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| Open AccessEpilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability
CDKL5 deficiency disorder is one of the most common genetic forms of epilepsy. Here the authors show that a model of CDKL5 deficiency disorder involves a channelopathy of CACNA1E gain-of-function, molecularly linking two distinct single-gene developmental and epileptic encephalopathies.
- Marisol Sampedro-Castañeda
- , Lucas L. Baltussen
- & Sila K. Ultanir
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Article
| Open AccessWake slow waves in focal human epilepsy impact network activity and cognition
Slow waves in sleep are crucial for homeostatic regulation of brain function. Here the authors show similar slow wave activity occurs during wakefulness in people with epilepsy to counter the impact of abnormal, epileptic, brain activity.
- Laurent Sheybani
- , Umesh Vivekananda
- & Matthew C. Walker
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Article
| Open AccessNR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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| Open AccessResting-state global brain activity affects early β-amyloid accumulation in default mode network
Why β-amyloid plaque initially accumulates in the default mode network of the cortex before Alzheimer’s disease diagnosis is not known. Here, the authors show that this accumulation is associated with a reduction of global brain activity in these regions.
- Feng Han
- , Xufu Liu
- & Xiao Liu
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Article
| Open AccessAssociations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases
Patients with autoimmune diseases require immunosuppressive treatments that affect their responses to infection and vaccination. Here, using mass cytometry, the authors to identify a role for myeloid cells in cellular and humoral responses following vaccination against SARS-CoV-2 in patients with neuroimmunological diseases.
- Meng Wang
- , Adeline Dehlinger
- & Chotima Böttcher
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Article
| Open AccessBrain-to-gut trafficking of alpha-synuclein by CD11c+ cells in a mouse model of Parkinson’s disease
Despite being implicated in several neurological diseases, the gut-brain axis remains poorly understood. Here the authors describe a mechanism of communication between the brain and the gut in a Parkinson’s disease mouse model mediated by CD11c+ macrophages.
- Rhonda L. McFleder
- , Anastasiia Makhotkina
- & Chi Wang Ip
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Article
| Open AccessPathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke
Reperfusion is a main strategy for restoring blood supply after ischemic stroke, but it induces neuroinflammation that undergoes dynamic progression, hindering the treatment of ischemic stroke. Here, the authors report a pathogenesis-adaptive nanosystem for sequential and on-demand regulation of reperfusion-induced dynamic neuroinflammation for ischemic stroke therapy.
- Di Wu
- , Jing Zhou
- & Zhong Chen
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Article
| Open AccessCovariance patterns between sleep health domains and distributed intrinsic functional connectivity
The relationship between sleep health and brain functional connectivity is not well understood. Here, the authors reveal a composite sleep health dimension which covaries with connectivity of the attentional and thalamic networks.
- Yulin Wang
- , Sarah Genon
- & Xu Lei
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Article
| Open AccessProteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Precise biomarkers for multiple sclerosis prognosis are vital for treatment decisions. Here, the authors identify specific proteins in cerebrospinal fluid that can predict short-term disease activity and long-term disability outcomes in persons with multiple sclerosis.
- Julia Åkesson
- , Sara Hojjati
- & Mika Gustafsson
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Article
| Open AccessStress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion
Exposure to stressors can trigger or exacerbate anxiety through an inflammatory response. Here, the authors demonstrate the function of a “brain-lymph node” axis in anxiety and provide insights into lymph nodes as stress-responsive endocrine organs.
- Dong-Dong Shi
- , Ying-Dan Zhang
- & Zhen Wang
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Article
| Open AccessThe α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.
- Ruben Smith
- , Francesca Capotosti
- & Oskar Hansson
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Article
| Open AccessPlasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts
Performance of plasma biomarkers of amyloid (A), tau (T) and neurodegeneration (N) for Alzheimer’s disease (AD) in Chinese cohorts is unknown. Here, the authors report that plasma ATN biomarkers can predict AD 8–10 years before symptoms in Chinese cohorts.
- Huimin Cai
- , Yana Pang
- & Longfei Jia
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Article
| Open AccessSoluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease
In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.
- Xingyu Zhang
- , Li Tang
- & Zhentao Zhang
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Article
| Open AccessNatural product P57 induces hypothermia through targeting pyridoxal kinase
Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme conditions. Here, the authors show that the natural product P57 induces hypothermia by targeting pyridoxal kinase and has a potential application in therapeutic hypothermia.
- Ruina Wang
- , Lei Xiao
- & Yongjun Dang
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Article
| Open AccessPatient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson’s disease
Neurotransmitter receptor distributions help explain structural and functional brain alterations in Parkinson’s disease. Distinct multi-receptor profiles are associated with the severity of motor, and visuospatial, psychiatric and memory symptoms.
- Ahmed Faraz Khan
- , Quadri Adewale
- & Yasser Iturria-Medina
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Article
| Open AccessHistidine modulates amyloid-like assembly of peptide nanomaterials and confers enzyme-like activity
In this work, the authors report that Histidine residues play a critical role in modulating amyloid-like assembly and building active sites for Fmoc–F–F and Aβ aggregates. Aβ1-42 filaments were found to perform peroxidase-like activity to enhance oxidative stress, which might also be ascribed to the interaction mode of His and F-F.
- Ye Yuan
- , Lei Chen
- & Lizeng Gao
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Article
| Open AccessCircular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease
Dopamine neurons control movements while pyramidal neurons regulate memory and language. Here the authors show that circular RNAs production in these neurons appears tailored to neuron identity and genetically linked to neuropsychiatric disease such as Parkinson’s and Alzheimer’s disease.
- Xianjun Dong
- , Yunfei Bai
- & Clemens R. Scherzer
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Article
| Open AccessPhenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA
GGGGCC repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. Here the authors show that CCCCGG antisense repeat RNA binds and inhibits phenylalanine-tRNA synthetase resulting in decreased levels of tRNAphe and phenylalanine rich proteins.
- Mirjana Malnar Črnigoj
- , Urša Čerček
- & Boris Rogelj
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Article
| Open AccessPathological pallidal beta activity in Parkinson’s disease is sustained during sleep and associated with sleep disturbance
Sleep disturbances are highly prevalent in patients with Parkinson’s disease. Here, the authors leverage intracranial recordings in such patients, finding that pathological pallidal activity is present during sleep and associated with sleep disturbance.
- Zixiao Yin
- , Ruoyu Ma
- & Jianguo Zhang
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Article
| Open AccessEffect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.
- Stephanie Langella
- , N. Gil Barksdale
- & Yakeel T. Quiroz
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Article
| Open AccessAt-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis
“In ALS clinical trials, efficacy is often assessed via subjective patient or clinician reports. The authors introduce a machine-learned severity score based on wearable sensor data from daily activities, which is reliable, sensitive, and could reduce clinical trial sizes.”
- Anoopum S. Gupta
- , Siddharth Patel
- & Fernando Vieira
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Article
| Open AccessRandomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Neuroinflammation and autophagy are two pillars of ALS pathogenesis targeted by rapamycin. Here, in a randomized, double-blind, phase 2 clinical trial, the authors find rapamycin to be safe and well tolerated in ALS patients, supporting further studies.
- Jessica Mandrioli
- , Roberto D’Amico
- & Andrea Cossarizza
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Matters Arising
| Open AccessFluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base
- Shinji Naganawa
- , Yutaka Kato
- & Michihiko Sone
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Matters Arising
| Open AccessThe pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain
- Geir Ringstad
- & Per Kristian Eide
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Article
| Open AccessDeep-learning based detection of vessel occlusions on CT-angiography in patients with suspected acute ischemic stroke
AI may enhance diagnostic accuracy in medicine. Here, authors developed an AI model to detect and localise vessel occlusions in patients with suspected ischemic stroke, outperforming commercial tools on pseudo-prospective multicenter benchmarking.
- Gianluca Brugnara
- , Michael Baumgartner
- & Philipp Vollmuth
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Article
| Open AccessSpatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting one in 5000 male births. To enrich our understanding of the underlying pathology, the authors apply spatial transcriptomics on dystrophic skeletal muscle to unravel markers related to histopathological changes in Duchenne mouse models.
- L.G.M. Heezen
- , T. Abdelaal
- & P. Spitali
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Article
| Open AccessMechanisms underlying pathological cortical bursts during metabolic depletion
Disruption to the brain’s oxygen supply triggers pathological dynamics and brain injuries. Here, the authors develop a model of coupled metabolic-neuronal activity that generates burst suppression patterns similar to those of infants after birth asphyxia.
- Shrey Dutta
- , Kartik K. Iyer
- & James A. Roberts
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Article
| Open AccessCompilation of reported protein changes in the brain in Alzheimer’s disease
Proteomic studies in Alzheimer’s disease may be useful for understanding disease mechanisms and potential therapeutic targets. Here the authors describe a resource collating known protein changes throughout the progression of Alzheimer’s disease in human brain tissue.
- Manor Askenazi
- , Tomas Kavanagh
- & Eleanor Drummond
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Article
| Open AccessGenome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
Here, the authors perform a meta-analysis in 26,699 people with seizures and 492,324 controls to identify 25 genome-wide significant copy-number variants. The discovered loci point to known disease genes and associations with clinical annotations.
- Ludovica Montanucci
- , David Lewis-Smith
- & Dennis Lal
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Article
| Open AccessLong-term neurological outcome after COVID-19 using all SARS-CoV-2 test results and hospitalisations in Denmark with 22-month follow-up
Hospitalisation with COVID-19 is associated with an increased risk of neurological sequelae. Here in a nationwide Danish register study, the authors show that positive SARS-CoV-2 PCR tests and hospitalisations with COVID-19 are associated with increased risk of neurological sequelae, but with comparable risks as after other infections of similar severity.
- Clara S. Grønkjær
- , Rune H. B. Christensen
- & Michael E. Benros
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Article
| Open AccessGain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders
An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.
- Carolina Gracia-Diaz
- , Yijing Zhou
- & Naiara Akizu
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Article
| Open AccessGenome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Giorgia Maria Ferlazzo
- , Anna Maria Gambetta
- & Graziano Martello
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Article
| Open AccessBlood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease
Understanding molecular processes behind variable clinical features of Parkinson’s disease is valuable. Distinct molecular patterns in the brains, reflected in the blood, reveal mechanisms linked to clinical diversity in cognitive and motor decline.
- Krithi Irmady
- , Caryn R. Hale
- & Robert B. Darnell
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Article
| Open AccessMacrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model
Migrasomes are recently discovered extracellular vesicles that are produced during cellular migration. Here, the authors show that macrophage-derived migrasomes are implicated in the progression of cerebral amyloid angiopathy (CAA) through increased complement signaling using skin biopsies from CAA patients and CAA mouse models.
- Mengyan Hu
- , Tiemei Li
- & Wei Cai
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Article
| Open AccessSpecific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies
Post-translational modifications on tau protein in the brain could distinguish primary tauopathies. Here, the authors assess insoluble and soluble tau extracted from post mortem human tauopathy brains and show 4R/3R tau isoform ratio in aggregates is associated with specific modifications on soluble tau protein.
- Nathalie Kyalu Ngoie Zola
- , Clémence Balty
- & Bernard J. Hanseeuw
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Article
| Open AccessLeveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males
The relationship between the components of repetitive head impacts and chronic traumatic encephalopathy (CTE) remains unclear. Here, the authors use American football helmet sensor data to show that duration of play, cumulative head impacts and linear and rotational accelerations are significantly associated with CTE pathology.
- Daniel H. Daneshvar
- , Evan S. Nair
- & Jesse Mez
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Article
| Open AccessVariants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.
- Katie L. Ayers
- , Stefanie Eggers
- & Andrew H. Sinclair
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Article
| Open AccessTherapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.
- Jie Ding
- , Sung-Jin Lee
- & Calvin J. Kuo
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Article
| Open AccessMulti-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health
Daly, Danson and colleagues employ a multi-omic approach in neuroglioma cells to characterise endolysosomal dysfunction caused by perturbation of the evolutionarily conserved Retromer complex, highlighting Retromer’s neuroprotective function.
- James L. Daly
- , Chris M. Danson
- & Peter J. Cullen
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Article
| Open AccessEvidence against a temporal association between cerebrovascular disease and Alzheimer’s disease imaging biomarkers
Whether a relationship exists between cerebrovascular disease and Alzheimer’s disease has been a source of controversy. Here, the authors show there is a very weak temporal relationship between the progression of Alzheimer’s disease biomarkers and those of cerebrovascular disease.
- Petrice M. Cogswell
- , Emily S. Lundt
- & Clifford R. Jack Jr
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Article
| Open AccessA pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder
Neurostimulation has been proposed as a potential approach for treatment-resistant PTSD. Here in a pilot study the authors show that amygdala theta activity is heightened during aversive and symptomatic experiences in patients with treatment-resistant post-traumatic stress disorder, and reduced following significant clinical improvement associated with closed-loop stimulation.
- Jay L. Gill
- , Julia A. Schneiders
- & Jean-Philippe Langevin
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Article
| Open AccessAssociation of gout with brain reserve and vulnerability to neurodegenerative disease
The potential association between neurodegenerative disease risk and gout is not fully understood. Here the authors showed that gout is causally related to several measures of brain structure which may explain their higher vulnerability to dementia.
- Anya Topiwala
- , Kulveer Mankia
- & Thomas E. Nichols
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Article
| Open AccessA randomized trial of Trendelenburg position for acute moderate ischemic stroke
The effect of head positioning in acute stroke is controversial. Here, the authors report the results of a clinical trial suggesting that the procedure, initiated within 24 hours of onset, is safe and feasible, but does not improve functional outcome in acute moderate stroke patients with large artery atherosclerosis.
- Hui-Sheng Chen
- , Nan-Nan Zhang
- & Thanh N. Nguyen
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Article
| Open AccessGut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder and their first-degree relatives
Microbiota-gut-brain axis may play an important role in Parkinson’s disease (PD). Here, the authors assess gut microbiota in early PD, REM sleep behaviour disorder (RBD) and first-degree relatives of RBD and show PD-like gut dysbiosis occurs in RBD and their first-degree relatives.
- Bei Huang
- , Steven W. H. Chau
- & Yun Kwok Wing
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Article
| Open AccessPlasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice
The cholinergic circuits involved in pain modulation remain poorly understood. Here, the authors show that reversal of plasticity in the ventral pallidum-basolateral amygdala cholinergic pathway relieves hyperalgesia and depression-like behaviours in a chronic pain mouse model.
- Ya-Wei Ji
- , Zi-Lin Shen
- & Cheng Xiao
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Article
| Open AccessA case study of percutaneous epidural stimulation to enable motor control in two men after spinal cord injury
Percutaneous spinal cord epidural stimulation (SCES) leads were implanted in two men with spinal cord injury (SCI) in an approved trial by the McGuire IRB committee. SCES decreased the assistance required from the exoskeleton. In one participant, SCES enabled standing and stepping in parallel bars and overground ambulation with a walker.
- Ashraf S. Gorgey
- , Robert Trainer
- & Timothy D. Lavis
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Article
| Open AccessPlasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders
Plasma neurodegeneration biomarkers are increasingly utilized to predict neurological disease. Here, authors show in different neurological disorders associations between plasma neurodegeneration biomarker concentrations and various measures of glymphatic and meningeal lymphatic functions.
- Per Kristian Eide
- , Aslan Lashkarivand
- & Henrik Zetterberg
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Article
| Open AccessCorrection of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy
In a double homozygous mouse model of myotonic dystrophy type 1, Hu et al. use antisense oligonucleotide correction of myotonia to induce a therapeutic shift from an overabundance of oxidative muscle fibers to mechanically stronger glycolytic fibers.
- Ningyan Hu
- , Eunjoo Kim
- & Thurman M. Wheeler
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Article
| Open AccessHematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Cerebral adrenoleukodystrophy (CALD) is a demyelinating disease caused by loss of ABCD1 gene function. Here the authors investigate white matter structural and microvascular changes in boys with CALD that received gene therapy with autologous hematopoietic stem-cells.
- Arne Lauer
- , Samantha L. Speroni
- & Patricia L. Musolino