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Article
| Open AccessNuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD
Hexanucleotide repeat expansion in the intron 1 of the C9ORF72 gene can cause amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). Here the authors use single molecule imaging to show nuclear export and translation of circular repeat-containing C9ORF72 intronic RNA.
- Shaopeng Wang
- , Malgorzata J. Latallo
- & Shuying Sun
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Article
| Open AccessMalignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia
Vaccination is an effective strategy in suppressing COVID-19 pandemic, but rare adverse effects have been reported, including cerebral venous thrombosis. Here the authors report two cases of middle cerebral artery infarct within 9-10 days following ChAdOx1 nCov-19 vaccination that also manifest pulmonary and portal vein thrombosis.
- M. De Michele
- , M. Iacobucci
- & D. Toni
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Article
| Open AccessEndo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.
- Marie P. Schützmann
- , Filip Hasecke
- & Wolfgang Hoyer
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Article
| Open AccessBrain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice
Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.
- Yann Ehinger
- , Ziyang Zhang
- & Dorit Ron
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Article
| Open AccessIdentifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.
- Ganna Leonenko
- , Emily Baker
- & Valentina Escott-Price
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Article
| Open AccessTherapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia
Familial dysautonomia is caused by splicing mutation of IKBKAP gene, which induces skipping of exon 20 and subsequent functional loss. Here, the authors report that a synthetic splice modulator RECTAS ameliorates pathogenic exon 20 skipping and shows therapeutic effects in cellular and animal models.
- Masahiko Ajiro
- , Tomonari Awaya
- & Masatoshi Hagiwara
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Article
| Open AccessA machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.
- Yanting Huang
- , Xiaobo Sun
- & Zhaohui S. Qin
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Article
| Open AccessSelf-healing polyurethane-elastomer with mechanical tunability for multiple biomedical applications in vivo
The unique properties of self-healing materials hold great potential in the field of biomedical engineering. Here, the authors designed a series of biodegradable and biocompatible self-healing elastomers with tunable mechanical properties, and apply them to various disease models in vivo, including aortic aneurism, bone fracture and nerve amputation.
- Chenyu Jiang
- , Luzhi Zhang
- & Xiaofeng Ye
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Article
| Open AccessA novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke
Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.
- Toshiko Yamazawa
- , Takuya Kobayashi
- & Takashi Murayama
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Article
| Open AccessGene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.
- Toni S. Pearson
- , Nalin Gupta
- & Krystof S. Bankiewicz
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Article
| Open AccessA generative network model of neurodevelopmental diversity in structural brain organization
The formation of large-scale brain networks represents crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. Here, the authors use generative network modelling to provide a computational framework for understanding neurodevelopmental diversity.
- Danyal Akarca
- , Petra E. Vértes
- & Duncan E. Astle
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Article
| Open AccessProkineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury
Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.
- Zhongyuan Bao
- , Yinlong Liu
- & Jing Ji
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Article
| Open AccessSETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome
Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
- Federica Banfi
- , Alicia Rubio
- & Alessandro Sessa
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Article
| Open AccessHigher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.
- William T. Hu
- , Tugba Ozturk
- & Gloria Chiang
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Article
| Open AccessBarrel cortex plasticity after photothrombotic stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits
Definitive evidence for functional remapping after stroke remains lacking. Here, the authors performed in vivo intrinsic signal imaging and two-photon calcium imaging of sensory-evoked responses before and after photothrombotic stroke and found no evidence of remapping of lost functionalities to new circuits in peri-infarct cortex.
- William A. Zeiger
- , Máté Marosi
- & Carlos Portera-Cailliau
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Article
| Open AccessKL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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Article
| Open AccessEfficient precise in vivo base editing in adult dystrophic mice
Base editing is one approach used to correct mutations causing cause Duchenne muscular dystrophy (DMD), but limitations are in the requirement for a specific PAM motif and the large size beyond the packaging capacity of adeno-associated virus (AAV). Here, the authors modify the NG-targeting adenine base editor to recognize a broader PAM, devise an intein split strategy to package the otherwise oversized adenine base editor into AAV, and show it efficiently restores dystrophin expression in muscle and heart when systemically injected in a mouse model of DMD
- Li Xu
- , Chen Zhang
- & Renzhi Han
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Article
| Open AccessA molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech
Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.
- Keith A. Josephs
- , Joseph R. Duffy
- & Jennifer L. Whitwell
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Article
| Open AccessOutcome after acute ischemic stroke is linked to sex-specific lesion patterns
Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.
- Anna K. Bonkhoff
- , Markus D. Schirmer
- & Natalia S. Rost
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Article
| Open AccessUBE4B, 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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Article
| Open AccessImpaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice
Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.
- Qian Wang
- , Ying Kong
- & Tian-Ming Gao
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Article
| Open AccessNon-productive angiogenesis disassembles Aß plaque-associated blood vessels
Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.
- Maria I. Alvarez-Vergara
- , Alicia E. Rosales-Nieves
- & Alberto Pascual
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Article
| Open AccessPredicting optimal deep brain stimulation parameters for Parkinson’s disease using functional MRI and machine learning
Deep brain stimulation programming for Parkinson’s disease entails the assessment of a large number of possible simulation settings, requiring numerous clinic visits after surgery. Here, the authors show that patterns of functional MRI can predict the optimal stimulation settings.
- Alexandre Boutet
- , Radhika Madhavan
- & Andres M. Lozano
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Article
| Open AccessFKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is α-dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane.
- A. J. Wood
- , C. H. Lin
- & P. D. Currie
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Article
| Open AccessThe genetic architecture of the human thalamus and its overlap with ten common brain disorders
Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
- Torbjørn Elvsåshagen
- , Alexey Shadrin
- & Tobias Kaufmann
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Article
| Open AccessRHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections. Here, the authors generate iPSC-derived neurons from patients with TSC. TSC2 +/− neurons show impaired mTOR-independent RhoA signaling-mediated axon guidance.
- Timothy S. Catlett
- , Massimo M. Onesto
- & Timothy M. Gómez
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Article
| Open AccessIncreased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
- Julie C. Lauterborn
- , Pietro Scaduto
- & Agenor Limon
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Article
| Open AccessAssociation of sleep duration in middle and old age with incidence of dementia
Sleep dysregulation has been linked to dementia, but it is unknown whether sleep duration earlier in life is associated with dementia risk. Here, the authors show higher dementia risk associated with short sleep duration (six hours or less) in a longitudinal study of middle and older age adults.
- Séverine Sabia
- , Aurore Fayosse
- & Archana Singh-Manoux
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Article
| Open AccessEnhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Narcolepsy type 1 (NT1) is a severe sleep disorder with strong association to the HLA type DQB1*0602 and increased incidence among children vaccinated with the Influenza A vaccine Pandemrix. Here the authors show that these children develop T and B cell autoimmunity against protein-O-mannosyltransferase 1 via cross-reactivity.
- A. Vuorela
- , T. L. Freitag
- & O. Vaarala
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Article
| Open AccessTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
- Ki Kim
- , Xin Wang
- & Arya Biragyn
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Article
| Open AccessIdentifying multiple sclerosis subtypes using unsupervised machine learning and MRI data
Multiple sclerosis is a heterogeneous progressive disease. Here, the authors use an unsupervised machine learning algorithm to determine multiple sclerosis subtypes, progression, and response to potential therapeutic treatments based on neuroimaging data.
- Arman Eshaghi
- , Alexandra L. Young
- & Olga Ciccarelli
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Article
| Open AccessDefective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.
- Gizem Inak
- , Agnieszka Rybak-Wolf
- & Alessandro Prigione
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Article
| Open AccessNAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients
HCCAA is a dominantly inherited disease which causes brain hemorrhages as a result of mutant cystatin C aggregation in carriers. Here, the authors show that n- acetyl cysteine can prevent aggregation of mutant protein in a cell model system and reverse protein deposition in the skin of mutation-carrying subjects.
- Michael E. March
- , Alvaro Gutierrez-Uzquiza
- & Hakon Hakonarson
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Article
| Open AccessNeurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy
X-linked adrenoleukodystophy (X-ALD) is a highly variable, progressive neurodegenerative disorder. In this study, neurofilament light chain protein (NfL) was identified as a potential early distinguishing biomarker.
- Isabelle Weinhofer
- , Paulus Rommer
- & Johannes Berger
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Article
| Open AccessCryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients have brain deposits with amyloid-like aggregates from large C-terminal fragments of the transactive response DNA-binding protein of 43 kDa (TDP-43). Here, the authors present the cryo-EM structure of amyloid fibrils generated from the complete C-terminal TDP-43 low complexity domain and they discuss the effects of disease-causing mutations and phosphorylation of specific Ser residues.
- Qiuye Li
- , W. Michael Babinchak
- & Witold K. Surewicz
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Article
| Open AccessShort antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease caused by toxic RNA containing expanded CGG repeats. Here, the authors show that synthetic oligonucleotides targeting the RNA repeats decrease the pleiotropic effect of this toxic molecule in cellular and animal models of the disease.
- Magdalena Derbis
- , Emre Kul
- & Krzysztof Sobczak
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Article
| Open AccessMachine learning identifies candidates for drug repurposing in Alzheimer’s disease
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.
- Steve Rodriguez
- , Clemens Hug
- & Artem Sokolov
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Article
| Open AccessThe docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.
- Wing K. Man
- , Bogachan Tahirbegi
- & Giuliana Fusco
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Article
| Open AccessVariant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models
C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.
- Yuanjing Liu
- , Jean-Cosme Dodart
- & Robert H. Brown Jr.
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Article
| Open AccessImpaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.
- Víctor Faundes
- , Martin D. Jennings
- & Siddharth Banka
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Article
| Open AccessBlood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia
Blood brain barrier (BBB) opening is being investigated as a therapeutic approach for neurodegenerative diseases. Here, the authors report the results of a phase I trial to evaluate the feasibility and safety of BBB opening of the right parieto-occipito-temporal cortex in Parkinson´s disease with dementia.
- Carmen Gasca-Salas
- , Beatriz Fernández-Rodríguez
- & José A. Obeso
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Article
| Open AccessThe nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization
The nuclear envelope tethers chromatin to the nuclear periphery to control genome architecture. Here, the authors show that Net39 preserves the integrity and gene expression of muscle nuclei in mice, and it may contribute to the pathogenesis of Emery–Dreifuss muscular dystrophy.
- Andres Ramirez-Martinez
- , Yichi Zhang
- & Eric N. Olson
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Article
| Open AccessA CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis
A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics. Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.
- Eoin F. McKinney
- , Iona Cuthbertson
- & Kenneth G. C. Smith
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Article
| Open AccessThe molecular dynamics of subdistal appendages in multi-ciliated cells
Cilia originate from a basal body and basal foot, but the precise molecular mechanisms of basal foot biogenesis are unclear. Here, the authors show that ANKS1A interacts with FOP to transform the subdistal appendages from an unpolarized structure to a polarized structure with a basal foot.
- Hyunchul Ryu
- , Haeryung Lee
- & Soochul Park
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Article
| Open AccessRecruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord
The efficacy of epidural electrical stimulation (EES) to engage arm muscles and improve movement after spinal cord injury is still unclear. Here, the authors investigated how EES can recruit upper-limb motor neurons by combining computational modelling with experiments in non-human primates.
- Nathan Greiner
- , Beatrice Barra
- & Marco Capogrosso
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Article
| Open AccessNon-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence
Aberrant synchronous oscillations have been associated with numerous brain disorders, including essential tremor. The authors show that synchronous cerebellar activity can casually affect essential tremor and that its underlying mechanism may be related to the temporal coherence of the tremulous movement.
- Sebastian R. Schreglmann
- , David Wang
- & Nir Grossman
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Article
| Open AccessAge-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
The dynamics of chromatin and transcriptional changes underlying Huntington’s disease remain poorly understood. Here the authors use a Huntington’s mouse model to profile the striatal chromatin landscape, finding that the Huntington’s mutation accelerates age-dependent epigenetic and transcriptional changes, and locally affects 3D chromatin organization.
- Rafael Alcalá-Vida
- , Jonathan Seguin
- & Karine Merienne
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Article
| Open AccessCerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
- Muralidharan Sargurupremraj
- , Hideaki Suzuki
- & Stéphanie Debette
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Perspective
| Open AccessIncreasing the reproducibility of fluid biomarker studies in neurodegenerative studies
Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.
- Niklas Mattsson-Carlgren
- , Sebastian Palmqvist
- & Oskar Hansson
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