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Article
| Open AccessStructural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing
Here, the authors use single-molecule long-read sequencing to decipher the role of structural variations in high-altitude adaptation, finding evidence that an intergenic deletion down-regulates EPAS1 by disrupting a super-enhancer.
- Jinlong Shi
- , Zhilong Jia
- & Kunlun He
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Article
| Open AccessTopological structures and syntenic conservation in sea anemone genomes
Slowly evolving cnidarians are useful models to study genome architecture. This study shows that sea anemones have a high degree of chromosomal macrosynteny, but poor microsynteny conservation. This is correlated with a small genome size and short distances of cis-regulatory elements to genes.
- Bob Zimmermann
- , Juan D. Montenegro
- & Ulrich Technau
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Article
| Open AccessGenes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
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Article
| Open AccessDissecting the basis for differential substrate specificity of ADAR1 and ADAR2
Human ADAR1 and ADAR2 edit millions of adenosines transcriptome-wide, altering RNA structure. Here the authors show that variations in RNA binding domains influence site-specific editing, enhancing ADAR2-targeted therapeutics.
- Marlon S. Zambrano-Mila
- , Monika Witzenberger
- & Schraga Schwartz
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Article
| Open AccessThe Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes
The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.
- Kaisa Thorell
- , Zilia Y. Muñoz-Ramírez
- & Charles S. Rabkin
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Article
| Open AccessDispersal from the Qinghai-Tibet plateau by a high-altitude butterfly is associated with rapid expansion and reorganization of its genome
The butterfly Parnassius glacialis experienced vast environmental transition when it dispersed out of the Qinghai-Tibet plateau. Here, the authors find that P. glacialis has an unusually large genome with rapid accumulation of transposable elements possibly facilitating its evolutionary adaptation.
- Youjie Zhao
- , Chengyong Su
- & Jiasheng Hao
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Article
| Open AccessRIF1 regulates early replication timing in murine B cells
Here the authors show that in activated B cells, RIF1 primarily binds early-replicating active chromatin and promotes early replication. RIF1 and MCM proteins establish early replication timing signatures genome-wide and ensure early replication of highly transcribed genes.
- Daniel Malzl
- , Mihaela Peycheva
- & Rushad Pavri
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Article
| Open AccessSingle cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines
Intra-cell line heterogeneity remains to be characterized. Here, the use of single multi-omics on a large panel of human cell lines identifies copy number variation, epigenetic variation and extrachromosomal DNA distribution as the main contributors to intra-cell line heterogeneity.
- Qionghua Zhu
- , Xin Zhao
- & Liang Wu
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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Article
| Open Accessvcfdist: accurately benchmarking phased small variant calls in human genomes
Accurately benchmarking small variant calling accuracy is critical for the continued improvement of human genome sequencing. Here, the authors show that current approaches are biased towards certain variant representations and develop a new approach to ensure consistent and accurate benchmarking, regardless of the original variant representations.
- Tim Dunn
- & Satish Narayanasamy
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Article
| Open AccessSTalign: Alignment of spatial transcriptomics data using diffeomorphic metric mapping
Spatial transcriptomics (ST) enables gene expression characterisation within tissue sections, but comparing across sections and technologies remains challenging. Here, authors develop STalign to spatially align ST data and demonstrate applications including aligning to common coordinate frameworks.
- Kalen Clifton
- , Manjari Anant
- & Jean Fan
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Article
| Open AccessOutward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation
The TAD boundaries comprise clustered arrays of CTCF sites with complex orientations. Here the authors show that the outward-oriented CTCF sites within clustered TAD boundaries are central for intra-TAD chromatin spatial contacts and gene regulation.
- Xiao Ge
- , Haiyan Huang
- & Qiang Wu
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Article
| Open AccessTAD evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function
The authors show that the deletion of ultraconserved TAD boundaries affects gene expression and phenotype, highlighting TAD evolution’s function. Human-specific TAD boundaries reveal a role in brain development and disease.
- Mariam Okhovat
- , Jake VanCampen
- & Lucia Carbone
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Article
| Open AccessIn vivo RNA interactome profiling reveals 3’UTR-processed small RNA targeting a central regulatory hub
Here the authors report a new approach to profile RNA-RNA interactions in live bacterial cells. The charted RNA interaction networks unveil a key mRNA regulatory hub targeted by twelve small RNAs, including a novel RNA involved in fatty acid metabolism.
- Fang Liu
- , Ziying Chen
- & Yanjie Chao
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Article
| Open AccessSaturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation
Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.
- Elizabeth J. Radford
- , Hong-Kee Tan
- & Matthew E. Hurles
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Article
| Open AccessMosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa
Mosaic chromosomal alterations (mCAs) in peripheral blood leukocytes are associated with an increased risk of malignancy. Here, the authors use genome-wide genotyping array data to investigate the prevalence of mCAs in sub-Saharan African children with versus those without Burkitt lymphoma.
- Weiyin Zhou
- , Anja Fischer
- & Sam M. Mbulaiteye
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Article
| Open AccessRare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
Here, the authors clarify the architecture of genetic risk on chromosome X in three male-biased psychiatric disorders. Leveraging this information they identify an exome-wide significant autism risk gene, MAGEC3, and provide a path forward for future gene discovery on this chromosome.
- Sheng Wang
- , Belinda Wang
- & A. Jeremy Willsey
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Article
| Open AccessThe PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer
The authors reconstruct high fidelity networks of protein-protein interactions between promoters and enhancers in prostate cancer and demonstrate the potential of such an analytical framework to obtain actionable insights into the disease and potential therapeutic targets.
- Alexandros Armaos
- , François Serra
- & Gian Gaetano Tartaglia
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Article
| Open AccessEvolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle
Hyaluronic acid is believed to plays a critical role in cancer resistance and longevity of the naked mole rat. Here, Zhao and colleagues show that accumulation of high levels of hyaluronic acid has co-evolved repeatedly in mammalian clades with adaptation to subterranean habitats.
- Yang Zhao
- , Zhizhong Zheng
- & Vera Gorbunova
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessJUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease
It has recently been reported a link between Alzheimer’s disease and mobilization of transposable elements (TEs) in heterochromatic regions. Here the authors demonstrate that dysregulation of the pioneer transcription factor c-JUN (AP-1) underlies aberrant transposable element mobilization, associated innate immune 2 response, and impaired neurogenesis in Alzheimer’s disease.
- Chiara Scopa
- , Samantha M. Barnada
- & Marco Trizzino
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Article
| Open AccessNitric oxide controls shoot meristem activity via regulation of DNA methylation
The authors show that gaseous Nitric Oxide (NO) promotes transit amplifying cell fate in the Arabidopsis shoot meristem. NO acts by modifying AGO4-WUSCHEL protein interactions in stem cells, directly linking NO signaling with DNA methylation.
- Jian Zeng
- , Xin’Ai Zhao
- & Jan U. Lohmann
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Article
| Open AccessAccurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix
The authors propose “HEELS”, a new method for precise local heritability estimation. It significantly reduces the variances of summary-statistics-based heritability estimators, offering an REML-like estimator without requiring individual-level data.
- Hui Li
- , Rahul Mazumder
- & Xihong Lin
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Article
| Open AccessDynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
Off-target toxicity of antisense oligonucleotides (ASOs) poses a challenge for their clinical use. Here, authors develop a toehold-bearing ASO architecture that mitigates a broad spectrum of off-target interactions, significantly enhancing the safety profile of ASO drugs.
- Chisato Terada
- , Kaho Oh
- & Tsuyoshi Yamamoto
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Article
| Open AccessWhole genomes from Angola and Mozambique inform about the origins and dispersals of major African migrations
African human genome variation remains under-sampled. Here, the authors present a collection of 350 whole genome sequences from Angola and Mozambique and model the timing and extent of significant demographic events in African history.
- Sam Tallman
- , Maria das Dores Sungo
- & Sandra Beleza
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Article
| Open AccessSMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors
The regulatory landscape of malignant rhabdoid tumor (MRT) due to SMARCB1 loss remains to be explored. Here, the authors perform multi-omics analysis using patient-derived MRT organoids and characterise the epigenetic reprogramming events underlying SMARCB1 loss.
- Ning Qing Liu
- , Irene Paassen
- & Jarno Drost
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Article
| Open AccessSoybean reduced internode 1 determines internode length and improves grain yield at dense planting
Many cereal crops have been bred to be more compact to allow high-density planting, but soybean has remained relatively overlooked. Here, the authors describe a compact soybean mutant, reduced internode 1, that significantly enhances grain yield under high-density planting conditions compared to an elite cultivar.
- Shichen Li
- , Zhihui Sun
- & Sijia Lu
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Article
| Open AccessHaplotype-based inference of recent effective population size in modern and ancient DNA samples
The authors introduce a new computational method, HapNe, for inferring the recent effective size of human populations. HapNe does not require high-quality genotype data, making it suitable for the study of ancient DNA samples.
- Romain Fournier
- , Zoi Tsangalidou
- & Pier Francesco Palamara
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Article
| Open AccessBuilding a eukaryotic chromosome arm by de novo design and synthesis
In Saccharomyces cerevisiae, the left arm of chromosome XII only requires 12 genes to maintain cell viability, whereas 25 genes are needed for robust fitness. Here the authors demonstrate that the entire arm can be replaced by a neochromosome with completely artificial sequences.
- Shuangying Jiang
- , Zhouqing Luo
- & Junbiao Dai
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Article
| Open AccessStrong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.
- Yask Gupta
- , David J. Friedman
- & Simone Sanna-Cherchi
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Article
| Open AccessUtilizing river and wastewater as a SARS-CoV-2 surveillance tool in settings with limited formal sewage systems
COVID-19 has impacted health systems unequally and widespread SARS-CoV-2 testing for community surveillance has been limited globally. This work in Malawi highlights how river and wastewater can be used to detect emerging SARS-CoV-2 waves, identify variants of concern, and provide an early warning system.
- Kayla G. Barnes
- , Joshua I. Levy
- & Nicholas Feasey
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Article
| Open AccessCell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.
- Hyun-Sik Yang
- , Ling Teng
- & Reisa A. Sperling
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Article
| Open AccessThe SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation
Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.
- Johannes Benedum
- , Vedran Franke
- & Dea Slade
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Article
| Open AccessDominance in self-compatibility between subgenomes of allopolyploid Arabidopsis kamchatica shown by transgenic restoration of self-incompatibility
Self-incompatibility in diploid Arabidopsis relatives is determined by a dominance relationship that is epigenetically regulated. Using transgenic methods, this study demonstrates that the dominance relationship between subgenomes of the allopolyploid species Arabidopsis kamchatica underlies it’s self-compatibility.
- Chow-Lih Yew
- , Takashi Tsuchimatsu
- & Kentaro K. Shimizu
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Article
| Open AccessLocal adaptation and future climate vulnerability in a wild rodent
A species’ response to anthropogenic climate change may depend on its adaptations to past climate changes. Here, the authors use whole-genome resequencing and genetic-environment association to identify genes important for local adaptation and project adaptation under future climate scenarios across bank vole populations in Britain.
- Silvia Marková
- , Hayley C. Lanier
- & Petr Kotlík
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Article
| Open AccessHDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis
The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.
- Michael F. Emmons
- , Richard L. Bennett
- & Keiran S. M. Smalley
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Article
| Open AccessGlobal genetic diversity, introgression, and evolutionary adaptation of indicine cattle revealed by whole genome sequencing
Indicine cattle make up half of all cattle populations worldwide. Using a large genomic dataset, this study finds historic migrations and extensive introgression with domestic and wild bovine species has facilitated this species physiological adaptation to extreme environments.
- Ningbo Chen
- , Xiaoting Xia
- & Chuzhao Lei
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Article
| Open AccessOVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
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Article
| Open AccessDNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis
Here the authors show that Inhibition of DNA topoisomerase 1 (TOP1i) increases the defects in root growth of a DNA damage repair-compromised mutant atm. They identify a mutant DNA polymerase ε (POL2A) which rescues the sensitivity of atm to TOP1i by modulating R-loops dynamics near DNA replication origins.
- Qin Li
- , Jincong Zhou
- & Qianwen Sun
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Article
| Open AccessA papain-like cysteine protease-released small signal peptide confers wheat resistance to wheat yellow mosaic virus
Soil-borne wheat yellow mosaic virus (WYMV) poses a serious threat to global wheat production. Here, the authors report that the nuclear inclusion protease-a produced by WYMV interacts with a small peptide catalyzed by TaRD21A protease activity to mediate WYMV resistance through activating MAPK signaling pathway.
- Peng Liu
- , Chaonan Shi
- & Jian Yang
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Article
| Open AccessThe rate of epigenetic drift scales with maximum lifespan across mammals
Epigenetic drift has been hypothesized to contribute to epigenetic clock signals and variation in lifespan across species. Here, the authors show that an empirical measure of epigenetic drift scales with maximum lifespan across four mammal species and accumulates in non-random genomic locations.
- Emily M. Bertucci-Richter
- & Benjamin B. Parrott
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Article
| Open AccessGene duplication and deletion caused by over-replication at a fork barrier
Gene duplications and deletions are important drivers of evolution and disease. Here, the authors show that excess DNA generated at a replication fork barrier can be integrated at a new genomic site causing both a gene duplication and a deletion.
- Judith Oehler
- , Carl A. Morrow
- & Matthew C. Whitby
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Article
| Open AccessEvaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
Proteomics of blood samples is a promising avenue for cancer diagnosis. Here, the authors conduct Mendelian randomisation analysis of protein levels across multiple cohorts, and identify 5 proteins that show promise as biomarkers for the long-term risk of breast cancer, and as potential drug targets.
- Anders Mälarstig
- , Felix Grassmann
- & Åsa K. Hedman
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Article
| Open AccessGlobal pathogenomic analysis identifies known and candidate genetic antimicrobial resistance determinants in twelve species
A global analysis of antimicrobial resistance (AMR) across 27,155 genomes and 69 drugs reveals patterns in AMR gene transfer between species and identifies 142 AMR gene candidates, two of which were tested and confirmed as contributing to AMR.
- Jason C. Hyun
- , Jonathan M. Monk
- & Bernhard O. Palsson
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Article
| Open AccessACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans
Dietary restriction is one of the most effective ways to delay ageing. Here, the authors discover a highly conserved lipid metabolism gene functions through transcriptional regulation mechanisms to regulate proteostasis, lifespan and healthspan in response to low nutrients in C. elegans.
- Zi Wang
- , Lina Zou
- & Di Chen
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Article
| Open AccessIn vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor
Mutations in mitochondrial DNA (mtDNA) play critical roles in human diseases. Here, the authors describe an integrated Cas12a sensor for sensing mtDNA mutations in vivo, showing potential for diagnostic and therapeutic purposes.
- Yanan Li
- , Yonghua Wu
- & Kaixiang Zhang
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Article
| Open AccessHigh-resolution temporal profiling of E. coli transcriptional response
Understanding how cells dynamically adapt to their environment is important, but temporal information about cellular behaviour is often limited. Here, Miano et al. apply unsupervised machine learning to a dataset describing the activity of over 1,800 promoters in E. coli, measured every 10 minutes, defining three primary stages of promoter activation in response to heavy metal stress.
- Arianna Miano
- , Kevin Rychel
- & Jeff Hasty
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Article
| Open AccessFear extinction is regulated by the activity of long noncoding RNAs at the synapse
Synaptic activity controls the extinction of conditioned fear. Here the authors discovered a new way that the brain controls memories of fear: a long noncoding RNA called Gas5 that coordinates the activity of RNA granules in the synaptic compartment.
- Wei-Siang Liau
- , Qiongyi Zhao
- & Timothy W. Bredy
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Article
| Open AccessLoss-of-function of an α-SNAP gene confers resistance to soybean cyst nematode
Here, the authors show that the soybean GmSNAP02 gene confers a unique mode of resistance to the soybean cyst nematode Heterodera glycines through loss-of-function mutations that implicate GmSNAP02 as a nematode virulence target.
- Mariola Usovsky
- , Vinavi A. Gamage
- & Andrew M. Scaboo
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