Featured
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Article
| Open AccessEngineering a microbial biosynthesis platform for de novo production of tropane alkaloids
Tropane alkaloids (TAs) are a group of phytochemicals that are used to treat neurological disorders. Here, the authors engineer baker’s yeast to produce tropine, a key intermediate in the biosynthetic pathway of TAs, and cinnamoyltropine, a non-canonical TA, from simple carbon and nitrogen sources.
- Prashanth Srinivasan
- & Christina D. Smolke
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Article
| Open AccessA role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis
Formicapyridines are similar to pentacyclic fasamycin and formicamycin aromatic polyketides but with a pyridine moiety. Here the authors rationally mutate the biosynthetic gene cluster to increase production and identify a non-catalytic role for the ABM superfamily of proteins.
- Zhiwei Qin
- , Rebecca Devine
- & Barrie Wilkinson
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Article
| Open AccessA conserved RNA structural motif for organizing topology within picornaviral internal ribosome entry sites
Picornaviruses use modular RNA domains in their internal ribosome entry sites (IRESs) for translation through non-canonical, cap-independent mechanisms. Here the authors report the crystal structure of domain V from the IRES of hepatitis A virus (HAV) ssRNA genome, suggesting that the functional homology among different types of picornaviral IRESs is structure-based.
- Deepak Koirala
- , Yaming Shao
- & Joseph A. Piccirilli
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Article
| Open AccessSynthetic molecular recognition nanosensor paint for microalbuminuria
Microalbuminuria, a clinical marker associated with cancer and hypertension, defined by low albumin levels in the urine, is normally detected by immunoassay. Herein, a nanosensor paint was developed using a polymer to mimic fatty acid binding to albumin, transduced by carbon nanotube fluorescence.
- Januka Budhathoki-Uprety
- , Janki Shah
- & Daniel A. Heller
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Article
| Open AccessHSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine
Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear. Here, the authors analyze proteome changes upon HSP90 inhibition and show that an m6A-mediated mechanism contributes to the heat shock-induced upregulation of DNAJB4.
- Weili Miao
- , Lin Li
- & Yinsheng Wang
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Article
| Open AccessA switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade
Autophagy mediated by the conjugation pathway for ubiquitin-like proteins plays a key role in controlling homeostasis in eukaryotic cells. Here the authors provide a molecular basis for allosteric activation of the E2 ligase Atg3, uncovering the mechanism underlying Atg8 lipidation and a novel mechanism regulating E1-E2-E3-mediated ubiquitin-like protein conjugation.
- Yumei Zheng
- , Yu Qiu
- & Brenda A. Schulman
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Article
| Open AccessBis-naphthopyrone pigments protect filamentous ascomycetes from a wide range of predators
It is thought that fungi protect themselves from predators by the production of toxic compounds. Here, Xu et al. show that a wide range of animal predators avoid feeding on Fusarium fungi, and this depends on fungal production of a bis-naphthopyrone pigment that is not toxic to the predators.
- Yang Xu
- , Maria Vinas
- & Petr Karlovsky
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Article
| Open AccessPhysiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin
The mechanism of iron-sulfur (Fe-S) cluster biosynthesis is not fully understood. Here, the authors develop a physiologically relevant in vitro model of Fe-S cluster assembly, allowing them to elucidate the sequence of Fe-S cluster synthesis along with the respective roles of ferredoxin-2 and frataxin.
- Sylvain Gervason
- , Djabir Larkem
- & Benoit D’Autréaux
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Article
| Open AccessSmall molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.
- Mélissanne de Wispelaere
- , Guangyan Du
- & Priscilla L. Yang
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Article
| Open AccessThe structural basis of N-acyl-α-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase
The antimicrobial β-lactone obafluorin is produced by a Nonribosomal Peptide Synthetase (NRPS). Here the authors present the crystal structure of the obafluorin NRPS and develop a reconstitution assay that allows them to analyse product formation from obafluorin NRPS mutants and alternate substrates.
- Dale F. Kreitler
- , Erin M. Gemmell
- & Andrew M. Gulick
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Article
| Open AccessA biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids
C19 hydroxylation is a unique feature of some bioactive steroids. Here, the authors developed a direct C19 hydroxylation approach to scalably access 19-OH-cortexolone in the host T. cucumeris and then converted the product into various pharmaceutically useful products via chemical synthesis.
- Junlin Wang
- , Yanan Zhang
- & Qianghui Zhou
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Article
| Open AccessTime-resolved NMR monitoring of tRNA maturation
Transfer RNA (tRNA) is regulated by RNA modifications. Here the authors employ time-resolved NMR to monitor modifications of yeast tRNAPhe in cellular extracts, revealing a sequential order and cross-talk between modifications.
- Pierre Barraud
- , Alexandre Gato
- & Carine Tisné
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Article
| Open AccessCryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs
Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.
- Scott A. Hollingsworth
- , Brendan Kelly
- & Ron O. Dror
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Article
| Open AccessGram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
The presence of the unnatural amino acid l-allo-enduracidine in the cyclic scaffold of teixobactin complicates its total synthesis. Here, the authors developed a convergent strategy for the scalable synthesis teixobactin and found two potent analogous.
- Yu Zong
- , Fang Fang
- & Yu Rao
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Article
| Open AccessArtificial cysteine-lipases with high activity and altered catalytic mechanism created by laboratory evolution
Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — accommodates bulky substrates.
- Yixin Cen
- , Warispreet Singh
- & Manfred T. Reetz
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Article
| Open AccessAcetylation regulates ribonucleotide reductase activity and cancer cell growth
Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates to provide dNTP precursors for DNA synthesis. Here the authors show that the availability of dNTPs, DNA replication, and cellular proliferation, are modulated by acetylation and deacetylation of RRM2 by KAT7 and Sirt2 respectively.
- Guo Chen
- , Yin Luo
- & Xingming Deng
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Article
| Open AccessStructural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP
The inner centromere protein (INCENP) activates Aurora kinase B (AURKB) and Aurora kinase C. Here the authors provide insights into the activation mechanism of AURKB/C by determining the crystal structure of fully active phosphorylated human AURKC bound to the phosphorylated C-terminal IN-box section of human INCENP.
- Kamal R. Abdul Azeez
- , Sneha Chatterjee
- & Jonathan M. Elkins
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Article
| Open AccessChemical genomics reveals histone deacetylases are required for core regulatory transcription
Core regulatory transcription factors are usually regulated by cell-type specific super enhancers (SEs). Here, the authors screen for chemical probes able to distinguish between SE-driven and promoter-driven transcription and find that histone deacetylases are selectively required for core regulatory transcription.
- Berkley E. Gryder
- , Lei Wu
- & Javed Khan
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Article
| Open AccessDietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain
Lipid droplets (LDs) are fat storage organelles that are initiated and expanded by seipins at ER contact sites. Here the authors show that the C. elegans seipin ortholog SEIP-1 is recruited to these sites by certain dietary fatty acids to support the expansion of a subset of LDs.
- Zhe Cao
- , Yan Hao
- & Ho Yi Mak
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Article
| Open AccessABCB1 protects bat cells from DNA damage induced by genotoxic compounds
Bats possess an extended lifespan compared to most mammals of their size, and have a low cancer incidence. Here the authors show that several bat species exhibit resistance to genotoxic agents that is in part attributable to high expression of the ABCB1 transporter.
- Javier Koh
- , Yoko Itahana
- & Koji Itahana
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Article
| Open AccessA split fluorescent reporter with rapid and reversible complementation
Monitoring protein-protein interactions via bimolecular fluorescence complementation is often limited by the slow kinetics and irreversibility of the complementation. Here the authors introduce a fluorescent reporter for real-time monitoring of reversible interactions based on complementation and binding of an exogenous chromophore.
- Alison G. Tebo
- & Arnaud Gautier
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Article
| Open AccessInsights into real-time chemical processes in a calcium sensor protein-directed dynamic library
Dynamic combinatorial chemistry (DCC) is instrumental in the discovery of ligands for pharmaceutical targets. Here, the authors adapted DCC to work at 4 degrees Celsius and used it to identify a ligand for Neuronal Calcium Sensor-1 that promotes NCS-1/Ric8a protein-protein interaction.
- Andrea Canal-Martín
- , Javier Sastre
- & Ruth Pérez-Fernández
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Article
| Open AccessA fast and specific fluorescent probe for thioredoxin reductase that works via disulphide bond cleavage
Thioredoxin reductase (TrxR) plays a crucial part in regulating cellular redox homeostasis. Here, the authors developed a fluorescent probe composed of a five-membered disulphide, a coumarin fluorophore and a urea linker that detects TrxR activity with fast response and high selectivity.
- Xinming Li
- , Baoxin Zhang
- & Jianguo Fang
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Article
| Open AccessPhosphorylated lipid-conjugated oligonucleotide selectively anchors on cell membranes with high alkaline phosphatase expression
Membrane-anchored DNA probes have been used to study molecular interactions and control cell assembly, but are not selective for different cell membranes. Here the authors develop a lipid-conjugated oligonucleotide for alkaline phosphatase-dependent cell membrane anchorage and use it to distinguish different cancer cells.
- Cheng Jin
- , Jiaxuan He
- & Weihong Tan
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Article
| Open AccessThe Polycomb protein Ezl1 mediates H3K9 and H3K27 methylation to repress transposable elements in Paramecium
H3K9me3 and H3K27me3 chromatin silencing marks are usually deposited by different SET-domain proteins. Here the authors show that the Enhancer-of-zeste-like protein Ezl1, from the unicellular eukaryote Paramecium tetraurelia, catalyzes methylation of histone H3 in vitro and in vivo with an apparent specificity toward K9 and K27, and controls the repression of transposable elements.
- Andrea Frapporti
- , Caridad Miró Pina
- & Sandra Duharcourt
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Article
| Open AccessSmall-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.
- Gerard Minuesa
- , Steven K. Albanese
- & Michael G. Kharas
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Article
| Open AccessKistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics
Kistamicin is a structurally divergent glycopeptide antibiotic (GPA) that contains a unique 15-membered A-O-B ring. Here, the authors obtained a crystal structure of the kistamicin OxyA/X-domain complex and analysed the cyclisation cascade leading to the formation of the A-O-B ring.
- Anja Greule
- , Thierry Izoré
- & Max J. Cryle
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Article
| Open AccessSingle-site glycine-specific labeling of proteins
Single-site labelling of proteins is desirable, e.g., for analytical purposes. Here, the authors developed a method in which they use an aldol-type reaction to modify proteins at N-terminal glycine residues in an efficient and selective manner, which is also applicable to cell lysates.
- Landa Purushottam
- , Srinivasa Rao Adusumalli
- & Vishal Rai
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Article
| Open AccessImportance of potassium ions for ribosome structure and function revealed by long-wavelength X-ray diffraction
Metal ions play essential roles in myriads of biological processes, from catalytic co-factors to supporting protein and nucleic acid structures. Here the authors use long-wavelength X-ray diffraction to locate hundreds of potassium ions taking part in the formation of rRNA tertiary structure, mediating rRNA–protein interactions and supporting ribosomal protein structures and function.
- Alexey Rozov
- , Iskander Khusainov
- & Gulnara Yusupova
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Article
| Open AccessThe UbiX flavin prenyltransferase reaction mechanism resembles class I terpene cyclase chemistry
The UbiD-UbiX decarboxylase system is required for the biosynthesis of quinone cofactors. Here, the authors combine structural and biochemical analyses to elucidate the UbiX reaction mechanism, showing that it resembles the mode of action of class I terpene cyclases.
- Stephen A. Marshall
- , Karl A. P. Payne
- & David Leys
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Article
| Open AccessTracking carrier protein motions with Raman spectroscopy
Acyl carrier proteins (ACPs), a universal and highly conserved carrier of acyl intermediates during fatty acid and polyketide synthesis, are difficult to visualise. Here, the authors developed a facile, Raman spectroscopy-based method to detect ACP-substrate interactions.
- Samuel C. Epstein
- , Adam R. Huff
- & Louise K. Charkoudian
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Article
| Open AccessDiscovery of processive catalysis by an exo-hydrolase with a pocket-shaped active site
Enzyme substrates and products often diffuse too rapidly to assess the catalytic implications of these movements. Here, the authors characterise the structural basis of product and substrate diffusion for an exo-hydrolase and discover a substrate-product assisted processive catalytic mechanism.
- Victor A. Streltsov
- , Sukanya Luang
- & Maria Hrmova
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Article
| Open AccessProteome-wide detection of S-nitrosylation targets and motifs using bioorthogonal cleavable-linker-based enrichment and switch technique
Reversible cysteine modifications play important roles in cellular redox signaling. Here, the authors develop a chemical proteomics strategy that enables the quantitative analysis of endogenous cysteine nitrosylation sites and their dynamic regulation under nitrosative stress conditions.
- Ruzanna Mnatsakanyan
- , Stavroula Markoutsa
- & René P. Zahedi
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Article
| Open AccessBridging the gap between transition metal- and bio-catalysis via aqueous micellar catalysis
Chemo-enzymatic tandem processes allow access to more complex non-racemic products. Here, the authors show that non-ionic surfactants, especially the tailor-made surfactant TPGS-750-M, enhance the activity of alcohol dehydrogenase to afford stereopure products in a 1-pot reaction.
- Margery Cortes-Clerget
- , Nnamdi Akporji
- & Bruce H. Lipshutz
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Article
| Open AccessAkt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
T-cell subsets differ in metabolic requirements for particular tasks. Here the authors characterize metabolic fluxes in naïve human CD4+ cells upon activation, and identify a role of Stat5 in glutaminolysis linked to IL-2 production.
- Nicholas Jones
- , Emma E. Vincent
- & Catherine A. Thornton
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Article
| Open AccessSide chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
Polyglutamine (polyQ) tracts are low-complexity regions and their expansion is linked to certain neurodegenerative diseases. Here the authors combine experimental and computational approaches to find that the length of the androgen receptor polyQ tract correlates with its helicity and show that the polyQ helical structure is stabilized by hydrogen bonds between the Gln side chains and main chain carbonyl groups.
- Albert Escobedo
- , Busra Topal
- & Xavier Salvatella
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Article
| Open AccessA chemical toolbox for the study of bromodomains and epigenetic signaling
Bromodomains are conserved protein interaction modules that recognize acetyl-lysine modifications. Here the authors present a set of 25 selective small molecule inhibitors covering 29 human bromodomain targets and comprehensively evaluate the selectivity of this probe-set.
- Qin Wu
- , David Heidenreich
- & Stefan Knapp
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Article
| Open AccessCeramides bind VDAC2 to trigger mitochondrial apoptosis
Ceramides are lipids that act directly on mitochondria to trigger apoptosis, but the underlying mechanism remains largely unclear. Here authors use a photoactivatable ceramide probe combined with a computation approach and functional studies to identify the voltage-dependent anion channel VDAC2 as a direct effector of ceramide-mediated cell death.
- Shashank Dadsena
- , Svenja Bockelmann
- & Joost C. M. Holthuis
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Article
| Open AccessImmunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors
Nanoparticles can stimulate tumour microenvironment to promote anti-tumour immunity. Here, the authors show that the combination of delivering drugs by a nanoscale coordination polymer and anti-PD-L1 is synergistic in treating murine colorectal cancer.
- Xiaopin Duan
- , Christina Chan
- & Wenbin Lin
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Article
| Open AccessReconstitution of the lipid-linked oligosaccharide pathway for assembly of high-mannose N-glycans
Attachment of the oligosaccharide Man9GlcNAc2 is required for glycoprotein folding and secretion but synthesizing this compound for structural and functional studies has remained challenging. Here, the authors achieve efficient Man9GlcNAc2 synthesis by reconstituting its biosynthetic pathway in vitro.
- Sheng-Tao Li
- , Tian-Tian Lu
- & Xiao-Dong Gao
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Article
| Open AccessBacterial glycosyltransferase-mediated cell-surface chemoenzymatic glycan modification
Glycan molecules can be modified directly on the cell surface via chemoenzymatic approaches. Here, the authors employ a set of four bacterial glycosyltransferases to develop a live cell-based killing assay to probe host cell glycan-mediated influenza A virus infection.
- Senlian Hong
- , Yujie Shi
- & Peng Wu
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Article
| Open AccessSpatiotemporal control of coacervate formation within liposomes
The understanding of liquid-liquid phase separation is crucial to cell biology and benefits from cell-mimicking in vitro assays. Here, the authors develop a microfluidic platform to study coacervate formation inside liposomes and show the potential of these hybrid systems to create synthetic cells.
- Siddharth Deshpande
- , Frank Brandenburg
- & Cees Dekker
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Article
| Open AccessEnzymatic synthesis of lignin derivable pyridine based polyesters for the substitution of petroleum derived plastics
The increasing concern of global plastic pollution has led to an increase in the production and characterization of bio-based and biodegradable alternatives. Here the authors show the synthesis of a series of fully bio-based alternatives based on 2,4-, 2,5-, and 2,6- pyridinedicarboxylic acids, via enzymatic catalysis.
- Alessandro Pellis
- , James W. Comerford
- & Thomas J. Farmer
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Article
| Open AccessBreast cancer quantitative proteome and proteogenomic landscape
Gene expression profiles can classify breast cancer into five clinically relevant subtypes. Here, the authors perform an in-depth quantitative profiling of the proteome of 45 breast tumors, and show they can recapitulate the transcriptome-based classifications and identify many potentially antigenic tumour-specific peptides.
- Henrik J. Johansson
- , Fabio Socciarelli
- & Janne Lehtiö
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Article
| Open AccessAn artificial triazole backbone linkage provides a split-and-click strategy to bioactive chemically modified CRISPR sgRNA
For CRISPR-Cas9 genome editing, Cas9 protein is guided to its target by single guide (sg) RNA. Here, the authors synthesised sgRNAs via convergent ‘click’ ligation of variable 20-mer RNAs that target the genome and a Cas9-binding 79-mer chimeric RNA/2´-OMe RNA of fixed sequence in a single tube.
- Lapatrada Taemaitree
- , Arun Shivalingam
- & Tom Brown
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Article
| Open AccessDirected self-assembly of herbal small molecules into sustained release hydrogels for treating neural inflammation
There is interest in the development of drug-based hydrogels for responsive sustained drug release. Here, the authors report on the self-assembly of natural small molecule, rhein, into hydrogels and the application of the hydrogels as stable controlled release agents for neuro-inflammatory therapy
- Jun Zheng
- , Rong Fan
- & Yang Wang
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Article
| Open AccessNucleobase pairing and photodimerization in a biologically derived metal-organic framework nanoreactor
Metal-organic frameworks have shown promise as nanoreactors, facilitating the synthesis of molecules that are otherwise difficult to isolate. Here, the authors design a framework featuring unobstructed adenine linkers to which thymine molecules can base-pair, allowing for thymine dimerization in the pores upon UV irradiation.
- Samantha L. Anderson
- , Peter G. Boyd
- & Kyriakos C. Stylianou
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Article
| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessCycles of external dependency drive evolution of avian carotenoid networks
The mechanisms that accommodate variable external dependencies in evolution are not clear. Here, the authors show that switches between external and internal metabolic controls of carotenoid-producing networks in birds are linked to shifts in evolutionary rates, with internalization of control resulting in bursts of evolutionary diversification.
- Alexander V. Badyaev
- , Alexander B. Posner
- & Dawn M. Higginson
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