Featured
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Article
| Open AccessThe evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba
Diels-Alderases (DAs), enzymes catalyzing [4 + 2] cycloaddition reactions, are of high interest, but insights into their evolution are lacking. Here, the authors investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites, suggesting they evolved from an ancestor functioning as a flavin adenine dinucleotide-dependent oxidocyclase.
- Qi Ding
- , Nianxin Guo
- & Xiaoguang Lei
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Article
| Open AccessDissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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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 AccessWidespread extracellular electron transfer pathways for charging microbial cytochrome OmcS nanowires via periplasmic cytochromes PpcABCDE
How do cells put electrons to rest? Using a minimal pathway to get rid of excess metabolic electrons, diverse environmentally important microbes overcome large spatial, kinetic, and thermodynamic barriers in order to survive in extreme anoxic conditions.
- Pilar C. Portela
- , Catharine C. Shipps
- & Nikhil S. Malvankar
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Article
| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
| Open Access2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels
Reactive sulfane sulfur species such as persulfides and H2S2 are important redox regulators and linked to H2S signaling, but their study is hindered by a lack of suitable donors to produce them. Here, the authors report 2H-thiopyran-2-thione sulfine (TTS), a compound which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S.
- Qi Cui
- , Meg Shieh
- & Ming Xian
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Article
| Open AccessBiosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol
Despite intensive investigation, stepwise reactions from diol to Taxol tetracyclic core skeleton remain unclear. Here, authors fill this gap by identifying two P450s and confirming the reaction order.
- Chengshuai Yang
- , Yan Wang
- & Zhihua Zhou
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Article
| Open AccessA citric acid cycle-deficient Escherichia coli as an efficient chassis for aerobic fermentations
While tricarboxylic acid cycle (TCA cycle) is required for heterotrophic microbes, it reduces carbon yield of industrial products due to the release of excess CO2. Here, the authors construct an E. coli strain without a functional TCA cycle and demonstrate its feasibility as a chassis strain for production of four separate compounds.
- Hang Zhou
- , Yiwen Zhang
- & Baixue Lin
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Article
| Open AccessStructure-based prediction and characterization of photo-crosslinking in native protein–RNA complexes
Feng et al. developed a computational method PxR3D-map to jointly analyze crosslinked nucleotides and amino acids in protein-RNA complexes, which revealed key structural features underlying photocrosslinking of protein and RNA in cells.
- Huijuan Feng
- , Xiang-Jun Lu
- & Chaolin Zhang
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Article
| Open AccessThunder-DDA-PASEF enables high-coverage immunopeptidomics and is boosted by MS2Rescore with MS2PIP timsTOF fragmentation prediction model
Human leukocyte antigen (HLA) class I peptide ligands (HLAIps) are targets for developing vaccines and immunotherapies. Here the authors report Thunder-DDA-PASEF, an immunopeptidomics method which enhances the identification of vital HLAIps crucial for vaccine and immunotherapy development.
- David Gomez-Zepeda
- , Danielle Arnold-Schild
- & Stefan Tenzer
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Article
| Open AccessToll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity
Toll/interleukin-1 receptor domain-containing proteins can catabolize NAD+. Here, Wang et al show that these proteins can also function as NAD-RNA decapping enzymes by releasing the NAM moiety from the NAD-RNA, resulting in the regulation of gene expression.
- Xufeng Wang
- , Dongli Yu
- & Xuemei Chen
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Article
| Open AccessSpatial engineering of single-atom Fe adjacent to Cu-assisted nanozymes for biomimetic O2 activation
Integrating heterogeneous single atom nanozyme (SAzyme) configurations and homogeneous enzyme-like mechanism is promising for optimizing SAzymes but elusive. Here the authors address this issue by developing a spatial engineering strategy to fabricate dual-sites SAzymes incorporating single atom Fe active centers (Fe–N4) and Cu atomic sites (Cu–N4) in a vertically stacked Fe–N4 and Cu–N4 geometry.
- Ying Wang
- , Vinod K. Paidi
- & Kwok-Yin Wong
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Article
| Open AccessBiosensor and machine learning-aided engineering of an amaryllidaceae enzyme
Amaryllidaceae alkaloids, such as the Alzheimer’s medication galantamine, are currently extracted from low-yielding daffodils. Here, authors pair biosensor-assisted screening with machine learning-guided protein design to rapidly engineer an improved Amaryllidaceae enzyme in a microbial host.
- Simon d’Oelsnitz
- , Daniel J. Diaz
- & Andrew D. Ellington
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Article
| Open AccessHomo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria
Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.
- Lukas Junk
- , Volker M. Schmiedel
- & Guido Boehmelt
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Article
| Open AccessDJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
- Aizhan Akhmadi
- , Adilkhan Yeskendir
- & Darkhan Utepbergenov
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Article
| Open AccessIn-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells
I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.
- Pavlína Víšková
- , Eva Ištvánková
- & Lukáš Trantírek
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Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
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Article
| Open AccessA druggable conformational switch in the c-MYC transactivation domain
Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation.
- Dilraj Lama
- , Thibault Vosselman
- & Marie Arsenian Henriksson
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Article
| Open AccessMirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins
Mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders but is hindered by the optimization required for D-protein chemical synthesis. Here, the authors report a general mirror-image phage display pipeline based on automated flow peptide synthesis and use it to prepare and characterize 12 L/D-protein pairs.
- Alex J. Callahan
- , Satish Gandhesiri
- & Bradley L. Pentelute
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Article
| Open AccessMetabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development
Sleep-disordered breathing (SDB) is a prevalent disorder linked to higher cardiovascular disease risk. Here, the authors show that summary scores reflecting SDB metabolite signatures are associated with increased risks for incident hypertension and diabetes, potentially useful in guiding risk stratification.
- Ying Zhang
- , Bing Yu
- & Tamar Sofer
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Article
| Open AccessEngineering self-deliverable ribonucleoproteins for genome editing in the brain
The delivery of CRISPR RNPs has potential advantages over other genome editing approaches, including reduced off-target editing and reduced immunogenicity. Here the authors report self-deliverable Cas9 RNPs capable of robustly editing cultured cells in vitro and the mouse brain upon direct injections.
- Kai Chen
- , Elizabeth C. Stahl
- & Jennifer A. Doudna
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Article
| Open AccessCreation of a point-of-care therapeutics sensor using protein engineering, electrochemical sensing and electronic integration
Low-cost point-of-care sensors are vital for precision medicine. Here, the authors have repurposed a glucometer for breast cancer therapeutic detection capable of sensing tamoxifen in human blood, utilizing blood glucose to power and amplify the therapeutic signals
- Rong Cai
- , Chiagoziem Ngwadom
- & Caroline M. Ajo-Franklin
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Article
| Open AccessSubstrate binding and catalytic mechanism of the Se-glycosyltransferase SenB in the biosynthesis of selenoneine
SenB is a Se-glycosyltransferase in the microbial biosynthesis pathway of selenoneine. Here, the authors perform the structure-function investigation, providing mechanistic insights into a two-step catalytic reaction of SenB.
- Wei Huang
- , Jun Song
- & Feng Long
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Article
| Open AccessIncreased CO2 fixation enables high carbon-yield production of 3-hydroxypropionic acid in yeast
CO2 fixation plays an important role to make bioproduction cost competitive. Here, the authors take 3-hydroxypropionic acid as an example to showcase how to achieve high carbon yield production through increasing the accessible bicarbonate, minimizing native CO2 release and avoiding carbon waste.
- Ning Qin
- , Lingyun Li
- & Zihe Liu
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Article
| Open AccessIterative design of training data to control intricate enzymatic reaction networks
Kinetic modeling of in vitro enzymatic reaction networks (ERNs) is severely hampered by the lack of training data. Here, authors introduce a methodology that combines an active learning-like approach and flow chemistry to create optimized datasets for an intricate ERN.
- Bob van Sluijs
- , Tao Zhou
- & Wilhelm T. S. Huck
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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 AccessEvolutionarily related host and microbial pathways regulate fat desaturation in C. elegans
Fatty acid desaturation is central to metazoan lipid metabolism. Here, using C. elegans as a model, the authors show that both endogenous and microbiota-dependent small molecule signals converge to promote lipid desaturation via the nuclear receptor NHR-49/PPARα.
- Bennett W. Fox
- , Maximilian J. Helf
- & Frank C. Schroeder
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Article
| Open AccessSpatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells
Here the authors report a strategy to directly capture substrates of lysine-modifying enzymes via post-translational modification (PTM)-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner.
- Hao Hu
- , Wei Hu
- & Xiao-Hua Chen
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Article
| Open AccessCyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-XL, with a distinct mechanism of targeting characterised.
- Fengwei Li
- , Junjie Liu
- & Dalei Wu
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Article
| Open AccessReconstitution of early paclitaxel biosynthetic network
Paclitaxel is an important anticancer drug whose biosynthetic pathway reconstruction is hindered by the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. Here, the authors tune the promoter strength for T5αH expression in Nicotiana plants to increase the levels of paclitaxel precursor taxadien-5α-ol by three-fold and reconstitute the six step early biosynthetic pathway of paclitaxel.
- Jack Chun-Ting Liu
- , Ricardo De La Peña
- & Elizabeth S. Sattely
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Article
| Open AccessTrabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes
The antitumor drug trabectedin is more toxic to DNA-repair-proficient cells. Here the authors show that this is caused by persistent DNA breaks induced from an abortive repair reaction and develop “TRABI-Seq” to map the breaks to transcribed regions of the genome. Trabectedin may thus be used as a diagnostic and therapeutic in precision oncology.
- Kook Son
- , Vakil Takhaveev
- & Orlando D. Schärer
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Article
| Open AccessProteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma
The molecular characterisation of soft tissue sarcomas (STSs) across diverse populations remains crucial. Here, the authors perform a proteomics and phosphoproteomics analysis of 272 Chinese STS patients across 12 subtypes, and obtain insights related to progression, metastasis, and immune signatures.
- Shaoshuai Tang
- , Yunzhi Wang
- & Chen Ding
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Article
| Open AccessLiquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection
The authors display the bottom-up design, assembly, and in-depth characterization of defined lipid-RNA structures in the core of lipid nanoparticles. The inverted structures are thermostable and provide better transfection over lamellar structures.
- Roy Pattipeiluhu
- , Ye Zeng
- & Thomas H. Sharp
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Article
| Open AccessStructure-guided engineering enables E3 ligase-free and versatile protein ubiquitination via UBE2E1
Ubiquitin E3 ligases are key to accessing ubiquitinated proteins, but only a few substrates have defined E3 ligases. Here, the authors reveal the mechanism of naturally occurring E3-independent ubiquitination and develop an E3-free enzymatic strategy for the versatile generation of ubiquitinated proteins.
- Xiangwei Wu
- , Yunxiang Du
- & Lei Liu
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Article
| Open AccessUsing the heme peroxidase APEX2 to probe intracellular H2O2 flux and diffusion
Previous genetically encoded H2O2 probes are based on reversible thiol oxidation. Here, a heme peroxidase is introduced as a thiol-independent H2O2 probe. APEX2 converts H2O2 into fluorescent or luminescent signals, allowing its quantification.
- Mohammad Eid
- , Uladzimir Barayeu
- & Tobias P. Dick
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Article
| Open AccessReaction engineering blocks ether cleavage for synthesizing chiral cyclic hemiacetals catalyzed by unspecific peroxygenase
Hemiacetal compounds are valuable building blocks in synthetic chemistry, but difficult to obtain by enzymatic synthesis. Here, the authors use reaction engineering of an immobilized unspecific peroxygenase from Agrocybe aegerita for selective C-H bond oxyfunctionalisation of environmentally significant cyclic ethers to chiral cyclic hemiacetals.
- Xiaofeng Han
- , Fuqiang Chen
- & Wuyuan Zhang
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Article
| Open AccessOverlay databank unlocks data-driven analyses of biomolecules for all
In this work, the authors report NMR lipids Databank to promote decentralised sharing of biomolecular molecular dynamics (MD) simulation data with an overlay design. Programmatic access enables analyses of rare phenomena and advances the training of machine learning models.
- Anne M. Kiirikki
- , Hanne S. Antila
- & O. H. Samuli Ollila
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Article
| Open AccessPlastid ancestors lacked a complete Entner-Doudoroff pathway, limiting plants to glycolysis and the pentose phosphate pathway
The Enter-Doudoroff (ED) pathway is an alternative to glycolysis present in some prokaryotes. Evans et al. show that its dehydratase enzyme, evolved from a branched chain amino acid pathway paralog, acquired a new function through mutations in its active site.
- Sonia E. Evans
- , Anya E. Franks
- & Michael A. Phillips
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Article
| Open AccessResolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open AccessSystems engineering of Escherichia coli for high-level glutarate production from glucose
Glutarate is a platform chemical widely used in the production of polyesters and polyamindes. Here, the authors design the shortest and thermodynamically favorable pathway, and increase glutarate production from glucose through systematic engineering of E. coli.
- Zhilan Zhang
- , Ruyin Chu
- & Cong Gao
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Article
| Open AccessEarly onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid
In this work, the authors characterize a small molecule fluorescent probe pioneering early diagnosis of Alzheimer’s disease through identification of amyloid-β oligomers in patients’ cerebrospinal fluid, demonstrating potential for clinical application.
- Jusung An
- , Kyeonghwan Kim
- & Jong Seung Kim
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Article
| Open AccessFluorogenic CRISPR for genomic DNA imaging
Conventional CRISPR-based approaches to monitor genomic loci can be hampered by high background and nonspecific nucleolar signal. Here, the authors propose a fluorogenic CRISPR (fCRISPR) tool that allows for high-contrast and sensitive imaging of genomic DNA.
- Zhongxuan Zhang
- , Xiaoxiao Rong
- & Xing Li
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Article
| Open AccessThe nature of carotenoid S* state and its role in the nonphotochemical quenching of plants
Plant Light Harvesting complexes adjust to light conditions via a quenching mechanism involving carotenoids. The authors use computational simulations to reveal how carotenoids’ quenching capacity is tuned by conformational changes of the complex.
- Davide Accomasso
- , Giacomo Londi
- & Benedetta Mennucci
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Article
| Open AccessLocation-agnostic site-specific protein bioconjugation via Baylis Hillman adducts
Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. Here, the authors report Baylis Hillman orchestrated protein aminothiol labelling (BHoPAL), a bioconjugation strategy for specific labelling of the 1,2-aminothiol moiety and combine it with a lipoic acid ligase-based technology to achieve labelling at any desired site within proteins.
- Mudassir H. Mir
- , Sangeeta Parmar
- & Dimpy Kalia
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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 AccessElucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Mycoplanecins show promising activity against tuberculosis. Here, the authors identify and study mycoplanecins’ biosynthesis, antibacterial effects, and binding mechanism to DnaN, suggesting potential for fighting multidrug-resistant tuberculosis.
- Chengzhang Fu
- , Yunkun Liu
- & Rolf Müller
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Article
| Open AccessA renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis
In vivo detection of cell senescence remains a challenge in aging research. This work introduces a novel fluorogenic probe for β-Gal activity that is excreted in urine, providing a simple diagnosis method to estimate the systemic load of senescent cells during aging and senolytic interventions.
- Sara Rojas-Vázquez
- , Beatriz Lozano-Torres
- & Ramón Martínez-Máñez
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Article
| Open AccessRational strain design with minimal phenotype perturbation
No consensus exists on the computationally tractable use of dynamic models for strain design. To tackle this, the authors report a framework, nonlinear-dynamic-model-assisted rational metabolic engineering design, for efficiently designing robust, artificially engineered cellular organisms.
- Bharath Narayanan
- , Daniel Weilandt
- & Vassily Hatzimanikatis
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Article
| Open AccessDNA mechanocapsules for programmable piconewton responsive drug delivery
The mechanical dysregulation of cells is associated with several diseases and strategies to deliver drugs based on the “mechanical phenotype” of a cell are desirable. Here, the authors design and characterize DNA mechanocapsules comprised of DNA tetrahedrons that are force responsive, and showed they can encapsulate macromolecular cargo and release it upon application of force.
- Arventh Velusamy
- , Radhika Sharma
- & Khalid Salaita
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