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| Open AccessLinoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome
Angelman syndrome (AS) is a neurogenetic disorder. Here, the authors found that PIEZO2 activity is reduced in sensory neurons from a mouse model of AS and used a linoleic acid-enriched diet to enhance PIEZO2 function and ameliorate AS-associated gait deficits.
- Luis O. Romero
- , Rebeca Caires
- & Julio F. Cordero-Morales
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Article
| Open AccessTEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.
- Lindsey Van Haute
- , Emily O’Connor
- & Rita Horvath
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Article
| Open AccessAn open label, non-randomized study assessing a prebiotic fiber intervention in a small cohort of Parkinson’s disease participants
This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.
- Deborah A. Hall
- , Robin M. Voigt
- & Ali Keshavarzian
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Article
| Open AccessT cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Glioblastoma is a highly aggressive, and also the most common, brain tumour type in adults. Here, the authors generate a nanoparticle encapsulating the TLR7/8 agonist, R848, which induces tumour regression in mice by reprogramming myeloid cells independently of T and NK cells.
- Verena Turco
- , Kira Pfleiderer
- & Michael Platten
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Article
| Open AccessForecasting individual progression trajectories in Alzheimer’s disease
Accurate prediction of disease progression in Alzheimer’s disease (AD) is necessary for optimal recruitment of patients to clinical trials. Here, the authors present AD Course Map, a statistical model which helps to predict disease progression in participants, thus decreasing the required sample size for a hypothetical trial.
- Etienne Maheux
- , Igor Koval
- & Stanley Durrleman
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Article
| Open AccessDefective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle
Marchioretti and colleagues show that in the skeletal muscle of SBMA mice and patients there is an early, but reversible alteration of expression of genes involved in muscle contraction and of mitochondrial respiration, followed by accumulation of calcium inside the mitochondria, which is concomitant with the onset of motor dysfunction, and late alteration of muscle structure.
- Caterina Marchioretti
- , Giulia Zanetti
- & Maria Pennuto
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Article
| Open AccessFTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke
The mechanisms behind how vascular repair is regulated after ischemic stroke are yet to be elucidated. Here, the authors describe that a circular RNA interacts with FTO to promote vascular repair following stroke in mice and primates via mediating m6 A modification.
- Bin Li
- , Wen Xi
- & Honghong Yao
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Article
| Open AccessGut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia
Familial dysautonomia is a rare genetic disease caused in part by neurodegeneration. Here, the authors show that the gut-metabolism axis is altered in both patients and transgenic mice and that disease pathology is ameliorated by controlling microbiome divergence.
- Alexandra M. Cheney
- , Stephanann M. Costello
- & Seth T. Walk
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Article
| Open AccessNear-infrared-IIb emitting single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown after traumatic brain injury
Monitoring the status of blood-brain barrier (BBB) and inhibiting reactive oxygen species (ROS)-mediated oxidative damage are key issues in the treatment of traumatic brain injury (TBI). Here, the authors design a near-infrared-IIb emitting Mn single-atom catalyst for imaging-guided therapy to alleviate ROS mediated neuroinflammation in the brain and simultaneously obtain timely feedback of therapeutic effect, promoting the reconstruction of BBB and recovery of neurological function after TBI in mice.
- Biao Huang
- , Tao Tang
- & Ran Cui
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Article
| Open AccessFunctional geometry of the cortex encodes dimensions of consciousness
Dimensions of consciousness such as wakefulness or awareness are well established but have not been mapped to the brain. Here, the authors show that dimensions of consciousness are encoded in the functional geometry of the cortex.
- Zirui Huang
- , George A. Mashour
- & Anthony G. Hudetz
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Article
| Open AccessDynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies
Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.
- Filipa Mota
- , Camilo A. Ruiz-Bedoya
- & Sanjay K. Jain
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Article
| Open AccessHuntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation
Here the authors evaluate single cell gene expression from mouse and human Huntington’s disease brains, finding incomplete oligodendrocyte maturation and pathways involved. Treating mice with thiamine/biotin ameliorates molecular pathology.
- Ryan G. Lim
- , Osama Al-Dalahmah
- & Leslie M. Thompson
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Article
| Open AccessA nigro–subthalamo–parabrachial pathway modulates pain-like behaviors
Maladaptive plastic changes in the brain are critical for pain maintenance. The authors identify a nigro–subthalamo–parabrachial pathway and reveal that reversing a series of neuronal and synaptic malfunctions in this pathway in acute and chronic pain mitigates hyperalgesia, providing potential therapeutic targets for pain modulation.
- Tao Jia
- , Ying-Di Wang
- & Chunyi Zhou
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Article
| Open AccessMolecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms
Multiple sclerosis (MS) changes the composition of the CSF. Here the authors use patient samples and aggregate CSF biomarkers into models that predict disability across all MS phenotypes, and identify potentially causal mechanisms and molecular disease heterogeneity.
- Peter Kosa
- , Christopher Barbour
- & Bibiana Bielekova
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Article
| Open AccessCausal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia
Previous observational studies of the diabetes drugs metformin vs. sulfonylureas have yielded mixed results about whether metformin reduces the risk of dementia, relative to the sulfonylureas. Here, the authors apply a novel competing risks approach to emulate dementia-related target trials in electronic health records of diabetic patients and a complementary systems pharmacology evaluation on human neural cells.
- Marie-Laure Charpignon
- , Bella Vakulenko-Lagun
- & Mark W. Albers
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Article
| Open AccessNeural precursor cells tune striatal connectivity through the release of IGFBPL1
The physiological role of endogenous neural protenitor cells of the subventricular zone in adult stage is not fully understood. Here the authors show that in mice, these cells tune neuronal activity of the striatum via insulin-like growth factor binding protein-like 1 and cognitive functions.
- Erica Butti
- , Stefano Cattaneo
- & Gianvito Martino
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Article
| Open AccessMetagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms
Here, the authors perform large-scale high-resolution Parkinson’s disease metagenomics analyses, revealing widespread dysbiosis characterized by overabundance of pathogens, immunogens, toxicants, and curli, reduction in neuroprotective and antiinflammatory molecules, and dysregulated neuroactive signaling.
- Zachary D. Wallen
- , Ayse Demirkan
- & Haydeh Payami
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Article
| Open AccessHypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia
Developing brain-protective hypothermia is a medical challenge. Here, the authors show that deep brain stimulation of a particular brain area is a new way to trigger the body into a hibernation-like state with reduced body temperature and brain protection in a mouse model of stroke.
- Shuai Zhang
- , Xinpei Zhang
- & Sheng-Tao Hou
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Article
| Open AccessVascular endothelium deploys caveolin-1 to regulate oligodendrogenesis after chronic cerebral ischemia in mice
OPC-vascular coupling contributes to myelin maintenance. Here the authors show Cav-1 stabilizes interactions and mediates OPC maturation in ischemia.
- Ying Zhao
- , Wusheng Zhu
- & Xinfeng Liu
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Article
| Open AccessAn alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons
Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington’s disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model.
- Florian Krach
- , Judith Stemick
- & Juergen Winkler
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Article
| Open AccessSevere Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.
- Manina M. Etter
- , Tomás A. Martins
- & Gregor Hutter
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Article
| Open AccessGeneralizable spelling using a speech neuroprosthesis in an individual with severe limb and vocal paralysis
Previous work has described a neuroprosthesis to directly decode full words in real time during attempts to speak. Here the authors demonstrate that a patient with anarthria can control this neuroprosthesis to spell out intended messages in real time using attempts to silently speak.
- Sean L. Metzger
- , Jessie R. Liu
- & Edward F. Chang
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Article
| Open AccessT cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression
Amyotrophic lateral sclerosis (ALS) is a primary neurodegenerative disease, which is characterized by increased immune cell infiltration of the central nervous system. Here authors show that the phenotypic profile of T cells in the blood and cerebrospinal fluid of newly diagnosed ALS patients can predict disease progression, thus providing evidence that T cells contribute to disease pathology.
- Solmaz Yazdani
- , Christina Seitz
- & Fang Fang
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Article
| Open AccessSpecialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
Whole genome sequencing is emerging as a first-line test for rare genetic diseases. In this study, authors maximise diagnoses by supplementing existing semiautomated analyses with clinically driven reevaluation of genomic data by a specialist multidisciplinary team.
- William L. Macken
- , Micol Falabella
- & Robert D. S. Pitceathly
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Article
| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
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Article
| Open AccessPericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
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Article
| Open AccessA pilot study combining noninvasive spinal neuromodulation and activity-based neurorehabilitation therapy in children with cerebral palsy
Here the authors report a single arm pilot trial to investigate combined spinal neuromodulation and activity-based neurorehabilitation therapy on voluntary sensory-motor function in children with cerebral palsy.
- Susan Hastings
- , Hui Zhong
- & V. Reggie Edgerton
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Article
| Open AccessEstimating individual treatment effect on disability progression in multiple sclerosis using deep learning
There are limited predictive biomarkers for drug treatment responses in individuals with multiple sclerosis. Here using existing clinical trials data, the authors propose a deep-learning predictive enrichment strategy to identify which participants are most likely to respond to a treatment.
- Jean-Pierre R. Falet
- , Joshua Durso-Finley
- & Douglas Lorne Arnold
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Article
| Open AccessPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.
- Ying Jiang
- , John J. Alam
- & Ralph A. Nixon
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Article
| Open AccessStress induced TDP-43 mobility loss independent of stress granules
Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.
- Lisa Streit
- , Timo Kuhn
- & Karin M. Danzer
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Article
| Open AccessSubcortical-cortical dynamical states of the human brain and their breakdown in stroke
Favaretto et al. show that the brain rapidly alternates between transient connectivity patterns, with cortical regions flexibly synchronizing with two groups of subcortical regions, and that this dynamic is abnormal in stroke patients.
- Chiara Favaretto
- , Michele Allegra
- & Maurizio Corbetta
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Article
| Open AccessPneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Pneumococcal infection of the cerebrospinal fluid results in bacterial lysis, the release of toxic factors and induction of neuroinflammation. Here, the authors show that the virulence factor pneumolysin enhances the neuroinflammatory response to Streptococcus pneumoniae by the enhancement of endocytosis.
- Sabrina Hupp
- , Christina Förtsch
- & Asparouh I. Iliev
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Article
| Open AccessEpigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
Parkinson’s disease and dementia with Lewy bodies are closely related neurodegenerative disorders, although the epigenetic similarities are not well known. Here, the authors study Lewy pathology and DNA methylation in postmortem human frontal cortex, identifying differentially methylated genomic loci.
- Lasse Pihlstrøm
- , Gemma Shireby
- & Mathias Toft
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Article
| Open AccessEarlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.
- Lukas Frontzkowski
- , Michael Ewers
- & Nicolai Franzmeier
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Article
| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
| Open AccessLocal molecular and global connectomic contributions to cross-disorder cortical abnormalities
Changes to structural and functional connectivity can give rise to neurodegeneration and neurodevelopmental diseases. Here the authors investigate molecular and connectomic patterns in 13 different neurological, psychiatric and neurodevelopmental diseases from the ENIGMA consortium.
- Justine Y. Hansen
- , Golia Shafiei
- & Bratislav Misic
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| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman
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Article
| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Article
| Open AccessStructural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression
Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.
- Sara Larivière
- , Jessica Royer
- & Boris C. Bernhardt
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Article
| Open AccessShared mechanisms across the major psychiatric and neurodegenerative diseases
Studying the shared genetic etiology of disease can help improve diagnosis and treatment. Here, the authors find evidence for shared genetic and molecular pathophysiology between several common psychiatric and neurodegenerative diseases using results of 25 GWAS and large-scale human brain transcriptomic and proteomic sequencing.
- Thomas S. Wingo
- , Yue Liu
- & Aliza P. Wingo
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Article
| Open AccessCryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
- Gamma Chi
- , Qiansheng Liang
- & Katharina L. Dürr
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Article
| Open AccessSLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
- Salima El Chehadeh
- , Kyung Ah Han
- & Ji Won Um
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Article
| Open AccessMultimodal deep learning for Alzheimer’s disease dementia assessment
Here the authors present a deep learning framework for dementia diagnosis, which can identify persons with normal cognition, mild cognitive impairment, Alzheimer’s disease, and dementia due to other etiologies.
- Shangran Qiu
- , Matthew I. Miller
- & Vijaya B. Kolachalama
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Article
| Open AccessDistributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders
The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
- Shahram Bahrami
- , Kaja Nordengen
- & Tobias Kaufmann
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Article
| Open AccessNUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
- Amanda M. Gleixner
- , Brandie Morris Verdone
- & Christopher J. Donnelly
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Article
| Open AccessSubthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia
Chemogenetic inactivation of the subthalamic nucleus in monkeys increases spike train variability in the pallidum and prolongs movement time, suggesting its role in stabilizing pallidal spike trains to achieve stable motor control.
- Taku Hasegawa
- , Satomi Chiken
- & Atsushi Nambu
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Article
| Open AccessStearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is characterized by lipid abnormalities which are not well understood. Here, the authors investigate the role of Stearoyl-CoA desaturase (SCD) in a mouse model of AD. They show that inhibiting SCD activity induces major brain and immune cell transcriptional changes and restores dendritic structure and learning and memory.
- Laura K. Hamilton
- , Gaël Moquin-Beaudry
- & Karl J. L. Fernandes
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Article
| Open AccessAn analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences
Sex differences occur in many neurological and psychiatric diseases, and yet research is not always designed optimally to identify these. Here the authors perform a study of how sex was incorporated into the design and analyses of papers published six journals in neuroscience and psychiatry in 2009 compared with 2019.
- Rebecca K. Rechlin
- , Tallinn F. L. Splinter
- & Liisa A. M. Galea
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Article
| Open AccessMicrovascular stabilization via blood-brain barrier regulation prevents seizure activity
The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy
- Chris Greene
- , Nicole Hanley
- & Matthew Campbell