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| 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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| 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
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Article
| Open AccessAndrogens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.
- Amina Zahaf
- , Abdelmoumen Kassoussi
- & Elisabeth Traiffort
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Article
| Open AccessCholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice
The corticostriatal dysfunction underlying Huntington’s disease remains incompletely understood. Here, the authors find increased intratelencephalic connectivity resulting from deficient cholinergic transmission in a mouse model of Huntington’s disease.
- Tristano Pancani
- , Michelle Day
- & D. James Surmeier
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Article
| 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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| 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