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| Open AccessCorrecting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator
Glucose-6-phosphate dehydrogenase (G6PD) deficiency provides insufficient protection from oxidative stress, contributing to diverse human pathologies. Here, the authors identify a small molecule that increases the activity and/or stability of mutant G6PD and show that it reduces oxidative stress in zebrafish and hemolysis in isolated human erythrocytes.
- Sunhee Hwang
- , Karen Mruk
- & Daria Mochly-Rosen
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Article
| Open AccessHigh-resolution NMR studies of antibiotics in cellular membranes
Antibiotics that target the peptidoglycan precursor lipid II are promising templates for next-generation antibiotics. Here authors use solid-state NMR and monitor lipid II-binding antibiotics, such as nisin, directly in cell membranes.
- João Medeiros-Silva
- , Shehrazade Jekhmane
- & Markus Weingarth
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| Open AccessAncient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket
In some countries, leaves of the shrub Mallotus oppositifolius have been used to treat epilepsy. Here, authors look at the structural and molecular basis for how chemical components of M. oppositifolius have their anticonvulsant effects, via modulation of potassium channel activity.
- Rían W. Manville
- & Geoffrey W. Abbott
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Article
| Open AccessTargeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells
ARID1A is highly inactivated in cancer. Here, the authors show that ARID1A has a synthetic lethal interaction with AURKA in colorectal cancer cells and that ARID1A deficiency activates the AURKA target CDC25C, whose inhibitors also cause cell death in the ARID1A-deficient cell lines.
- Changjie Wu
- , Junfang Lyu
- & Joong Sup Shim
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Article
| Open AccessRed blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude
Unwanted uptake in the liver and limited accumulation in target organs is a major obstacle to targeted drug delivery. Here, the authors report on the hitchhiking of nanocarriers on red blood cells and the targeted upstream delivery to different target organs in mice, pigs and ex vivo human lungs.
- Jacob S. Brenner
- , Daniel C. Pan
- & Vladimir Muzykantov
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Article
| Open AccessHeavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing
Resistance of gRNA to ubiquitous ribonucleases is required for CRISPR-Cas9-based therapeutics. Here, the authors explore chemical modifications at all positions of the crRNA guide and tracrRNA cofactor, and identify modified versions that are more potent and stable than their unmodified counterparts in editing human cells.
- Aamir Mir
- , Julia F. Alterman
- & Erik J. Sontheimer
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Article
| Open AccessIntermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses
Sepsis is a life-threatening condition. Here, the authors show that intermedin alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Patients with high intermedin levels exhibit a low risk of shock, lower severity scores, and greatly improved survival outcomes.
- Fei Xiao
- , Denian Wang
- & Wei Zhang
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Article
| Open AccessRational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors
Zika virus (ZIKV) is an emerging global health issue, but currently no licensed vaccine achieves lasting protective immunity. Here the authors show that a ZIKV vaccine containing the envelop protein without the transmembrane domain and the precursor membrane protein can provide effective protection in mouse models.
- César López-Camacho
- , Peter Abbink
- & Arturo Reyes-Sandoval
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Article
| Open AccessVariations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment
Patients with schizophrenia show varied response to antipsychotics. Here, the authors demonstrate in patients under antipsychotics treatment that a haplotype associated with lower dysbindin-1 expression correlated with better executive functions, providing further mechanistic support from mouse models.
- Diego Scheggia
- , Rosa Mastrogiacomo
- & Francesco Papaleo
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Article
| Open AccessTargetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.
- Samuel Y. Ng
- , Noriaki Yoshida
- & Raphael Koch
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Article
| Open AccessChemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice
Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells. Here, the authors report the development and in vivo validation of a non-internalising ADC with the capacity to target cancer cells and release its therapeutic cargo extracellularly via a chemical trigger.
- Raffaella Rossin
- , Ron M. Versteegen
- & Marc S. Robillard
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Article
| Open AccessSnord116-dependent diurnal rhythm of DNA methylation in mouse cortex
Many genes have oscillating gene expression pattern in circadian centers of the brain. This study shows cortical diurnal DNA methylation oscillation in a mouse model of Prader-Willi syndrome, and describes corresponding changes in gene expression and chromatin compaction.
- Rochelle L. Coulson
- , Dag H. Yasui
- & Janine M. LaSalle
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Article
| Open AccessVibrio vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits RIG-I-mediated antiviral innate immunity
Quorum sensing signaling molecules are known to be critical determinants in bacterial pathogenesis. Here the authors show the quorum sensing molecule cFP from Vibrio vulnificus inhibits the RIG-I mediated antiviral interferon response and enhances susceptibility to viral infection.
- Wooseong Lee
- , Seung-Hoon Lee
- & Jong-Won Oh
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| Open AccessGold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival
Surface-enhanced Raman spectroscopy (SERS) visualizes fingerprints of intermolecular vibrations of many metabolites. Here the authors report a SERS imaging technique that enables the visualization of metabolites distribution and automated extraction of tumour boundaries in frozen tissues.
- Megumi Shiota
- , Masayuki Naya
- & Makoto Suematsu
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Article
| Open AccessHorizontal antimicrobial resistance transfer drives epidemics of multiple Shigella species
Antimicrobial resistance (AMR) in Shigella species is a public health concern. Here, Baker et al. show how horizontal transfer of an AMR plasmid among Shigella species contributes to epidemics in men who have sex with men in England.
- Kate S. Baker
- , Timothy J. Dallman
- & Nicholas Thomson
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Article
| Open AccessDesigner exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment
Exosomes function as intercellular information transmitters and are candidates for delivery of therapeutic agents. Here the authors present EXOtic, a synthetic biology device for in-situ production of designer exosomes and demonstrate in vivo application in models of Parkinson's disease.
- Ryosuke Kojima
- , Daniel Bojar
- & Martin Fussenegger
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Article
| Open AccessAggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis
Aggregation is sequence-specific and nucleated by short aggregating protein segments (APR). Here authors use a multidisciplinary approach to show that in E.coli some frequently occurring APRs lead to protein aggregation and ultimately bacterial cell death, which could serve as antibacterial strategy.
- Ladan Khodaparast
- , Laleh Khodaparast
- & Joost Schymkowitz
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| Open AccessA community approach to mortality prediction in sepsis via gene expression analysis
Sepsis is characterized by deregulated host response to infection. Efficient therapies are still needed but a limitation for sepsis treatment is the heterogeneity in patients. Here Sweeney et al. generate prognostic models based on gene expression to improve risk stratification classification and prediction for 30-day mortality of patients.
- Timothy E. Sweeney
- , Thanneer M. Perumal
- & Raymond J. Langley
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| Open AccessA ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.
- Dennis Wolf
- , Nathaly Anto-Michel
- & Andreas Zirlik
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Article
| Open AccessStructure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform.
- Anuj Khandelwal
- , Caitlin N. Kent
- & Brian S. J. Blagg
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Article
| Open AccessA PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
- Jean-Louis Guéant
- , Céline Chéry
- & David S. Rosenblatt
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| Open AccessA machine learning approach to integrate big data for precision medicine in acute myeloid leukemia
Identification of markers of drug response is essential for precision therapy. Here the authors introduce an algorithm that uses prior information about each gene’s importance in AML to identify the most predictive gene-drug associations from transcriptome and drug response data from 30 AML samples.
- Su-In Lee
- , Safiye Celik
- & Pamela S. Becker
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Article
| Open AccessDNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty
Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) often occur among HIV-infected individuals. Here, the authors report an epigenome-wide association analysis of IDU and HCV in HIV-infected individuals, finding that their associated methylation signatures inform HIV frailty.
- Xinyu Zhang
- , Ying Hu
- & Ke Xu
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Article
| Open AccessAllosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation
G protein-coupled receptors are considered promising therapeutic targets. Here, the authors have identified nanobodies, or single-domain llama antibodies, that specifically enhance agonist-induced activity of a type of G protein-coupled receptor, the mGlu2 receptor.
- Pauline Scholler
- , Damien Nevoltris
- & Jean-Philippe Pin
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Article
| Open AccessGenetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis
Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.
- Carole Henique
- , Guillaume Bollée
- & Pierre-Louis Tharaux
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Article
| Open AccessMicroneedle-array patches loaded with dual mineralized protein/peptide particles for type 2 diabetes therapy
Diabetes treatments often rely on frequent and scheduled drug administration, which reduces patient compliance and increases treatment cost. Here, the authors develop a microneedle-array patch that separately loads drug-releasing module and glucose-sensing element for on-demand, long-term diabetes therapy.
- Wei Chen
- , Rui Tian
- & Xiaoyuan Chen
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Article
| Open AccessIntertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy
Nucleic acid nanomedicines are promising for cancer drug delivery. Here, the authors show using a mouse model the tumor immunotherapeutic efficacy of nanovaccines based on intertwining DNA-RNA nanocapsules loaded with DNA CpG, Stat3-silencing short hairpin RNA and tumor-specific peptide neoantigens.
- Guizhi Zhu
- , Lei Mei
- & Xiaoyuan Chen
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Article
| Open AccessAndrogen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma
The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
- Qingbo Huang
- , Yin Sun
- & Chawnshang Chang
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Article
| Open AccessFrequent miRNA-convergent fusion gene events in breast cancer
Fusion gene research traditionally focuses on fusions that result in hybrid proteins or promoter switching events. Here, the authors demonstrate enrichment of fusions in miRNA host genes in breast cancer, highlighting that disparate fusions could have convergent impact on miRNA.
- Helena Persson
- , Rolf Søkilde
- & Carlos Rovira
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| Open AccessPrinting of small molecular medicines from the vapor phase
Traditional approaches used in the pharmaceutical industry are not precise or versatile enough for customized medicine formulation and manufacture. Here the authors produce a method to form coatings, with accurate dosages, as well as a means of closely controlling dissolution kinetics.
- Olga Shalev
- , Shreya Raghavan
- & Max Shtein
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| Open AccessEstablishing multiple omics baselines for three Southeast Asian populations in the Singapore Integrative Omics Study
The Singapore Genome Variation projects characterized the genetics of Singapore’s Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.
- Woei-Yuh Saw
- , Erwin Tantoso
- & Yik-Ying Teo
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Article
| Open AccessCombined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi
Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.
- Iwei Yeh
- , Ursula E. Lang
- & Arnaud de la Fouchardière
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Article
| Open AccessThrombopoiesis is spatially regulated by the bone marrow vasculature
Megakaryocyte maturation is thought to occur as the cells migrate from a vessel-distant (endosteal) niche to the vessel within the bone. Here, the authors show that megakaryocytes represent largely sessile cells in close contact with the vasculature and homogeneously distributed in the bone marrow.
- David Stegner
- , Judith M. M. vanEeuwijk
- & Katrin G. Heinze
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Article
| Open AccessEngineered botulinum neurotoxin B with improved efficacy for targeting human receptors
Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy.
- Liang Tao
- , Lisheng Peng
- & Min Dong
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Article
| Open AccessHypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance
Sodium/proton exchangers (NHEs) are critical regulators of pH within the cell and the extracellular microenvironment. Here, the authors show that hypoxia induces mobilization of NHE6 from endosomal compartment to the plasma membrane in a PKC-dependent manner inducing hyper acidification of endosomes and drug resistance.
- Fabrice Lucien
- , Pierre-Paul Pelletier
- & Claire M. Dubois
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| Open AccessThe critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis
A major cause of transplanted organ failure is graft arteriosclerosis. Qiuet al. show that a key protease of post-translational SUMO modification, SENP1, is crucial for graft arteriosclerosis by regulating the activity of GATA2 transcription factor in the endothelium, and promoting endothelial inflammation and alloimmunity.
- Cong Qiu
- , Yuewen Wang
- & Luyang Yu
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Article
| Open AccessA tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
Artemisinin-resistantPlasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodiummouse models.
- Paul M. O’Neill
- , Richard K. Amewu
- & Stephen A. Ward
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Article
| Open AccessA potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibitsPlasmodium falciparum in vitroand in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.
- Ebere Sonoiki
- , Caroline L. Ng
- & Philip J. Rosenthal
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Article
| Open AccessProtein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation
What keeps blood from clotting in homeostasis is a puzzle. Here, the authors suggest that lack of the enzyme disulfide isomerase (PDI) in the blood is key, and show that PDI is secreted only after vascular injury to act on substrates that include vitronectin, affecting its binding to αVβ3 and αIIbβ3 integrins and enabling thrombus formation.
- Sheryl R. Bowley
- , Chao Fang
- & Bruce Furie
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Article
| Open AccessErythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent
Humans that reach high altitude soon after the first ascent show faster adaptation to hypoxia. Songet al. show that this adaptive response relies on decreased red blood cell uptake of plasma adenosine due to reduced levels of nucleoside transporter ENT1 resulting from coordinated adenosine generation by ectonucleotidase CD73 and activation of A2B receptors.
- Anren Song
- , Yujin Zhang
- & Yang Xia
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Article
| Open AccessMutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome
Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring theS34F mutation in the U2AFspliceosome gene is sensitive to compounds that further perturb the spliceosome.
- Cara Lunn Shirai
- , Brian S. White
- & Matthew J. Walter
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Article
| Open AccessSaturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2
The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.
- Yi Wang
- , Yuanyuan Qian
- & Guang Liang
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Article
| Open AccessBiallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
JAK1 mediates intracellular signalling from multiple cytokine receptors. Here, Elettoet al. identify JAK1 mutations that disrupt multiple signalling pathways and are associated with primary immunodeficiency, atypical mycobacterial infection susceptibility and early-onset metastatic bladder carcinoma.
- Davide Eletto
- , Siobhan O. Burns
- & Sergey Nejentsev
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Article
| Open AccessIn vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery
Gene editing approaches are widely used for correcting mutations, but their application is largely limited to cells and not living animals. Here the authors show that in vivoγPNA-mediated editing of a β-globin mutation is promoted by SCF and leads to sustained normalization of blood haemoglobin levels β-thalassemic mice.
- Raman Bahal
- , Nicole Ali McNeer
- & Peter M. Glazer
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Article
| Open AccessCarbon nanotubes allow capture of krypton, barium and lead for multichannel biological X-ray fluorescence imaging
Biological applications of x-ray fluorescence (XRF) imaging are currently limited to mapping naturally occurring elements in tissues. Here, the authors encapsulate toxic elements in functionalized single walled nanotubes, and use them as non-toxic XRF contrast agents for imaging specific cellular organelles.
- Christopher J. Serpell
- , Reida N. Rutte
- & Benjamin G. Davis
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Article
| Open AccessAn endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy
Nephropathy is a common and hard-to-treat consequence of diabetes. Here Kato et al. show that a megacluster of microRNAs regulates early development of diabetic nephropathy in mice, and that inhibition of the cluster's host long non-coding RNA transcript attenuates disease symptoms, suggesting a new therapy for diabetic nephropathy.
- Mitsuo Kato
- , Mei Wang
- & Rama Natarajan
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Article
| Open AccessFoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase
Dopaminergic neurons are important for regulating energy homeostasis. Here, the authors show the transcription factor FoxO1 negatively regulates tyrosine hydroxylase expression in midbrain dopaminergic neurons, and plays an important role in regulation of glucose homeostasis, energy expenditure, and resistance to diet-induced obesity.
- Khanh V. Doan
- , Ann W. Kinyua
- & Ki Woo Kim
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Article
| Open AccessPlatelet clearance via shear-induced unfolding of a membrane mechanoreceptor
The platelets detect and respond to shear stress generated by blood flow. Here the authors show that the binding of the soluble von Willebrand factor to its receptor GPIba under physiological shear stress induces receptor's domain unfolding on the platelet and signalling into the platelet, leading to platelets clearance.
- Wei Deng
- , Yan Xu
- & Renhao Li
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Article
| Open AccessNeutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
- Linda Labberton
- , Ellinor Kenne
- & Thomas Renné