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| 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 AccessA comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons
The limited size of some neuronal types and their entangled environment renders it difficult to study their transcription regulation. Here the authors present a comparative analysis of histone modifications and transcription in dopaminergic and serotonergic neurons and embryonic neural progenitors.
- Erik Södersten
- , Konstantinos Toskas
- & Johan Holmberg
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Article
| Open AccessEGFL7 reduces CNS inflammation in mouse
Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.
- Catherine Larochelle
- , Timo Uphaus
- & Frauke Zipp
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Article
| Open AccessImpaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor
Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.
- David L. Gray
- , John A. Allen
- & Michael D. Ehlers
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Article
| Open AccessNeuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms
Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.
- Christopher H. Douse
- , Stuart Bloor
- & Yorgo Modis
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Article
| Open AccessFasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling
Stimulant drugs are most commonly used to treat ADHD. Here, the authors demonstrate that in adolescents with ADHD who also have genetic variation in genes impacting metabotropic glutamate signaling, the non-stimulant mGluR activator fasoracetam is well tolerated and may be beneficial in alleviating symptoms of this disease.
- Josephine Elia
- , Grace Ungal
- & Hakon Hakonarson
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Article
| Open AccessCUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts
Repeat-associated non-AUG (RAN) translation contributes to the pathogenic mechanism of several microsatellite expansion diseases. Here the authors delineate the different steps involved in recruiting the ribosome to initiate G4C2 RAN translation to produce poly-Glycine Alanine, poly-Glycine Proline, and poly-Glycine Arginine repeats.
- Ricardos Tabet
- , Laure Schaeffer
- & Clotilde Lagier-Tourenne
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Article
| Open AccessPhf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway
Mutations in PHF8 gene are genetically associated with X-linked mental retardation. Here, Chen et al. show that Phf8 KO mouse have cognitive and synaptic plasticity impairment, and pharmacological inhibition of mTOR signaling can partially alleviate such defects.
- Xuemei Chen
- , Shuai Wang
- & Charlie Degui Chen
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Article
| Open AccessC9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation
Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors show that (GGGGCC) n translation can initiate without a 5′-cap, and this cap-independent translation is upregulated by stress mediated through eIF2α phosphorylation.
- Weiwei Cheng
- , Shaopeng Wang
- & Shuying Sun
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Article
| Open AccessLoss of mtDNA activates astrocytes and leads to spongiotic encephalopathy
Astrocytes in the brain are metabolically dynamic. Here, Ignatenko, Chilov and colleagues delete mitochondrial DNA (mtDNA) in a cell type specific manner, and show that inactivation of mtDNA helicase Twinkle in astrocytes leads to spongiotic encephalopathy.
- Olesia Ignatenko
- , Dmitri Chilov
- & Anu Suomalainen
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Article
| Open AccessCirculating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis
MiRNAs are small RNA molecules that can regulate gene expression. Here the authors show that expression of several exosomal miRNAs are altered in patients with multiple sclerosis, and that let-7i modulates regulatory T cell homeostasis to contribute to pathogenesis.
- Kimitoshi Kimura
- , Hirohiko Hohjoh
- & Takashi Yamamura
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Article
| Open AccessNetwork connectivity determines cortical thinning in early Parkinson’s disease progression
In Parkinson’s disease (PD), neurodegeneration spreads from the brainstem to the cerebral cortex. Here, in a longitudinal study of PD patients, the authors found that cortical thinning followed neural connectivity from a “disease reservoir”.
- Y. Yau
- , Y. Zeighami
- & A. Dagher
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Article
| Open AccessSystematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
Progressive multiple sclerosis is an inflammatory and degenerative disease of the central nervous system, for which effective treatment is lacking. The authors carry out a screen to identify orally available generic medications, and show that the antidepressant clomipramine reduces pathology in mouse models.
- Simon Faissner
- , Manoj Mishra
- & V. Wee Yong
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Article
| Open AccessPAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle
Facioscapulohumeral muscular dystrophy is a myopathy linked to ectopic expression of the DUX4 transcription factor. The authors show that the suppression of targets genes of the myogenesis regulator PAX7 is a signature of FSHD, and might explain oxidative stress sensitivity and epigenetic changes.
- Christopher R. S. Banerji
- , Maryna Panamarova
- & Peter S. Zammit
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Article
| Open AccessEvidence for causal top-down frontal contributions to predictive processes in speech perception
The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.
- Thomas E. Cope
- , E. Sohoglu
- & James B. Rowe
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Article
| Open AccessDownregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches
Drugs targeting myostatin reverse muscle wasting in animal models, but have limited efficacy in patients. The authors show that the myostatin pathway is downregulated in patients, possibly explaining the poor outcome of anti-myostatin approaches, and that it can be reactivated by correcting disease-causing mutations in mice.
- Virginie Mariot
- , Romain Joubert
- & Julie Dumonceaux
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Article
| Open AccessRods progressively escape saturation to drive visual responses in daylight conditions
Rod photoreceptors are thought to be saturated under bright light. Here, the authors describe the physiological parameters that mediate response saturation of rod photoreceptors in mouse retina, and show that rods can drive visual responses in photopic conditions.
- Alexandra Tikidji-Hamburyan
- , Katja Reinhard
- & Thomas A. Münch
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Article
| Open AccessTranscriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis
CD4+ T cells secreting interleukin-17 (TH17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human TH 17 co-expressing interferon-γ (TH1/17) has a molecular signature similar to “pathogenic” mouse TH 17 but distinct from “non-pathogenic” mouse TH 17.
- Dan Hu
- , Samuele Notarbartolo
- & Howard L. Weiner
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Article
| Open AccessGenome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus
Most SNPs are located in non-coding genomic regions and their function remains elusive. Here, the authors perform a genome-wide scan of expression and DNA methylation quantitative trait loci in human hippocampal tissue to provide a resource for the functional interpretation of SNPs in brain disorders.
- Herbert Schulz
- , Ann-Kathrin Ruppert
- & Sven Cichon
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Article
| Open AccessHIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration
HIV infection results in elevated beta-amyloid (Aβ) levels in the brain, but the underlying mechanisms are unclear. Here, the authors show that amyloid precursor protein inhibits virion production and that HIV Gag, counteracting this antiviral function, results in secretase-dependent Aβ production and neuron degeneration.
- Qingqing Chai
- , Vladimir Jovasevic
- & Mojgan H. Naghavi
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Article
| Open AccessSupramammillary glutamate neurons are a key node of the arousal system
Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.
- Nigel P. Pedersen
- , Loris Ferrari
- & Patrick M. Fuller
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Article
| Open AccessExperimental transfusion of variant CJD-infected blood reveals previously uncharacterised prion disorder in mice and macaque
It is hypothesised that exposure to bovine spongiform encephalopathy through contaminated food could have resulted in a large proportion of latent variant Creutzfeldt-Jakob disease cases in humans. Here the authors demonstrate that inoculation with blood from non-symptomatic, vCJD infected humans, results in a unique prion-like disorder in mice and macaques.
- Emmanuel E. Comoy
- , Jacqueline Mikol
- & Jean-Philippe Deslys
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Article
| Open AccessLow frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings
Transcranial alternating current stimulation (tACS) has been proposed to enhance neural rhythms supporting memory. Here, the authors leverage human intracranial recordings to show that low-frequency tACS does not entrain key rhythms in non-REM sleep or resting wakefulness.
- Belen Lafon
- , Simon Henin
- & Anli A. Liu
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Article
| Open AccessReducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice
Sarcolipin is an inhibitor of the ATP dependent calcium pump SERCA, and is abnormally elevated in Duchenne muscular dystrophy. The authors show that reducing sarcolipin expression ameliorates skeletal muscle pathology and cardiomyopathy and extends life span in mouse models of DMD.
- Antanina Voit
- , Vishwendra Patel
- & Gopal J. Babu
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Article
| Open AccessSilencing Nfix rescues muscular dystrophy by delaying muscle regeneration
Strategies aimed at promoting muscle regeneration to treat muscular dystrophy have met with limited success. Here the authors show instead that delaying muscle regeneration, by ablation of the transcription factor Nfix, ameliorates muscular dystrophy in mice.
- Giuliana Rossi
- , Chiara Bonfanti
- & Graziella Messina
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Article
| Open AccessCis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae
Induction of the cis form of phosphorylated tau (cis P-tau) has previously been shown to occur in animal models of traumatic brain injury (TBI), and blocking this form of tau using antibody was beneficial in a rodent model of severe TBI. Here the authors show that cis P-tau induction is a feature of several different forms of TBI in humans, and that administration of cis P-tau targeting antibody to rodents reduces or delays pathological features of TBI.
- Onder Albayram
- , Asami Kondo
- & Xiao Zhen Zhou
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Article
| Open AccessMyoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle
Exon skipping is a strategy for the treatment of Duchenne muscular dystrophy, but has variable efficacy. Here, the authors show that dystrophin restoration occurs preferentially in areas of myofiber regeneration, where antisense oligonucleotides are stored in macrophages and delivered to myoblasts and newly formed myotubes
- James S. Novak
- , Marshall W. Hogarth
- & Terence A. Partridge
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Article
| Open AccessInference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer’s disease
“mRNA abundance is determined by the rates of transcription and decay. Here, the authors propose a method for estimating the rate of differential mRNA decay from RNA-seq data and model mRNA stability in the brain, suggesting a link between mRNA stability and Alzheimer’s disease.”
- Rached Alkallas
- , Lisa Fish
- & Hamed S. Najafabadi
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Article
| Open AccessCross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.
- Beben Benyamin
- , Ji He
- & Dongsheng Fan
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Article
| Open AccessNeutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage
Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.
- Xiurong Zhao
- , Shun-Ming Ting
- & Jaroslaw Aronowski
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Article
| Open AccessMuscle pathology from stochastic low level DUX4 expression in an FSHD mouse model
Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
- Darko Bosnakovski
- , Sunny S. K. Chan
- & Michael Kyba
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Article
| Open AccessAn injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle. Here the authors show an injection of imidazole poly(organophosphazenes), a hydrogel with thermosensitive sol–gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model.
- Le Thi Anh Hong
- , Young-Min Kim
- & Byung Gon Kim
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Article
| Open AccessThe non-coding RNA BC1 regulates experience-dependent structural plasticity and learning
Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.
- Victor Briz
- , Leonardo Restivo
- & Claudia Bagni
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Article
| Open AccessLong-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy
Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.
- Caroline Le Guiner
- , Laurent Servais
- & George Dickson
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Article
| Open AccessMicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain
Dysregulation of voltage gated potassium channels is a feature of neuropathic pain. Here in a rat model the authors identify the microRNA cluster miR-17-92 as a regulator of voltage gated potassium channels in the dorsal root ganglion neurons.
- Atsushi Sakai
- , Fumihito Saitow
- & Hidenori Suzuki
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Article
| Open AccessAntisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice
X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.
- Hichem Tasfaout
- , Suzie Buono
- & Jocelyn Laporte
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Article
| Open AccessFetal and postnatal metal dysregulation in autism
The contribution of metal exposure to the etiology of ASD is unclear. Here the authors tested whether elemental dysregulation contributes to ASD risk by analysing tooth metal biomarkers from ASD discordant twins, and found significant differences in metal uptake between ASD cases and their control twin siblings, but only during certain developmental periods.
- Manish Arora
- , Abraham Reichenberg
- & Sven Bölte
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Article
| Open AccessFibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core
Huntington's disease is caused by a polyglutamine stretch expansion in the first exon of huntingtin. Here, the authors use infrared spectroscopy and solid-state NMR and show that polymorphic huntingtin exon1 fibres differ in their flanking regions but not their core polyglutamine amyloid structures.
- Hsiang-Kai Lin
- , Jennifer C. Boatz
- & Patrick C. A. van der Wel
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Article
| Open AccessLipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis
Drug delivery in brain tumours is still a significant clinical concern. In this study, the authors develop a biomimetic lipoprotein nanoparticle for the efficient delivery of ATF5 siRNA inRas-activated brain cancer cells, where the nanoparticle is internalized by macropinocytosis in a Ras-dependent manner.
- Jia-Lin Huang
- , Gan Jiang
- & Xiao-Ling Gao
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Article
| Open AccessProtein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy
Maternal diabetes can induce neural tube defects (NTD). Here, the authors show that in mice, deletion ofPrkca(encoding protein kinase C-alpha) restores autophagy, via suppression of miR-129-2 and reversal of reduced peroxisome proliferator-activated receptor c coactivator 1alpha, so reducing NTDs.
- Fang Wang
- , Cheng Xu
- & Peixin Yang
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Article
| Open AccessAdrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke
Risk of infection is high after stroke, but the causes are not clear. Here the authors implicate altered beta–adrenergic signalling after stroke that results in a reduction in IgM-mediated protection by marginal zone B cells.
- Laura McCulloch
- , Craig J. Smith
- & Barry W. McColl
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Article
| Open AccessDiurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer’s disease
Diurnal and seasonal rhythms modulate brain function, but we do not know the genomic basis for these rhythms. Here, Limet al. show diurnal and seasonal rhythms of gene expression in the human brain, their relationship to histone acetylation and DNA methylation, and their disruption in Alzheimer’s disease.
- Andrew S. P. Lim
- , Hans-Ulrich Klein
- & Philip L. De Jager
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Article
| Open AccessPABPN1 gene therapy for oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy is caused by trinucleotide repeat expansions in thePABPN1gene. Here the authors use AAV-based gene therapy to knockdown the mutant gene and replace it with a wild-type allele, and show effectiveness in mice and in patient cells.
- A. Malerba
- , P. Klein
- & G. Dickson
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Article
| Open AccessA chemical chaperone improves muscle function in mice with a RyR1 mutation
Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.
- Chang Seok Lee
- , Amy D. Hanna
- & Susan L. Hamilton
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Article
| Open AccessGenetic correlation between amyotrophic lateral sclerosis and schizophrenia
Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
- Russell L. McLaughlin
- , Dick Schijven
- & Michael C. O’Donovan
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Article
| Open AccessDNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons
Transcriptional changes occur in the dorsal root ganglion in response to nerve injury and may contribute to neuropathic pain. Here the authors show that the DNA methyltransferase DNMT3a is upregulated in rodents following nerve injury, and may contribute to pain-like behaviour by decreasing expression of the voltage-gated potassium channel Kv1.2.
- Jian-Yuan Zhao
- , Lingli Liang
- & Yuan-Xiang Tao
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Article
| Open AccessTransient auditory nerve demyelination as a new mechanism for hidden hearing loss
Hidden hearing loss (HHL) is an auditory neuropathy that impairs one’s ability to hear, particularly in a noisy environment. Here the authors show that in mice, transient loss of cochlear Schwann cells results in permanent disruption of the cochlear heminodal structure, leading to auditory deficits characteristic of HHL.
- Guoqiang Wan
- & Gabriel Corfas
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Article
| Open AccessMuscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy
CRISPR/Cas9-mediated gene editing is an emerging strategy to treat Duchenne muscular dystrophy. Here the authors develop multiple CRISPR/Cas9-based approaches to correct different dystrophin gene mutations, and show significant restoration of dystrophin expression in skeletal and cardiac muscle in mice.
- Niclas E. Bengtsson
- , John K. Hall
- & Jeffrey S. Chamberlain
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Article
| Open AccessDysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation
D2 receptor-expressing medium spiny neurons (D2-MSNs) are thought to suppress goal-directed behaviours. Here authors ablate D2-MSNs specifically in the ventrolateral striatum, and find that surprisingly, it leads to a reduction in goal-directed motivation in mice.
- Iku Tsutsui-Kimura
- , Hiroyuki Takiue
- & Kenji F. Tanaka
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