Liang
- & Mamoun M. Alhamadsheh
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Article
| Open AccessIdentification of oleoylethanolamide as an endogenous ligand for HIF-3α
Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.
- Xiaotong Diao
- , Fei Ye
- & Dalei Wu
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Article
| Open AccessDevelopment of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19
Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.
- Hengrui Liu
- , Sho Iketani
- & Brent R. Stockwell
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Article
| Open AccessLeveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors
Peptide fragments derived from the interfaces of protein-protein interactions (PPIs) provide useful templates for designing small molecule PPI inhibitors. Here, the authors utilize the multivalency of an MdmX-binding p53 peptide to develop a weak inhibitor of MdmX into potent Mdm2/MdmX inhibitors.
- Xiyao Cheng
- , Rong Chen
- & Zhengding Su
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Article
| Open AccessDefining molecular glues with a dual-nanobody cannabidiol sensor
Molecular glue has been used as a broad term describing a class of protein interaction-promoting compounds. Here, the authors outline two unifying thermodynamic features to formally define molecular glues and guide their prospective discovery.
- Shiyun Cao
- , Shoukai Kang
- & Ning Zheng
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Article
| Open AccessBicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase
Current treatments for toxoplasmosis are limited by adverse reactions and inability to cure chronic infections dominated by semi-dormant cyst forms. Here the authors demonstrate the potential of small molecule inhibitors of PheRS for controlling acute and chronic toxoplasmosis.
- Joshua B. Radke
- , Bruno Melillo
- & L. David Sibley
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Article
| Open AccessHypocrates is a genetically encoded fluorescent biosensor for (pseudo)hypohalous acids and their derivatives
There are a lack of tools to study the dynamics of (pseudo)hypohalous acids in live cells. Here the authors report a genetically encoded fluorescent biosensor, Hypocrates, for (pseudo)hypohalous acids and their derivatives which they use in cells and in a zebrafish tail fin injury model.
- Alexander I. Kostyuk
- , Maria-Armineh Tossounian
- & Vsevolod V. Belousov
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Article
| Open AccessSiderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut
Zinc is an essential cofactor for bacterial metabolism. Here, the authors show that the probiotic bacterium Escherichia coli Nissle 1917 utilizes the siderophore yersiniabactin as a zincophore, allowing the microbe to grow in zinc-limited media and to thrive in the inflamed gut.
- Judith Behnsen
- , Hui Zhi
- & Manuela Raffatellu
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Article
| Open AccessHydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation
A major question in redox signaling is how H2O2 oxidizes target protein thiols in the presence of glutathione peroxidases and peroxiredoxins. We reveal signaling by H2O2 via its enzymatic conversion to an alkyl hydroperoxide that stereo-specifically escapes peroxidases and oxidizes target proteins.
- Raphael F. Queiroz
- , Christopher P. Stanley
- & Roland Stocker
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Article
| Open Access2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases
The human 2-oxoglutarate (2OG) oxygenases FIH and AspH are relevant drug targets. Here, the authors show that synthetic and naturally occurring 2OG derivatives can selectively modulate FIH and AspH activities, suggesting that these compounds may serve as a basis to develop 2OG oxygenase-targeting probes and drugs.
- Yu Nakashima
- , Lennart Brewitz
- & Christopher J. Schofield
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Article
| Open AccessA scalable workflow to characterize the human exposome
Humans are exposed to millions of chemicals but mass spectrometry (MS)-based targeted biomonitoring assays are usually limited to a few hundred known hazards. Here, the authors develop a workflow for MS-based untargeted exposome profiling of known and unidentified environmental chemicals.
- Xin Hu
- , Douglas I. Walker
- & Dean P. Jones
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Article
| Open AccessSubcellular localization of biomolecules and drug distribution by high-definition ion beam imaging
Multiplexed ion beam imaging can provide subcellular localisation information but with limited resolution. Here the authors report an ion beam imaging method with nanoscale resolution which they use to assess the subcellular distribution of cisplatin.
- Xavier Rovira-Clavé
- , Sizun Jiang
- & Garry P. Nolan
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Article
| Open AccessTetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Yi Yang
- , Adam Csakai
- & Hang Yin