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| 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 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 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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Article
| Open AccessAstrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway
Mutations of α2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of α2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.
- Sarah E. Smith
- , Xiaoying Chen
- & Azad Bonni
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Article
| Open AccessEssential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain
Altered fatty acid intake during pregnancy is associated with neurodevelopmental disorders. Here, the authors show that maternal omega-3 fatty acids deficiency results in altered microglia-mediated phagocytosis of synaptic elements leading to impaired cognitive functions in the offspring in mice.
- C. Madore
- , Q. Leyrolle
- & S. Layé
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Article
| Open AccessA clinically applicable deep-learning model for detecting intracranial aneurysm in computed tomography angiography images
Interpretation of Computed Tomography Angiography for intracranial aneurysm diagnosis can be time-consuming and challenging. Here, the authors present a deep-learning-based framework achieving improved performance compared to that of radiologists and expert neurosurgeons.
- Zhao Shi
- , Chongchang Miao
- & Long Jiang Zhang
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Article
| Open AccessPlasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals
Previously it was shown that an N-terminal tau fragment (NT1) measured in plasma can differentiate individuals with Alzheimer’s disease from healthy controls. Here the authors show that plasma levels of NT1 can associate with future cognitive decline in cognitively normal elderly individuals.
- Jasmeer P. Chhatwal
- , Aaron P. Schultz
- & Dennis J. Selkoe
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Article
| Open AccessCardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury
Clinical neuroprotective strategies for acute spinal cord injury (SCI) have largely overlooked the heart. Here the authors show cardiac contractility is immediately impaired in a porcine model of T2 SCI, and cardio-centric treatment with dobutamine optimizes cord oxygenation and mitigates haemorrhage.
- Alexandra M. Williams
- , Neda Manouchehri
- & Christopher R. West
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Article
| Open AccessIntegrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.
- Gokul Ramaswami
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessRapid vessel segmentation and reconstruction of head and neck angiograms using 3D convolutional neural network
Manual postprocessing of computed tomography angiography (CTA) images is extremely labor intensive and error prone. Here, the authors propose an artificial intelligence reconstruction system that can automatically achieve CTA reconstruction in healthcare services.
- Fan Fu
- , Jianyong Wei
- & Jie Lu
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Article
| Open AccessGenetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults
Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.
- Edith Hofer
- , Gennady V. Roshchupkin
- & Sudha Seshadri
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Article
| Open AccessGlioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy
Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.
- Soniya Bastola
- , Marat S. Pavlyukov
- & Ichiro Nakano
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Article
| Open AccessRNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.
- Mauro Montalbano
- , Salome McAllen
- & Rakez Kayed
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Article
| Open AccessBlood substitution therapy rescues the brain of mice from ischemic damage
Acute stroke causes complex, pathological, and systemic responses which remain challenging to treat. Here, the authors show that substituting the blood of stroke model mice with whole-blood from naive healthy donor mice reduces infarct volume and improves neurological deficits.
- Xuefang Ren
- , Heng Hu
- & James W. Simpkins
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Article
| Open AccessDeep neural networks enable quantitative movement analysis using single-camera videos
In the context of diseases impairing movement, quantitative assessment of motion is critical to medical decision-making but is currently possible only with expensive motion capture systems and trained personnel. Here, the authors present a method for predicting clinically relevant motion parameters from an ordinary video of a patient.
- Łukasz Kidziński
- , Bryan Yang
- & Michael H. Schwartz
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Article
| Open AccessLoss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly
Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly characteristics and scRNA-seq reveals a role for NARS1 in radial glial cell proliferation.
- Lu Wang
- , Zhen Li
- & Joseph G. Gleeson
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Article
| Open AccessA blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia. No clinical blood tests are available for diagnosis. The authors identified three miRNAs in whole-blood that are downregulated in sCJD patients, and discriminate sCJD from Alzheimer’s disease patients and healthy controls.
- Penny J. Norsworthy
- , Andrew G. B. Thompson
- & Emmanuelle A. Viré
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Article
| Open AccessA neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy
High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature.
- Giovanni J. Ughi
- , Miklos G. Marosfoi
- & Ajit S. Puri
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Article
| Open AccessThe circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders
Antenatal glucocorticoid therapy is indicated for mothers at risk of preterm delivery. Here, the authors show that the circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders later in life in mice and in a retrospective observational study in human infants.
- Mariana Astiz
- , Isabel Heyde
- & Henrik Oster
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Article
| Open AccessStructural characterization of a novel human adeno-associated virus capsid with neurotropic properties
Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.
- Hung-Lun Hsu
- , Alexander Brown
- & Guangping Gao
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Article
| Open AccessTranscriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica
Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.
- Agnieshka M. Agasing
- , Qi Wu
- & Robert C. Axtell
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Article
| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessPermissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma
Gut microbiome has been linked to cavernous angioma (CA), a common vascular disease, but the role in humans remains unclear. Here, the authors combine 16S rRNA sequencing and shotgun metagenomics to profile the microbiome in a large cohort of human subjects with and without CA, and among subjects with different CA clinical features.
- Sean P. Polster
- , Anukriti Sharma
- & Issam A. Awad
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Article
| Open AccessA unified neurocognitive model of semantics language social behaviour and face recognition in semantic dementia
Semantic dementia patients present with a core semantic impairment and variations of language, behavioural and face recognition abilities. Here, the authors build a unified multidimensional model to capture all these graded symptoms and map them to the variations in the patients’ frontotemporal atrophy.
- Junhua Ding
- , Keliang Chen
- & Matthew. A. Lambon Ralph
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Article
| Open AccessNeutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke
Following ischemic insult, neovascularization and vascular remodelling play an essential part in the repair of brain damage. Here the authors show that neutrophil extracellular traps serve a detrimental role in the regeneration process, limiting the functional recovery of the brain post injury.
- Lijing Kang
- , Huilin Yu
- & Bing-Qiao Zhao
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Article
| Open AccessMutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity
Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.
- Laure Asselin
- , José Rivera Alvarez
- & Juliette D. Godin
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Article
| Open AccessIncreased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
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Article
| Open AccessGenome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants
Cerebral small vessel disease (CSVD) is a major cause of stroke and associated with structural changes of the brain. Here, Persyn et al. perform genome-wide association studies for magnetic resonance imaging (MRI) markers of CSVD, explore genetic correlations and prioritize candidate genes.
- Elodie Persyn
- , Ken B. Hanscombe
- & Hugh S. Markus
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Article
| Open AccessNoninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources
Noninvasive electromagnetic measurements are utilized effectively to estimate large scale dynamic brain networks. Sohrabpour et al. propose a novel electrophysiological source imaging approach to estimate the location and size of epileptogenic tissues in patients with epilepsy.
- Abbas Sohrabpour
- , Zhengxiang Cai
- & Bin He
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Article
| Open AccessCerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the AD brain. Here the authors demonstrate that CSF p-tau217 shows better performance as an AD biomarker than p-tau181.
- Shorena Janelidze
- , Erik Stomrud
- & Oskar Hansson
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Article
| Open AccessAnalysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease
Parkinson’s disease (PD) is a common neurodegenerative disorder with a complex etiology involving genetics and the environment. Here, Vallerga et al. identify two CpG probes associated with PD in a blood cell type-corrected epigenome-wide meta-analysis, implicating the SLC7A11 gene as a plausible biological target.
- Costanza L. Vallerga
- , Futao Zhang
- & Jacob Gratten
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Article
| Open AccessA disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy
The neural circuits through which the substantia nigra pars reticulata (SNr) exerts its role in epilepsy control are not known. Here the authors reveal that a long-range SNr-parafascicular nucleus disinhibitory circuit participates in regulating seizures in temporal lobe epilepsy and inhibition of this circuit can alleviate severity of epileptic seizures.
- Bin Chen
- , Cenglin Xu
- & Zhong Chen
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Article
| Open AccessInsights into the aetiology of snoring from observational and genetic investigations in the UK Biobank
Snoring is common in the population and tends to be more prevalent in older and/or male individuals. Here, the authors perform GWAS for habitual snoring, identify 41 genomic loci and explore potential causal relationships with anthropometric and cardiometabolic disease traits.
- Adrián I. Campos
- , Luis M. García-Marín
- & Miguel E. Rentería
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Article
| Open AccessSerum neurofilament light levels in normal aging and their association with morphologic brain changes
Neurofilament (NfL) levels in CSF and blood have been established as a biomarker of neuronal damage in neurodegenerative diseases, and there is an age-dependent increase in NfL levels in CSF. Here the authors demonstrate that serum NfL levels increase in healthy aging people and predict and correlate with brain volume loss.
- Michael Khalil
- , Lukas Pirpamer
- & Jens Kuhle
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Article
| Open AccessTracking regional brain growth up to age 13 in children born term and very preterm
In this longitudinal study, the authors tracked the course of brain development from birth to adolescence (age 13 years) and examined the effects of very preterm birth. Very preterm children showed slower brain growth from age 0 (term equivalent) to age 7.
- Deanne K. Thompson
- , Lillian G. Matthews
- & Peter J. Anderson
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Article
| Open AccessNon-invasive recording from the human olfactory bulb
Measures of neural processing can be obtained non-invasively from all areas of the human brain but one, the olfactory bulb. Here, the authors show that signals obtained from EEG electrodes at the nasal bridge represent responses from the human olfactory bulb, the so-called Electrobulbogram.
- Behzad Iravani
- , Artin Arshamian
- & Johan N. Lundström
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Article
| Open AccessCerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia
Diagnosis of vascular dementia is hampered by the lack of biochemical markers for this disease. Here, the authors show that vascular dementia is associated with increased lipocalin-2 in cerebrospinal fluid, compared to controls and patients with other forms of dementia.
- Franc Llorens
- , Peter Hermann
- & Inga Zerr
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Article
| Open AccessCerebrospinal fluid tracer efflux to parasagittal dura in humans
Mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study demonstrates that trans-arachnoid molecular passage does occur and suggests that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.
- Geir Ringstad
- & Per Kristian Eide
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Article
| Open AccessFunctional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease
Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.
- Nicolai Franzmeier
- , Julia Neitzel
- & Balebail Ashok Raj
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Article
| Open AccessGenomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke
Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.
- Gad Abraham
- , Rainer Malik
- & Martin Dichgans
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Article
| Open AccessA VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2
The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Here, the authors show that VEGFRs peptide vaccination can improve hearing and reduce tumor volume in NF2 patients, including in previously bevacizumab resistant tumors.
- Ryota Tamura
- , Masato Fujioka
- & Masahiro Toda
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Article
| Open AccessElimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
Mutations in Ftkn cause Fukuyama muscular dystrophy, and heart failure is the main cause of death in thes patients. Here the authors show that acute elimination of Fktn in adult mice causes early mortality, and this is associated with myocyte dysfunction, with disorganised Golg-microtubule networks, and that the pathology can be ameliorated with colchicine treatment.
- Yoshihiro Ujihara
- , Motoi Kanagawa
- & Yuki Katanosaka
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Article
| Open AccessStructural heterogeneity of α-synuclein fibrils amplified from patient brain extracts
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.
- Timo Strohäker
- , Byung Chul Jung
- & Markus Zweckstetter
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Article
| Open AccessMultimodal image registration and connectivity analysis for integration of connectomic data from microscopy to MRI
Many approaches exist to process data from individual imaging modalities, but integrating them is challenging. The authors develop an automated resource that enables co-registered network- and tract-level analysis of macroscopic in-vivo imaging and microscopic imaging of cleared tissue.
- Maged Goubran
- , Christoph Leuze
- & Michael Zeineh
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Article
| Open AccessThe landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease
Parkinson’s disease (PD) is characterized by neurodegeneration associated with loss of dopaminergic (DA) neurons and deposition of Lewy bodies. Here, Wang et al. use co-expression network analysis to pinpoint disease pathways and propose reduced expression of STMN2 as a cause of presynaptic function loss in PD.
- Qian Wang
- , Yuanxi Zhang
- & Bin Zhang
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Article
| Open AccessIn vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
T cells from narcolepsy patients were recently reported to recognize hypocretin, a wakefulness-promoting neurohormone, suggesting autoimmune origin of the disease. Here the authors show that hypocretin-specific T cells expand both in healthy controls and in narcolepsy patients, and identify preliminary features that may distinguish them.
- Wei Jiang
- , James R. Birtley
- & Elizabeth D. Mellins
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Article
| Open AccessStroke among cancer patients
The risk of fatal stroke is increased in children, adolescent, and young (<40 years) cancer patients after diagnosis. Here, the authors report a retrospective, population-based study and show that the risk of stroke among cancer patients is twice that of the general population and rises with longer follow up time.
- Nicholas G. Zaorsky
- , Ying Zhang
- & Brad E. Zacharia