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| Open AccessDiscovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.
- Edmund C. Lee
- , Tania Valencia
- & Vishal Patel
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Article
| Open AccessA high-resolution 3D epigenomic map reveals insights into the creation of the prostate cancer transcriptome
In prostate cancer, chromatin structure can impact the transcriptome. Here, the authors develop high resolution chromatin interaction maps in prostate cancer cells using in situ Hi-C, revealing prostate cancer-specific TADs and enhancer-promoter loops surrounding the androgen receptor (AR) locus.
- Suhn Kyong Rhie
- , Andrew A. Perez
- & Peggy J. Farnham
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Article
| Open AccessExtensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations
Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.
- Robert Fragoza
- , Jishnu Das
- & Haiyuan Yu
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Article
| Open AccessCircAnks1a in the spinal cord regulates hypersensitivity in a rodent model of neuropathic pain
Circular RNAs are non-coding RNAs that are enriched in the CNS, but their role in chronic pain is not known. Here the authors show that CircAnks1a in dorsal horn neurons contributes to pain-like hypersensitivity in a rodent model of neuropathic pain, via a VEGF mechanism.
- Su-Bo Zhang
- , Su-Yan Lin
- & Wen-Jun Xin
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Article
| Open AccessAccurate detection of m6A RNA modifications in native RNA sequences
We currently lack generic methods to map RNA modifications across the entire transcriptome. Here, the authors demonstrate that m6A RNA modifications can be detected with high accuracy using nanopore direct RNA sequencing.
- Huanle Liu
- , Oguzhan Begik
- & Eva Maria Novoa
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Article
| Open AccessIn vitro role of Rad54 in Rad51-ssDNA filament-dependent homology search and synaptic complexes formation
Homologous recombination uses a template to accurately repair DNA double-strand breaks and stalled replication forks to maintain genome stability. Here authors use electron microscopy to investigate the role of Rad54 in homology search and synaptic complex formation.
- Eliana Moreira Tavares
- , William Douglass Wright
- & Pauline Dupaigne
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Article
| Open AccessSpatially clustered loci with multiple enhancers are frequent targets of HIV-1 integration
HIV-1 usually targets active genes and integrates near the nuclear pore compartment. Here the authors show that recurrently targeted genes are proximal to super-enhancer genomic elements, which cluster in specific spatial compartments of the T cell nucleus, suggesting a role for nuclear organisation in viral infection.
- Bojana Lucic
- , Heng-Chang Chen
- & Marina Lusic
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Article
| Open AccessCRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation
CRISPR-Cas9 genome editing is presumed to knock out gene function by generating a frameshift during NHEJ repair. Here, the authors investigate mRNA and protein expression in edited lines and find genome editing can generate internal ribosome entry sites or alternatively spliced variants.
- Rubina Tuladhar
- , Yunku Yeu
- & Lawrence Lum
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Article
| Open AccessMechanism of centromere recruitment of the CENP-A chaperone HJURP and its implications for centromere licensing
The CENP-A chaperone HJURP associates with Mis18α, Mis18β, and M18BP1 to target centromeres and deposit new CENP-A. Here the authors provide evidence that two repeats in human HJURP previously proposed to be functionally distinct are interchangeable and bind concomitantly to the 4:2:2 Mis18α:Mis18β:M18BP1 complex without dissociating it.
- Dongqing Pan
- , Kai Walstein
- & Andrea Musacchio
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Article
| Open AccessMitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements
Off-target effects in CRISPR screens for essential regulatory elements have not been systematically evaluated. Here the authors find Cas9 nuclease, CRISPRi/a each have distinct off-target effects, and that these can be accurately identified and removed using the GuideScan sgRNA specificity score.
- Josh Tycko
- , Michael Wainberg
- & Michael C. Bassik
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Article
| Open AccessTranslational coupling via termination-reinitiation in archaea and bacteria
Archaea and bacteria often have gene pairs with overlapping stop and start codons, suggesting translational coupling. Here, Huber et al. analyse overlapping gene pairs from 720 genomes, and validate translational coupling via termination-reinitiation for 14 gene pairs in Haloferax volcanii and Escherichia coli.
- Madeleine Huber
- , Guilhem Faure
- & Jörg Soppa
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Article
| Open AccessRoles for DNA polymerase δ in initiating and terminating leading strand DNA replication
DNA polymerases epsilon and delta, respectively, perform the majority of leading and lagging strand replication of the eukaryotic nuclear genome. Here the authors map the ribonucleotide fingerprints of the polymerases to show the special roles of polymerase delta on both strands during replication initiation and termination.
- Zhi-Xiong Zhou
- , Scott A. Lujan
- & Thomas A. Kunkel
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Article
| Open AccessCDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity
CDK5 is known to drive glioblastoma tumorigenicity but the downstream molecular mechanism is unknown. Here, the authors show that CDK5 activates STAT3 signalling via the nuclear import of TRIM59, which leads to the degradation of the tumour suppressor macroH2A1.
- Youzhou Sang
- , Yanxin Li
- & Haizhong Feng
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Article
| Open AccessThe poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation
While the biological roles of ubiquitin chains are well studied, little is known about the functions of SUMO polymers. Here, the authors identify poly-SUMOylation substrates and provide evidence that SUMO polymers regulate the accumulation of CCAN subunits at chromatin and centromeres.
- Frauke Liebelt
- , Nicolette S. Jansen
- & Alfred C. O. Vertegaal
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Article
| Open AccessProtein prenylation restrains innate immunity by inhibiting Rac1 effector interactions
Macrophage specific deletion of GGTase-I, a prenylation enzyme, in mice induces inflammatory response and rheumatoid arthritis. Here the authors show that GGTase-I deficiency and the resulting reduction of RAC1 prenylation increase RAC1 interaction with the adaptor protein IQGAP1, leading to GTP-loading of RAC1 and enhanced proinflammatory cytokine production.
- Murali K. Akula
- , Mohamed X. Ibrahim
- & Martin O. Bergo
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Article
| Open AccessThe transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition
RPSAP52 is an antisense-transcribed pseudogene of HMGA2 that positively regulates HMGA2 expression. Here, the authors show that reexpression of RPSAP52 promotes tumorigenicity by facilitating IGF2BP2 binding to its mRNA targets and consequently regulates the balance of LIN28B and let-7 levels.
- Cristina Oliveira-Mateos
- , Anaís Sánchez-Castillo
- & Sonia Guil
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Article
| Open AccessDefects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome
The biosynthesis of N6-threonylcarbamoylated adenosine 37 in tRNA (t6A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.
- Christelle Arrondel
- , Sophia Missoury
- & Géraldine Mollet
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Article
| Open AccessPituitary cell translation and secretory capacities are enhanced cell autonomously by the transcription factor Creb3l2
Pituitary POMC secreting cells achieve high hormone expression levels after birth but the mechanism for this regulation is unclear. Here, the authors show that this process is driven cell autonomously by the differentiation factor Tpit that activates the bZIP transcription factors Creb3l2 and XBP1 to enhance translation and secretory capacities.
- Konstantin Khetchoumian
- , Aurélio Balsalobre
- & Jacques Drouin
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Matters Arising
| Open AccessReply to ‘Concerns about the feasibility of using “precision guided sterile males” to control insects’
- Nikolay P. Kandul
- , Junru Liu
- & Omar S. Akbari
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Matters Arising
| Open AccessConcerns about the feasibility of using “precision guided sterile males” to control insects
- Jérémy Bouyer
- & Marc J. B. Vreysen
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Article
| Open AccessEngineered ribosomes with tethered subunits for expanding biological function
Ribo-T is a tethered ribosome complex capable of orthogonal ribosome-mRNA functionality, but has low activity. Here the authors evolve new tether designs that support faster growth and increased protein expression.
- Erik D. Carlson
- , Anne E. d’Aquino
- & Michael C. Jewett
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Article
| Open AccessCryoEM structures of Arabidopsis DDR complexes involved in RNA-directed DNA methylation
RNA polymerase V transcription in plants, which is needed DNA methylation and transcriptional silencing, requires components of the DDR complex. Here the authors show that all components of the DDR complex co-localize with Pol V and report the cryoEM structures of two complexes associated with Pol V recruitment.
- Somsakul Pop Wongpalee
- , Shiheng Liu
- & Steven E. Jacobsen
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Article
| Open AccessAssisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood
Use of Assisted Reproductive Technologies (ART) is increasing globally but their impact on long term health remains unclear. Here the authors show that ART-conceived individuals show variation in epigenetic profile at birth that largely resolves by adulthood, with no evidence of an impact on long term outcomes.
- Boris Novakovic
- , Sharon Lewis
- & Richard Saffery
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Article
| Open AccessReplication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
Mismatch repair (MMR)-deficient cancers are characterized by microsatellite instability (MSI) and hypermutation. Here authors reveal a mechanism by which replication stress induces MSI and associated induction of mutations in vitro.
- Yusuke Matsuno
- , Yuko Atsumi
- & Ken-ichi Yoshioka
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Article
| Open AccessA high-resolution map of non-crossover events reveals impacts of genetic diversity on mammalian meiotic recombination
During meiotic recombination, genetic information is transferred or exchanged between parental chromosome copies. Using a large hybrid mouse pedigree, the authors generated high-resolution maps of these transfer/exchange events and discovered new properties governing their processing and resolution.
- Ran Li
- , Emmanuelle Bitoun
- & Simon R. Myers
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Article
| Open AccessMycobacterial dynamin-like protein IniA mediates membrane fission
Tuberculosis drugs induce the expression of IniA, but so far little has been known about its structure and function. Here the authors present the apo and GTP bound crystal structures of Mycobacterium smegmatis IniA, which folds as a bacterial dynamin-like protein and show that IniA mediates membrane fission in vitro.
- Manfu Wang
- , Xiangyang Guo
- & Zihe Rao
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Article
| Open AccessMaximizing binary interactome mapping with a minimal number of assays
Comprehensive mapping of binary protein-protein interactions requires to combine several complementary assays. Here, the authors show that complete coverage could be reached with a minimal number of assays as long as they explore various experimental conditions.
- Soon Gang Choi
- , Julien Olivet
- & Yves Jacob
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Article
| Open AccessConformational heterogeneity in human interphase chromosome organization reconciles the FISH and Hi-C paradox
Studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci is paradoxically larger compared to another pair with a smaller value of the contact probability. Here the authors use a theory based on a Generalized Rouse Model for Chromosomes to resolve this paradox.
- Guang Shi
- & D. Thirumalai
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Article
| Open AccessA phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease of substantial phenotypic heterogeneity in different ethnic groups. Here, using data from a multi-ethnic cohort, the authors describe an approach based on clinical and molecular data to subtype SLE patients into three clusters of severity.
- Cristina M. Lanata
- , Ishan Paranjpe
- & Lindsey A. Criswell
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Article
| Open AccessRST1 and RIPR connect the cytosolic RNA exosome to the Ski complex in Arabidopsis
Cytosolic RNA degradation by the RNA exosome requires the Ski complex. Here the authors show that the proteins RST1 and RIPR assist the RNA exosome and the Ski complex in RNA degradation, thereby preventing the production of secondary siRNAs from endogenous mRNAs.
- Heike Lange
- , Simon Y. A. Ndecky
- & Dominique Gagliardi
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Article
| Open AccessEZHIP constrains Polycomb Repressive Complex 2 activity in germ cells
Polycomb Repressive Complex 2 (PRC2) plays critical roles in transcriptional silencing during development. Here the authors identify EZHIP as a cofactor of PRC2 expressed predominantly in the gonads, finding that EZHIP limits the enzymatic activity of PRC2 in germ cells in mice.
- Roberta Ragazzini
- , Raquel Pérez-Palacios
- & Raphaël Margueron
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Article
| Open AccessEngineered CRISPRa enables programmable eukaryote-like gene activation in bacteria
CRISPR activation strategies in bacteria are limited due to the reliance on σ70 promoters. Here the authors demonstrate eukaryote-like gene activation with high dynamic ranges using σ54- dependent promoters.
- Yang Liu
- , Xinyi Wan
- & Baojun Wang
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Article
| Open AccessA conserved regulatory program initiates lateral plate mesoderm emergence across chordates
Numerous tissues are derived from the lateral plate mesoderm (LPM) but how this is specified is unclear. Here, the authors identify a pan-LPM reporter activity found in the zebrafish draculin (drl) gene that also shows transgenic activity in LPM-corresponding territories of several chordates, including chicken, axolotl, lamprey, Ciona, and amphioxus.
- Karin D. Prummel
- , Christopher Hess
- & Christian Mosimann
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Article
| Open AccessPioneer and nonpioneer factor cooperation drives lineage specific chromatin opening
Pioneer transcription factor Pax7 specifies melanotrope cells, which then allows for the binding of Tpit transcription factor. Here, authors find that while binding of heterochromatin targeting by Pax7 is independent of Tpit, Pax7-dependent chromatin opening requires Tpit.
- Alexandre Mayran
- , Kevin Sochodolsky
- & Jacques Drouin
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Article
| Open AccesshCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy
Acute myeloid leukemia cells are often resistant to radiotherapy and chemotherapy. Here, the authors suggest that hCINAP contributes to the resistance of acute myeloid leukemia cells by regulating SUMOylation of Nucleophosmin during the DNA-damage response.
- Ruidan Xu
- , Shuyu Yu
- & Xiaofeng Zheng
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Article
| Open AccessStructural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome
The COP9 signalosome (CSN) regulates Cullin-RING Ligase 2 (CRL2) but the molecular basis for their interaction is unknown. Here the authors use structural mass spectrometry and cryo-EM approaches to assess the structures and dynamics of CSN-CRL2 complexes.
- Sarah V. Faull
- , Andy M. C. Lau
- & Argyris Politis
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Article
| Open AccessNucleosome and ubiquitin position Set2 to methylate H3K36
Set2 methyltransferase catalyzes the lysine 36 methylation of histone H3 (H3K36me) and the enzyme is mutated in many cancers. The authors provide mechanistic insights into how Set2 methylates nucleosomes by determining the 3.8 Å cryo-EM structure of Set2 bound to a H2B ubiquitinated nucleosome core particle.
- Silvija Bilokapic
- & Mario Halic
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Article
| Open AccessCrystal structure and substrate-induced activation of ADAMTS13
The plasma metalloprotease ADAMTS13 regulates the platelet-tethering function of von Willebrand factor (VWF) in a shear-dependent manner. Here the authors present the ADAMTS13 crystal structure of the 70kDa N-terminal metalloprotease to spacer domains, and using kinetic measurements they identify a substrate binding induced allosteric mechanism for ADAMTS13, where VWF functions both as an activating cofactor and substrate.
- Anastasis Petri
- , Hyo Jung Kim
- & James T. B. Crawley
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Article
| Open AccessThe Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis
Long term estrogen deprivation can result in apoptosis in breast cancer cells. Here, the authors show that this apoptosis is induced by the long-range chromatin interaction of loci containing the ESR1 and FOXO3 genes, resulting in FOXO3-mediated apoptosis.
- Mohamed Osama Ali Abdalla
- , Tatsuro Yamamoto
- & Noriko Saitoh
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Article
| Open AccessStructural basis for lamin assembly at the molecular level
Lamins are intermediate filaments and the major component of the nuclear lamina. Here the authors determine the crystal structure of a construct comprising the N-terminal half of human lamin A/C and use their structure and cross-linking and biochemical experiments to discuss lamin assembly.
- Jinsook Ahn
- , Inseong Jo
- & Nam-Chul Ha
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Article
| Open AccessMapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq)
The authors introduce ACT-seq: a Tn5-based method for rapidly profiling epigenetic marks in bulk-cell and single-cell samples. ACT-seq avoids many laborious or time-consuming steps required for similar techniques including chromatin fragmentation and end repair.
- Benjamin Carter
- , Wai Lim Ku
- & Keji Zhao
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Article
| Open AccessPAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma
Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
- Melusine Bleu
- , Swann Gaulis
- & Giorgio G. Galli
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Article
| Open AccessGenome-wide systematic identification of methyltransferase recognition and modification patterns
Single molecule real-time DNA sequencing allows genome-wide identification of DNA methylation patterns. Here, Jensen et al. present a high-throughput method that allows rapid coupling of DNA methylation patterns with their corresponding methyltransferase genes in bacteria.
- Torbjørn Ølshøj Jensen
- , Christian Tellgren-Roth
- & Alex Toftgaard Nielsen
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Article
| Open AccessN-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals
O-glycosylation of neuropilin-1 is involved in cancer migration and invasion. Here, the authors show that defects in N-glycosylation of two neuropilin-1 splice variants enhance the co-internalisation of Met, it’s interaction with β1-integrin, and subsequent constitutive activation of FAK/p130Cas signalling in endosomes to promote colorectal cancer metastasis.
- Xiuping Huang
- , Qing Ye
- & Qing-Bai She
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Article
| Open AccessCancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
DICER is involved in the processing of miRNAs, where the RNase IIIa and IIIb domains are thought to cut the 3p and 5p hairpin arms, respectively. Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.
- Jeffrey Vedanayagam
- , Walid K. Chatila
- & Eric C. Lai
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Article
| Open AccessArkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain
The cellular functions of poly-SUMO chains of different compositions are not fully understood. Here, the authors characterize Arkadia/RNF111 as a SUMO-targeted ubiquitin ligase that recognizes proteins with hybrid SUMO1-capped SUMO2/3 chains and targets them for proteasomal degradation.
- Annie M. Sriramachandran
- , Katrin Meyer-Teschendorf
- & R. Jürgen Dohmen
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Article
| Open AccessDissecting the heterogeneity of DENV vaccine-elicited cellular immunity using single-cell RNA sequencing and metabolic profiling
Using a combination of single-cell RNA sequencing and TCR clonotype analysis on longitudinal samples from dengue vaccinated individuals, Waickman et al. here define a transcriptional signature in acutely-activated T cells that is associated with durable CD8+ T cell memory.
- Adam T. Waickman
- , Kaitlin Victor
- & Jeffrey R. Currier
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Article
| Open AccessA CRISPR-Cas12a-derived biosensing platform for the highly sensitive detection of diverse small molecules
Bacterial allosteric transcription factors can sense and respond to a variety of small molecules. Here the authors present CaT-SMelor which uses Cas12a and allosteric transcription factors to detect small molecules in the nanomolar range.
- Mindong Liang
- , Zilong Li
- & Li-Xin Zhang
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Article
| Open AccessIn vivo Hox binding specificity revealed by systematic changes to a single cis regulatory module
Hox proteins are expressed in partially overlapping regions to inform development along the embryo’s head-tail axis. Here the authors analyse a cis regulatory module directly regulated by seven different Drosophila Hox proteins to uncover how different Hox class proteins differentially control its expression.
- Carlos Sánchez-Higueras
- , Chaitanya Rastogi
- & James C.-G. Hombría
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