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| Open AccessInflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis
Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.
- Tanuja Chitnis
- , Ferhan Qureshi
- & Sergio E. Baranzini
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Article
| Open AccessTDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.
- Marta Garcia-Montojo
- , Saeed Fathi
- & Avindra Nath
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Article
| Open AccessEffects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis
Although SPI1 gene was identified as a risk factor for Alzheimer’s disease, its role in the disease remains unclear. Here, the authors show that decreasing SPI1 level exacerbates disease symptoms, whereas increasing its level ameliorates phenotypes.
- Byungwook Kim
- , Luke Child Dabin
- & Jungsu Kim
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Article
| Open AccessSex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus
Schizophrenia research has traditionally overlooked sex differences. Here, the authors show the importance of sex-based analysis across multi-brain regions by identifying sex-specific genes and genetic interactions in schizophrenia and sex-specific risk.
- Kynon J. M. Benjamin
- , Ria Arora
- & Jennifer A. Erwin
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Article
| Open AccessPharmacological inhibition of α-synuclein aggregation within liquid condensates
Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.
- Samuel T. Dada
- , Zenon Toprakcioglu
- & Michele Vendruscolo
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Article
| Open AccessDisease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls
Amyotrophic Lateral Sclerosis (ALS) is highly heritable but the mechanisms of sporadic ALS are not fully understood. In this study, the authors identify drivers of variation and disease-relevant changes in the epigenomic profile of iPSC-derived motor neuron lines generated from ALS patients and healthy controls as part of the Answer ALS program.
- Stanislav Tsitkov
- , Kelsey Valentine
- & Ernest Fraenkel
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Article
| Open AccessCerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases
CSF biomarker concentrations may be influenced by non-disease related interindividual variability. Here, the authors show that reference proteins can capture this variability and enhance the accuracy of Alzheimer’s disease biomarkers.
- Linda Karlsson
- , Jacob Vogel
- & Oskar Hansson
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Article
| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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Article
| Open AccessAstroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model
Fragile X syndrome is a neurodevelopmental disorder with altered neuronal excitability and behavior. Here, the authors show that dysfunction of astroglial Kir4.1 potassium channels drives neuronal and behavioral impairments in a fragile X mouse model.
- Danijela Bataveljic
- , Helena Pivonkova
- & Nathalie Rouach
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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Article
| Open AccessRobust compression and detection of epileptiform patterns in ECoG using a real-time spiking neural network hardware framework
Costa et al. designed a modular spiking neural network in a neuromorphic device with heterogeneous silicon neurons that remotely detects epileptiform discharges and High Frequency Oscillations in intra-operative EEG during epilepsy surgery in real-time.
- Filippo Costa
- , Eline V. Schaft
- & Johannes Sarnthein
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Article
| Open AccessNeural signatures of indirect pathway activity during subthalamic stimulation in Parkinson’s disease
Subthalamic deep brain stimulation produces evoked resonant neural activity (ERNA) which has been linked to therapeutic benefit. Using a multimodal approach, the authors propose that ERNA reflects activation of the basal ganglia indirect pathway network.
- Leon A. Steiner
- , David Crompton
- & Luka Milosevic
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Article
| Open AccessStress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice
Cross talk between periphery and the central nervous system may contribute to stress associated behaviours. Here the authors identified liver-derived lipocalin 2 as a peripheral factor that elicits anxiety-like behaviours via modulating medial prefrontal neural activity.
- Lan Yan
- , Fengzhen Yang
- & Li Zhang
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Article
| Open AccessPlasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease
The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy.
- Fernando Gonzalez-Ortiz
- , Bjørn-Eivind Kirsebom
- & Kaj Blennow
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Article
| Open AccessNative-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology
Native state proteomics of PV interneurons revealed unique molecular features of high translational and metabolic activity, and enrichment of Alzheimer’s risk genes. Early amyloid pathology exerted unique effects on mitochondria, mTOR signaling and neurotransmission in PV neurons.
- Prateek Kumar
- , Annie M. Goettemoeller
- & Srikant Rangaraju
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Article
| Open AccessColitis reduces active social engagement in mice and is ameliorated by supplementation with human microbiota members
Past intestinal distress is associated with diminished social behavior in mice. Here, the authors show that treatment with microbiota members that are enriched in neurotypical people versus people with ASD can ameliorate colitis severity and associated sociability deficits.
- D. Garrett Brown
- , Michaela Murphy
- & June L. Round
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Article
| Open AccessStructural bases of inhibitory mechanism of CaV1.2 channel inhibitors
CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.
- Yiqing Wei
- , Zhuoya Yu
- & Yan Zhao
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Article
| Open AccessStructure of alpha-synuclein fibrils derived from human Lewy body dementia tissue
The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.
- Dhruva D. Dhavale
- , Alexander M. Barclay
- & Paul T. Kotzbauer
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Article
| Open AccessA midbrain GABAergic circuit constrains wakefulness in a mouse model of stress
Neural circuit mechanisms underlying prevention of hyperarousal in acute stress conditions are not fully understood. Here authors show GAD2-positive GABAergic neurons in the midbrain dorsal raphe nucleus constrain the increase of wakefulness to prevent hyperarousal in a mouse model of stress.
- Shuancheng Ren
- , Cai Zhang
- & Zhian Hu
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Article
| Open AccessSpatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology
The impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.
- Thomas M. Goralski
- , Lindsay Meyerdirk
- & Michael X. Henderson
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Article
| Open AccessUltrastructure of human brain tissue vitrified from autopsy revealed by cryo-ET with cryo-plasma FIB milling
Here the authors report a method for cryogenic electron microscopy imaging of human brain tissue samples directly obtained from autopsy, offering insights into cellular ultrastructure and a tool to study potential pathologic features.
- Benjamin C. Creekmore
- , Kathryn Kixmoeller
- & Yi-Wei Chang
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Article
| Open AccessSKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
Secretory autophagy (SA) plays a crucial role in neuroinflammation-driven neurodegeneration, through SKA2 and FKBP5. SKA2 regulation of SA can inhibit IL-1β release. Its dysfunction leads to neurodegeneration, and is linked to Alzheimer’s disease.
- Jakob Hartmann
- , Thomas Bajaj
- & Nils C. Gassen
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Article
| Open AccessPlasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology
A range of blood-based biomarkers have shown high specificity for Alzheimer’s disease (AD) pathophysiology with phosphorylated-tau (p-tau) being the most promising test. Here, the authors show the utility of plasma p-tau212 in autopsy-confirmed AD and memory clinic patient cohorts.
- Przemysław R. Kac
- , Fernando González-Ortiz
- & Thomas K. Karikari
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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Article
| Open AccessExpression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia
Mutations in profilin 1 (PFN1), which modulates actin dynamics, are associated with ALS. Here the authors show that expression of ALS-PFN1 is sufficient to induce deficits in human microglia-like cells, including impaired phagocytosis and lipid metabolism, and that gain-of-function interactions between ALS-PFN1 and PI3P may underlie these deficits.
- Salome Funes
- , Jonathan Jung
- & Daryl A. Bosco
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Article
| Open AccessHTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Sheng Chen
- , Anuradhika Puri
- & Meredith E. Jackrel
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Article
| Open AccessA blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Review Article
| Open AccessNeuropathogenesis-on-chips for neurodegenerative diseases
This review focuses on recent advances in on-chip platforms for patient-like in vitro modeling of the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic lateral sclerosis. The authors advocate for broader usage of these human-relevant models in the academic and pharmaceutical fields.
- Sarnai Amartumur
- , Huong Nguyen
- & Chaejeong Heo
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Article
| Open AccessIdentification of four biotypes in temporal lobe epilepsy via machine learning on brain images
Brain imaging-based disease progression modelling is a promising technique for disease stratification. Here the authors characterize distinct ‘trajectories’ of brain atrophy in temporal lobe epilepsy and identify four subtypes with distinct neuroanatomical signatures.
- Yuchao Jiang
- , Wei Li
- & Dongmei An
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Article
| Open AccessNumerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson’s disease
Virtual reality, robotics and digital online technologies reveal heightened visual overestimation when estimating the number of humans, indexing presence hallucinations in healthy participants and patients with Parkinson’s disease.
- Louis Albert
- , Jevita Potheegadoo
- & Olaf Blanke
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Article
| Open AccessIdentification of gene regulatory networks affected across drug-resistant epilepsies
Epilepsy is a chronic, heterogeneous disease with an urgent need for novel therapies. Here, the authors show a systematic comparison of the global molecular signature of refractory epilepsies elucidating the key mechanisms of the disease pathology.
- Liesbeth François
- , Alessia Romagnolo
- & Eleonora Aronica
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Article
| Open AccessPCDHA9 as a candidate gene for amyotrophic lateral sclerosis
Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.
- Jie Zhong
- , Chaodong Wang
- & Zhiheng Xu
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Article
| Open AccessFUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease
Dysfunction of Fused in Sarcoma (FUS) leads to increased mitochondrial DNA (mtDNA) damage, mutations, and mitochondrial dysfunction. This study shows that FUS collaborates with mtDNA Ligase IIIα to maintain mtDNA repair and integrity.
- Manohar Kodavati
- , Haibo Wang
- & Muralidhar L. Hegde
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Article
| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessAn artificial protein modulator reprogramming neuronal protein functions
Direct modulation of protein by artificial catalysts as enzyme mimetics remains hindered by the lack of highly efficient catalytic centers. Here, the authors present the development of artificial protein modulators (APROMs) with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein.
- Peihua Lin
- , Bo Zhang
- & Daishun Ling
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Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
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Article
| Open AccessQuantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
In tauopathies, the microtubule-associated protein tau is hyperphosphorylated and aggregated. Here the authors identified a polypharmacological small molecule that inhibits aggregation, reduces phosphorylation, and restores microtubule interaction of tau.
- Luca Pinzi
- , Christian Conze
- & Roland Brandt
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Article
| Open AccessStalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis
Ribosome associated quality control (RQC) is a new area of biological investigation with emerging connection to a broad range of diseases. Here authors show that mitochondrial stress can upregulate a new RQC pathway important for tissue homeostasis.
- Ji Geng
- , Shuangxi Li
- & Bingwei Lu
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Article
| Open AccessDeep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.
- Brian Walitt
- , Komudi Singh
- & Avindra Nath
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Article
| Open AccessIntegrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice
Astrocytes adopt diverse states in response to brain injuries. Here, the authors develop a platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO (tissue-digital microfluidic isolation of single cells for -Omics) to uncover the spatial boundaries of molecularly distinct reactive astrocyte populations in stroke.
- Erica Y. Scott
- , Nickie Safarian
- & Maryam Faiz
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Article
| Open AccessA transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration
The etiology of TDP-43 proteinopathy in ALS and FTD is complex. Here, the authors show that prior to disease onset in the rNLS8 mouse model, cortex neurons elicit a transient increase in protective chaperones that combat TDP-43 aggregation.
- Rebecca San Gil
- , Dana Pascovici
- & Adam K. Walker
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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Article
| Open AccessThe secondary somatosensory cortex gates mechanical and heat sensitivity
How and where somatosensory information is encoded in the cortex is unclear and important for developing new pain therapies. Here the authors show a crucial role for the secondary somatosensory cortex (S2) in accurate perception of sensory stimuli.
- Daniel G. Taub
- , Qiufen Jiang
- & Clifford J. Woolf
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Article
| Open AccessTransient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy
Epileptic seizures need better treatments. Here, the authors show that seizure intensity is predicted and controlled by pre-seizure activity of hypothalamic orexin cells, and can be reduced by a hypothalamic deep brain stimulation.
- Han-Tao Li
- , Paulius Viskaitis
- & Denis Burdakov
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Article
| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Article
| Open AccessSex dependence of opioid-mediated responses to subanesthetic ketamine in rats
In rats, functional ultrasound imaging reveals that blocking opioid receptors modulates the effects of subanesthetic ketamine on neural activity in males but not in females, with parallel changes in ketamine’s effects on brain structure and behavior.
- Tommaso Di Ianni
- , Sedona N. Ewbank
- & Raag D. Airan
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Article
| Open AccessiPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment.
- Lauren Rylaarsdam
- , Jennifer Rakotomamonjy
- & Alicia Guemez-Gamboa
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