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| Open AccessUnstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
- Rahel T. Florian
- , Florian Kraft
- & Christel Depienne
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Article
| Open AccessTau deposition is associated with functional isolation of the hippocampus in aging
Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.
- Theresa M. Harrison
- , Anne Maass
- & William J. Jagust
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Article
| Open AccessBi-allelic variants in RNF170 are associated with hereditary spastic paraplegia
Disturbances in IP3 receptor-mediated release of Ca2+ from the endoplasmatic reticulum are associated with neurodegenerative disease. Here, the authors identify in four families with hereditary spastic paraplegia biallelic mutations in RNF170 that associate with increased basal levels of IP3 receptors.
- Matias Wagner
- , Daniel P. S. Osborn
- & Rebecca Schüle
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Article
| Open AccessDisruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders
Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.
- Hui Guo
- , Elisa Bettella
- & Evan E. Eichler
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Article
| Open AccessContribution of retrotransposition to developmental disorders
Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.
- Eugene J. Gardner
- , Elena Prigmore
- & Matthew E. Hurles
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Article
| Open AccessConsciousness-specific dynamic interactions of brain integration and functional diversity
How do diversity (entropy) and integration of activity across brain regions interact to support consciousness? Here the authors show that anaesthetised individuals and patients with disorders of consciousness exhibit overlapping reductions in both diversity and integration in the brain’s default mode network.
- Andrea I. Luppi
- , Michael M. Craig
- & Emmanuel A. Stamatakis
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Article
| Open AccessSrc inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor gene. Here the authors show that Src kinase signaling is activated in a mouse model of the disease, and that Src inhibition improves pathology and behavioral symptoms in mice.
- Madoka Iida
- , Kentaro Sahashi
- & Masahisa Katsuno
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Article
| Open AccessDifferentiation but not ALS mutations in FUS rewires motor neuron metabolism
While energy metabolism has been repeatedly linked to ALS, motor neuron metabolism remains poorly studied. Here, authors show that human iPSCs rewire specific metabolic routes when they differentiate into functional motor neurons and that ALS-causing mutations in FUS do not affect energy metabolism.
- Tijs Vandoorne
- , Koen Veys
- & Ludo Van Den Bosch
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Article
| Open AccessModulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis
Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here, authors show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity and can be targeted to rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion
- Anthony Giampetruzzi
- , Eric W. Danielson
- & Claudia Fallini
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Article
| Open AccessGenome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes
A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.
- Heming Wang
- , Jacqueline M. Lane
- & Richa Saxena
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Article
| Open AccessHsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor
Hsp chaperones stabilize the inactive conformation of androgen receptor (AR) and are released upon hormone-induced AR activation. Here, the authors locate the Hsp binding region on AR, and show that Hsp70 reduces AR aggregation and promotes AR degradation in cellular and mouse models of a neuromuscular disorder.
- Bahareh Eftekharzadeh
- , Varuna C. Banduseela
- & Xavier Salvatella
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Article
| Open AccessA human memory circuit derived from brain lesions causing amnesia
Memory is hypothesised to depend on different brain regions that interact in a network. Here, the authors use case studies of stroke patients with amnesia from the literature to identify brain regions that are part of this network.
- Michael A. Ferguson
- , Chun Lim
- & Michael D. Fox
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Article
| Open AccessNon-coding variability at the APOE locus contributes to the Alzheimer’s risk
Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.
- Xiaopu Zhou
- , Yu Chen
- & Nancy Y. Ip
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Article
| Open AccessAMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”
- Vincenzo Salpietro
- , Christine L. Dixon
- & Henry Houlden
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Article
| Open AccessPaternal-age-related de novo mutations and risk for five disorders
Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.
- Jacob L. Taylor
- , Jean-Christophe P. G. Debost
- & Elise B. Robinson
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Article
| Open AccessLocus coeruleus-CA1 projections are involved in chronic depressive stress-induced hippocampal vulnerability to transient global ischaemia
Depression and transient ischaemic attacks are tightly regulated but the neural circuits underlying depression-modulated ischaemic injury are not known. Here, the authors show that the locus coeruleus-CA1 pathway is involved in depression-associated ischaemia susceptibility.
- Qian Zhang
- , Dian Xing Hu
- & Bo Tian
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Article
| Open AccessActivating an anterior nucleus gigantocellularis subpopulation triggers emergence from pharmacologically-induced coma in rodents
The reticular activating system (RAS) of the brainstem regulates wakefulness, and stimulation of RAS areas can reverse effects of anaesthesia. Here, the authors show that stimulation of a particular RAS area, the anterior portion of nucleus gigantocellularis, can produce arousal from deep coma.
- S. Gao
- , A. Proekt
- & D. W. Pfaff
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Article
| Open AccessAβ-induced vulnerability propagates via the brain’s default mode network
Amyloid-β (Aβ) deposition occurs in Alzheimer's disease but its relation to disease features such as local brain hypometabolism or cognitive decline is unclear. Here, the authors show that Aβ aggregation in the brain’s default mode network leads to hypometabolism in distant but functionally connected areas.
- Tharick A. Pascoal
- , Sulantha Mathotaarachchi
- & Pedro Rosa-Neto
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Article
| Open AccessA systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.
- Lohith Madireddy
- , Nikolaos A. Patsopoulos
- & Sergio E. Baranzini
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| Open AccessInterpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline
Convolutional neural networks have been applied to various areas of medical imaging and histology. Here the authors develop an automated approach using interpretable neural networks to determine Alzheimer’s disease plaque and cerebral amyloid angiopathy burden in post-mortem human brain tissue.
- Ziqi Tang
- , Kangway V. Chuang
- & Brittany N. Dugger
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Article
| Open AccessFelodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing
A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.
- Farah H. Siddiqi
- , Fiona M. Menzies
- & David C. Rubinsztein
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| Open AccessA PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy
Diagnosis and classification of peripheral neuropathy (PN) is facilitated by nerve conduction (NC) studies. Here, Bjornsdottir et al. find a low-frequency PRPH splice-donor variant that associates with NC amplitude and neurological assessment of recalled PRPH variant carriers reveals increased risk of a mild sensory-negative PN.
- Gyda Bjornsdottir
- , Erna V. Ivarsdottir
- & Kari Stefansson
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| Open AccessNRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies
Onion bulbs are a hallmark of demyelinating peripheral neuropathies. Here the authors identify Neuregulin-1 type I expression in Schwann cells as an essential mechanism involved in the formation of these characteristic structures.
- Robert Fledrich
- , Dagmar Akkermann
- & Ruth M. Stassart
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Article
| Open AccessSocial networks and risk of delayed hospital arrival after acute stroke
Rapid arrival to hospital after stroke is critical for patients to receive effective treatment. Here, the authors examine how stroke patients’ social network structure relates to stroke arrival time, and show that small and close-knit personal networks predict delayed arrival.
- Amar Dhand
- , Douglas Luke
- & Jin-Moo Lee
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Article
| Open AccessA genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome
Carpal tunnel syndrome (CTS) is caused by entrapment of the median nerve at the wrist. Here, Wiberg et al. perform a GWAS for CTS in the UK Biobank cohort and identify 16 genetic loci, and find a causal relationship between short stature and CTS risk using Mendelian randomisation.
- Akira Wiberg
- , Michael Ng
- & Dominic Furniss
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Article
| Open AccessPrioritizing Parkinson’s disease genes using population-scale transcriptomic data
GWAS have identified over 41 susceptibility loci for Parkinson’s disease (PD). Here, the authors integrate PD GWAS summary statistics with transcriptome data from monocytes and DLFPC tissue in a TWAS approach and find 66 significant associations with PD risk highlighting lysosomal and innate immune functions.
- Yang I. Li
- , Garrett Wong
- & Towfique Raj
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Article
| Open AccessBiallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.
- Jennifer Friedman
- , Desiree E. Smith
- & Joseph G. Gleeson
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| Open AccessBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.
- Aleksandra Siekierska
- , Hannah Stamberger
- & Peter De Jonghe
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Article
| Open AccessCorrespondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain
The brain primarily uses glucose to generate energy, but the relationship of neuronal activity to glucose utilization is not necessarily a simple linear one. Here, the authors introduce relative power (rPWR) and relative cost (rCST) as new metrics to quantify how brain activity relates to glucose consumption.
- Ehsan Shokri-Kojori
- , Dardo Tomasi
- & Nora D. Volkow
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Article
| Open AccessCombining lifestyle risks to disentangle brain structure and functional connectivity differences in older adults
Lifestyle factors such as smoking and exercise contribute to the health of the brain during aging, but previous studies have focused on the effects of single lifestyle variables. Here, the authors examine the combined and individual effects of four lifestyle variables on brain structure and function.
- Nora Bittner
- , Christiane Jockwitz
- & Svenja Caspers
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Article
| Open AccessSingle-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development
Midbrain dopamine (mDA) neurons are significantly associated with Parkinson’s disease and yet there is no systematic molecular classification of these heterogenous group of cells. Here authors use single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3 (broad mDA neuronal marker) to identify and characterize seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons.
- Katarína Tiklová
- , Åsa K. Björklund
- & Thomas Perlmann
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Article
| Open AccessReductions in prefrontal activation predict off-topic utterances during speech production
The ability to speak coherently is essential for effective communication, but little is known about the neural systems that support coherence. Here, the authors show that activity in two prefrontal cortex regions, BA10 and BA45, predicts the level of coherence in the speech of healthy older adults.
- Paul Hoffman
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Article
| Open AccessEarly preclinical detection of prions in the skin of prion-infected animals
There are currently no validated methods for the diagnosis of prion disease at the preclinical stage. Here the authors show that serial protein misfolding cyclic amplification and real-time quaking-induced conversion can be used to detect prions in the skin of prion-inoculated hamsters and humanized transgenic mice at early preclinical stages.
- Zerui Wang
- , Matteo Manca
- & Wen-Quan Zou
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Article
| Open AccessModel-based lesion mapping of cognitive control using the Wisconsin Card Sorting Test
The frontal cortex is involved in cognitive control, e.g. cognitive flexibility and behavioral inhibition, but the roles of frontal subdivisions are unclear. Here, the authors used computational modelling of cognitive control task performance to map lesions responsible for impairments in specific cognitive operations.
- Jan Gläscher
- , Ralph Adolphs
- & Daniel Tranel
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Article
| Open AccessSpatial fine-mapping for gene-by-environment effects identifies risk hot spots for schizophrenia
Schizophrenia (SCZ) risk is influenced by genetic and environmental factors. Here, the authors develop a statistical method for analyzing gene-by-environment effects in SCZ risk across Denmark with fine spatial resolution.
- Chun Chieh Fan
- , John J. McGrath
- & Carsten Bøcker Pedersen
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Article
| Open AccessClosed-loop functional optogenetic stimulation
Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.
- Shriya S. Srinivasan
- , Benjamin E. Maimon
- & Hugh M. Herr
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Article
| Open AccessGenome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.
- Bassel Abou-Khalil
- , Pauls Auce
- & Fritz Zimprich
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Article
| Open AccessNeural network analysis of sleep stages enables efficient diagnosis of narcolepsy
The diagnosis of sleep disorders such as narcolepsy and insomnia currently requires experts to interpret sleep recordings (polysomnography). Here, the authors introduce a neural network analysis method for polysomnography that could reduce time spent in sleep clinics and automate narcolepsy diagnosis.
- Jens B. Stephansen
- , Alexander N. Olesen
- & Emmanuel Mignot
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Article
| Open AccessHigh-throughput brain activity mapping and machine learning as a foundation for systems neuropharmacology
A major goal in neuropharmacology is to develop new tools to effectively test the therapeutic potential of pharmacological agents to treat neurological and psychiatric conditions. Here, authors present an in vivo drug screening system that generates large-scale brain activity maps to be used with machine learning to predict the therapeutic potential of clinically relevant drug leads.
- Xudong Lin
- , Xin Duan
- & Peng Shi
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Article
| Open AccessTamoxifen therapy in a murine model of myotubular myopathy
Myotubular myopathy is a severe muscle disease for which no effective treatment exists. Here, the authors show that tamoxifen ameliorates pathology and extends survival in a mouse model of the disease, and that the effect is mediated via estrogen receptor signaling and involves modulation of DNM2 expression.
- Nika Maani
- , Nesrin Sabha
- & James J. Dowling
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Article
| Open AccessSlc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations
Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2.
- Victoria A. Baronas
- , Runying Y. Yang
- & Harley T. Kurata
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Article
| Open AccessSleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients
Many brain-injured patients retain large cortical islands that are intact, active and reactive but blocked in a state of low complexity, leading to unconsciousness. Here, the authors show that this loss of complexity is due to the pathological engagement of sleep-like neuronal mechanisms.
- M. Rosanova
- , M. Fecchio
- & M. Massimini
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Article
| Open AccessAn intrinsic association between olfactory identification and spatial memory in humans
Olfaction, the sense of smell, may have originally evolved to aid navigation in space, but there is no direct evidence of a link between olfaction and navigation in humans. Here the authors show that olfaction and spatial memory abilities are correlated and rely on similar brain regions in humans.
- Louisa Dahmani
- , Raihaan M. Patel
- & Véronique D. Bohbot
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Article
| Open AccessA distal centriolar protein network controls organelle maturation and asymmetry
Removal of daughter centriole-specific/enriched proteins (DCPs) and assembly of distal appendages (DA) are important for centrosome asymmetry. Here, the authors report that a centriolar distal end protein network regulates DCP removal, DA assembly, and ciliary vesicle docking.
- Lei Wang
- , Marion Failler
- & Brian D. Dynlacht
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Article
| Open AccessA scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks
An individual’s social network—their friends, family, and acquaintances—is important for their health, but existing tools for assessing social networks have limitations. Here, the authors introduce a quantitative social network assessment tool on a secure open-source web platform and show its utility in a nation-wide study.
- Amar Dhand
- , Charles C. White
- & Philip L. De Jager
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Article
| Open AccessAnalysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies
Patients with myotonic dystrophy need to undergo invasive muscle biopsies to monitor disease progression and response to therapy. Here, the authors show that extracellular RNAs in human urine can be used as biomarkers to differentiate patients from unaffected controls, and to monitor exon skipping in patients with Duchenne muscular dystrophy taking the drug eteplirsen.
- Layal Antoury
- , Ningyan Hu
- & Thurman M. Wheeler
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Article
| Open AccessSingle cell molecular alterations reveal target cells and pathways of concussive brain injury
Traumatic brain injury (TBI) affects the hippocampus and can lead to neurological and psychiatric disorders. Here, the authors perform single-cell RNA sequencing to reveal molecular pathways across a range of cell types affected during TBI.
- Douglas Arneson
- , Guanglin Zhang
- & Xia Yang
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Article
| Open AccessStructural insights into SorCS2–Nerve Growth Factor complex formation
The Sortilin-related CNS-expressed receptor 2 (SorCS2)–proneurotrophin signaling system regulates neuronal plasticity and its dysfunction is linked to schizophrenia. Here the authors present the structures of the SorCS2 ectodomain alone and in complex with Nerve Growth Factor, which provides insights into SorCS2 ligand binding and signaling.
- Nadia Leloup
- , Lucas M. P. Chataigner
- & Bert J. C. Janssen
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Article
| Open AccessEpigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by aggregation of Tau, encoded by MAPT. Here, the authors perform an EWAS for PSP in prefrontal lobe tissue and find hypermethylation of DLX1 and its antisense transcript DLX1AS to associate with MAPT expression.
- Axel Weber
- , Sigrid C. Schwarz
- & Ulrich Müller