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A lineage-resolved cartography of microRNA promoter activity in C. elegans empowers multidimensional developmental analysis
By tracing promoter expression in lineage-mapped single cells, Xu et al. present a whole-body cartography of microRNA transcriptional activities during C. elegans embryogenesis and demonstrate its broad utility in multifaceted functional analyses.
- Weina Xu
- , Jinyi Liu
- & Zhuo Du
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Article
| Open Access
Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans
Wang et al. profile age-dependent miRNAomic changes in worm tissues and extracellular vesicles (EVs). They show that ageing controls miRNAs in a tissue-specific manner and their findings further suggest a complex EV-mediated miRNA trafficking network across tissues.
- Xueqing Wang
- , Quanlong Jiang
- & Yidong Shen
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Article
| Open Access
Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Article
| Open Access
LncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation
The roles of long non-coding RNAs (lncRNAs) in different subtypes of gastric cancer (GC) remain to be characterized. Here, the authors identify lncRNA MIR200CHG as a master regulator of Microsatellite stable (MSS)/epithelial-mesenchymal transition (EMT) GC subtype, which inhibits EMT and metastasis by stabilizing miR-200c.
- Yixiao Zhu
- , Chengmei Huang
- & Xin Wang
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Article
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Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
Regulatory miRNAs have significant therapeutic potential. Here the authors developed a screen to identify small molecule drugs that modulate miRNome profiles in human neurons and validated cardiac glycosides as inducers of the neuroprotective miR-132.
- Lien D. Nguyen
- , Zhiyun Wei
- & Anna M. Krichevsky
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| Open Access
Epigenomic analysis of formalin-fixed paraffin-embedded samples by CUT&Tag
Conducting epigenomic studies on FFPE samples is traditionally challenging due to chromatin damage caused due to exposure to formaldehyde. Here, the authors show that an optimisation of their previous CUTAC method allows the production of high-resolution maps of regulatory elements from FFPE samples.
- Steven Henikoff
- , Jorja G. Henikoff
- & Eric C. Holland
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| Open Access
Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage
Macrophages are increasingly recognized as key drivers of lung damage in acute pneumonia including COVID-19. Here, the authors report on a first-in-class, inhalable, carbohydrate-coupled microRNA-inhibitor for selective targeting of macrophages and that prevents pulmonary hyperinflammation.
- Christina Beck
- , Deepak Ramanujam
- & Stefan Engelhardt
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Screening of Drosophila microRNA-degradation sequences reveals Argonaute1 mRNA’s role in regulating miR-999
miRNAs typically bind to target mRNAs to induce their degradation but when base-pairing between miRNAs and the target RNAs are extended, miRNAs themselves can be degraded. Here, by employing AGO1-CLASH in Drosophila cells, the authors show that RNA sequence in AGO1 mRNA 3′UTR induces decay of miR-999.
- Peike Sheng
- , Lu Li
- & Mingyi Xie
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| Open Access
Identification of a physiologic vasculogenic fibroblast state to achieve tissue repair
Here, the authors report on the discovery of physiological vasculogenic fibroblasts capable of forming functional blood vessels. In vivo tissue reprogramming triggered by topical tissue nanotransfection (TNT) of a single anti-miR-200b oligonucleotide achieved therapeutic tissue vascularization.
- Durba Pal
- , Subhadip Ghatak
- & Chandan K. Sen
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2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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Article
| Open Access
MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans.
- Mary P. LaPierre
- , Katherine Lawler
- & Markus Stoffel
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Article
| Open Access
TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance
The authors reveal insights into miRNA tailing specificity of TENTs and their effect on miRNA levels by combinatory KOs of TENT2, TUT4 and TUT7. They show uridylation is linked to TENT2 and identify non-redundant functions between TUT4 and TUT7.
- Acong Yang
- , Xavier Bofill-De Ros
- & Shuo Gu
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Article
| Open Access
Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Kiss1 neurons are essential for puberty and fertility. Here, the authors show that canonical microRNA biosynthesis in Kiss1 neurons plays an essential role in the control of puberty and fertility, especially in females, likely via repression of repressors on the Kiss1 gene.
- Juan Roa
- , Miguel Ruiz-Cruz
- & Manuel Tena-Sempere
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MicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake
The microRNA miR-21 is induced in the islets of patients with glucose intolerance and diabetic mice. Here the authors report that deletion of miR-21 in pancreatic β-cells impairs glucose-stimulated insulin secretion via reduced glucose uptake, while a miR-21 agomir reduces blood glucose leves in diabetic male mice.
- Ruiling Liu
- , Cuilian Liu
- & Qingguo Ruan
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Article
| Open Access
Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function
The miR-1/133/206 gene family codes for the most abundant microRNAs in striated muscles. Here, Klockner et al show that inactivation of all family members in skeletal muscle prevents formation of normal neuromuscular junctions due to increased expression of the adaptor protein CRK.
- Ina Klockner
- , Christian Schutt
- & Thomas Braun
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Small extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1
The pathological mechanisms that lead to Ossification of the posterior longitudinal ligament (OPLL) are unclear. Here, the authors show that OPLL ligament cells produce small extracellular vesicles that induce ossification via miR-320e/TAK1 signaling in mice and human posterior longitudinal ligament cells.
- Chen Xu
- , Zicheng Zhang
- & Wen Yuan
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Article
| Open Access
Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui
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Article
| Open Access
Single-molecule imaging of microRNA-mediated gene silencing in cells
For decades, miRNAs have been studied primarily by ensemble methods, where a bulk collection of molecules is measured outside cells. Here, Kobayashi and Singer report methods to image miRNA function at the single-molecule level inside cells.
- Hotaka Kobayashi
- & Robert H. Singer
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Article
| Open Access
Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo
Bone remodeling involves a switch between bone formation and resorption, but the mechanisms is unclear. Here, the authors show that intercellular communication via extracellular vesicles secreted by mature osteoblasts is a key factor for the switching, via a microRNA-mediated mechanism.
- Maki Uenaka
- , Erika Yamashita
- & Masaru Ishii
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| Open Access
MicroRNA-365 regulates human cardiac action potential duration
An abnormal cardiac action potential underlies different types of cardiac arrhythmias. Here the authors show that microRNA-365 regulates the cardiac action potential by modulating key cardiac repolarizing channels.
- Dena Esfandyari
- , Bio Maria Ghéo Idrissou
- & Stefan Engelhardt
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Article
| Open Access
Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy is a myopathy caused by aberrant de-repression of the DUX4 gene. Here, the authors show that miR-675 inhibits DUX4 expression and protects muscles from DUX4-mediated cell death when administered to mice using AAV, and that upregulation of miR-675 via small molecules inhibits DUX4 and DUX4-associated biomarkers in myotubes derived from patients.
- Nizar Y. Saad
- , Mustafa Al-Kharsan
- & Scott Q. Harper
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Article
| Open Access
A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome
The RNA genome of the Hepatitis C Virus binds to the liver-specific miR122. Here the authors report the crystal structure of the Ago2:miR122:HCV complex showing that the viral RNA’s structural element traps the Ago2:miR-122 complex on the 5’ end of the viral genome to protect it from degradation.
- Luca F. R. Gebert
- , Mansun Law
- & Ian J. MacRae
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Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage
Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.
- Pietro Carotenuto
- , Francesco Amato
- & Chiara Braconi
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Article
| Open Access
Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism
Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.
- Julie Massart
- , Rasmus J. O. Sjögren
- & Anna Krook
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Article
| Open Access
A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration
Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.
- Andrea Raso
- , Ellen Dirkx
- & Leon J. De Windt
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| Open Access
Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
- Yoshiaki Ito
- , Tokio Matsuzaki
- & Hiroshi Asahara
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Article
| Open Access
A pig BodyMap transcriptome reveals diverse tissue physiologies and evolutionary dynamics of transcription
A comprehensive transcriptomic survey of the pig could enable mechanistic understanding of tissue specialization and accelerate its use as a biomedical model. Here the authors characterize four distinct transcript types in 31 adult pig tissues to dissect their distinct structural and transcriptional features and uncover transcriptomic variability related to tissue physiology.
- Long Jin
- , Qianzi Tang
- & Mingzhou Li
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Article
| Open Access
Single-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum
miRNA profiling from patient blood can be used for cancer diagnosis. Here the authors present an electro-optical nanopore sensing platform which allows sensitive and specific miRNA detection directly in human serum and apply to monitoring of miR-141-3p and miR-375-3p in different stage of prostate cancer.
- Shenglin Cai
- , Thomas Pataillot-Meakin
- & Joshua B. Edel
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| Open Access
Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells
Cells infected with pathogens can release signals that instruct neighbouring cells to mount an immune response or that reduce these cells’ susceptibility to infection. Here, Aguilar et al. show the opposite effect: cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells by activating their ER-stress response.
- Carmen Aguilar
- , Susana Costa
- & Ana Eulalio
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Article
| Open Access
miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Homeostasis of the intestinal epithelium is crucial for the maintenance of the epithelial barrier. Here, the authors show that mir-802 ablation in the mouse intestine impairs enterocyte differentiation and glucose absorption, enhances Paneth cell function by increasing Tmed9-mediated defensin secretion, and increases epithelial cell turnover.
- Algera Goga
- , Büsra Yagabasan
- & Markus Stoffel
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Article
| Open Access
UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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| Open Access
Mastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.
- Do-Kyun Kim
- , Geethani Bandara
- & Ana Olivera
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Article
| Open Access
Cell-type-specific profiling of loaded miRNAs from Caenorhabditis elegans reveals spatial and temporal flexibility in Argonaute loading
C. elegans miRNAs associate with AGO proteins ALG-1 and ALG-2. Here the authors provide a map of miRNAs loaded into ALG-1 and ALG-2 from intestine, body wall muscles and nervous system in C. elegans providing insights into spatial and temporal AGO loading flexibility.
- Christopher A. Brosnan
- , Alexander J. Palmer
- & Steven Zuryn
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Article
| Open Access
SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression
Enhancers shape gene expression patterns and are involved in disease pathogenesis. Here the authors demonstrate a strategy to screen functional regulatory elements for non-coding RNAs ― illustrated with miR-146a ― and link autoimmune disease risk genetic variants to autoimmune disease etiology.
- Guojun Hou
- , Isaac T. W. Harley
- & Nan Shen
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| Open Access
Unravelling the developmental and functional significance of an ancient Argonaute duplication
The sea anemone Nematostella vectensis expresses miRNAs and two Argonaute (AGO) proteins. Here the authors show that NveAGO1 and NveAGO2 are loaded with overlapping but different sets of miRNAs and that NveAGO2 binds both miRNAs and endo-siRNAs. Both AGO proteins are essential for development.
- Arie Fridrich
- , Vengamanaidu Modepalli
- & Yehu Moran
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| Open Access
Quantification of purified endogenous miRNAs with high sensitivity and specificity
MicroRNAs are potentially powerful biomarkers, though clinical use requires rapid and reliable profiling. Here the authors report amplification-free multicolour single-molecule imaging with single base mismatch sensitivity.
- Soochul Shin
- , Yoonseok Jung
- & Sungchul Hohng
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Article
| Open Access
Characterization and mitigation of gene expression burden in mammalian cells
The design of genetic networks in mammalian cells is still slow and often fails. Here the authors show that miRNA-based incoherent feedforward loop circuits can be used to alleviate cellular burden.
- Timothy Frei
- , Federica Cella
- & Velia Siciliano
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Article
| Open Access
Dicer-like 5 deficiency confers temperature-sensitive male sterility in maize
Small RNAs act to regulate gene or transposon activity during plant development. Here, the authors show that maize Dicer-like 5 is required for 24-nt phased, secondary small interfering RNA production in anthers and that dicer-like 5 mutants show abnormal tapetal development and temperature-sensitive sterility.
- Chong Teng
- , Han Zhang
- & Virginia Walbot
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Article
| Open Access
AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2
3′ end of microRNAs binds to the PAZ domain of Argonaute (AGO) proteins. Here the authors show that terminal nucleotidyltransferases TUT4/7 and exonuclease DIS3L2 induce tailing and decay of 3’ end exposed-microRNAs in AGO PAZ mutant expressing- or cancer cells.
- Acong Yang
- , Tie-Juan Shao
- & Shuo Gu
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Article
| Open Access
XPO5 promotes primary miRNA processing independently of RanGTP
XPO5 mediates nuclear export of miRNA hairpin precursors (pre-miRNAs) through a RanGTP-dependent binding. Here the authors employ HITS-CLIP and biochemical analysis and show that XPO5 binds and promotes nuclear processing of clustered pri-miRNAs, with extensive double-stranded regions, independently of RanGTP.
- Jingjing Wang
- , Jerome E. Lee
- & Rui Yi
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Article
| Open Access
Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion
Obesity predisposes to type 2 diabetes, but the mechanisms of obesity-associated β cell dysfunction are incompletely understood. Here the authors report that obesity increases the levels of miR-802, which impairs insulin transcription and secretion by targeting NeuroD1 and Fzd5.
- Fangfang Zhang
- , Dongshen Ma
- & Liang Jin
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Article
| Open Access
Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment
Evidence for sperm small noncoding RNA-mediated intergenerational transmission implies communication from responsive somatic cells to sperm. Here, authors show that epididymal cells alter extracellular vesicle cargo after stress exposure, to impact offspring neurodevelopment and stress reactivity.
- Jennifer C. Chan
- , Christopher P. Morgan
- & Tracy L. Bale
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Article
| Open Access
Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium
The role of neutrophils in the development of atherosclerosis has long been an enigma, with few neutrophils detected within the plaque. Here, the authors show that microvesicles released from neutrophils increase vascular inflammation and enhance atherosclerotic plaque formation through delivery of miR-155.
- Ingrid Gomez
- , Ben Ward
- & Victoria Ridger
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Article
| Open Access
miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
miRNA142-3p and Tet2 are separately known to regulate Treg. Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.
- Martin G. Scherm
- , Isabelle Serr
- & Carolin Daniel
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Article
| Open Access
DNA methylation directs microRNA biogenesis in mammalian cells
Long primary transcripts of microRNAs are co-transcriptionally cleaved by the enzyme Drosha. Here the authors suggest that DNA methylation in miRNA loci in mammalian cells increases Drosha binding, slowing RNA polymerase II elongation to enhance miRNA biogenesis.
- Ohad Glaich
- , Shivang Parikh
- & Carmit Levy
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| Open Access
Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.
- Lena Lampe
- , Marius Jentzsch
- & Elena A. Levashina
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Article
| Open Access
A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing
Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.
- Yifei Zhou
- , Xueqing Wang
- & Yidong Shen
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Article
| Open Access
FIERY1 promotes microRNA accumulation by suppressing rRNA-derived small interfering RNAs in Arabidopsis
Arabidopsis AGO1 binds both microRNA (miRNA) and endogenous small interfering RNA (siRNA). Here the authors show that 5′−3′ RNA degradation suppresses siRNA biogenesis from ribosomal RNA to prevent overloading of AGO1 with ribosomal siRNA and maintain miRNA-directed post translational gene silencing.
- Chenjiang You
- , Wenrong He
- & Beixin Mo
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Article
| Open Access
Discovery 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
An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress