Human pluripotent stem cell-derived microglia shape neuronal morphology and enhance network activity in vitro.

Background: Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining neuronal health, but are often overlooked in traditional neuron-focused in vitro models.

New Method: In this study, we developed a novel co-culture system of human pluripotent stem cell (hPSC)-derived microglia and neurons to investigate how hPSC-derived microglia influence neuronal morphology and network activity. Using high-content morphological analysis and multi-electrode arrays (MEA), we demonstrate that these microglia successfully incorporate into neuronal networks and modulate key aspects of neuronal function.

Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer's disease: a magnetoencephalography study.

Understanding the nature and onset of neurophysiological changes, and the selective vulnerability of central hub regions in the functional network, may aid in managing the growing impact of Alzheimer's disease on society. However, the precise neurophysiological alterations occurring in the pre-clinical stage of human Alzheimer's disease remain controversial. This study aims to provide increased insights on quantitative neurophysiological alterations during a true early stage of Alzheimer's disease.

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study.

Microbiome influences multiple human systems, but its effects on gene methylation is unknown. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbial pathways using data generated by shotgun metagenomic sequencing (n = 683).

Endosomal sorting protein SNX4 limits synaptic vesicle docking and release.

Sorting nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how SNX4 affects synapse function remains unknown. We generated a conditional SNX4 knock-out mouse model and report that SNX4 cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal.

Inhibitory maturation and ocular dominance plasticity in mouse visual cortex require astrocyte CB1 receptors.

Endocannabinoids, signaling through the cannabinoid CB1 receptor (CB1R), regulate several forms of neuronal plasticity. CB1Rs in the developing primary visual cortex (V1) play a key role in the maturation of inhibitory circuits. Although CB1Rs were originally thought to reside mainly on presynaptic axon terminals, several studies have highlighted an unexpected role for astrocytic CB1Rs in endocannabinoid mediated plasticity.

Gene Therapy for Inherited Liver Disease: To Add or to Edit.

Patients suffering from an inherited severe liver disorder require lifelong treatment to prevent premature death. Until recently, the only curative treatment option was liver transplantation, which requires lifelong immune suppression. Now, liver-directed gene therapy, which is a much less invasive procedure, has become a market-approved treatment for hemophilia A and B.

Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins.

Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins.

Sleep and physical activity patterns in relation to daily-life symptoms in psychosis: An actigraphy and experience sampling study.

Sleep disturbances and reduced physical activity (PA) are important risk factors for poor physical and mental health outcomes in people with psychosis. However, the precise interrelations between sleep, PA and psychopathology remain unclear. This study combined experience sampling (ESM) and actigraphy in thirty-two patients with a schizophrenia spectrum disorder to investigate interrelations of day-to-day variations in actigraphic estimates of PA and sleep and psychotic and affective symptoms.

Negative Life Events and Epigenetic Ageing: A Study in the Netherlands Twin Register.

We aimed to understand the long-term impact of negative life events on epigenetic aging in 1783 adults from the Netherlands Twin Register, analyzing five epigenetic biomarkers (Hannum, Horvath, PhenoAge, GrimAge, DunedinPACE) and a series of negative life events, including victimization and economic hardship. In population-level analyses, associations between a higher number of negative life events (particularly financial adversities, sexual crimes, and job loss) were seen for the GrimAge biomarker. The association between the number of negative life events and financial problems and epigenetic age acceleration measured by the GrimAge biomarker persisted after adjusting for BMI, smoking, and white blood cell counts.

KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.

Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro.

Brain magnetic resonance imaging of patients with spinal muscular atrophy type 2 and 3.

Background And Objective: Proximal spinal muscular atrophy (SMA) is caused by deficiency of the ubiquitously expressed survival motor neuron protein. Although primarily a hereditary lower motor neuron disease, it is probably also characterized by abnormalities in other organs. Brain abnormalities and cognitive impairment have been reported in severe SMA.

Metabolomics profiling of Type D personality traits.

Objective: Type D (Distressed) personality combines negative affectivity (NA) and social inhibition (SI) and is associated with an increased risk of cardiometabolic diseases. Here, we examined the association of Type D traits with 230 (predominantly) lipid metabolites and metabolite ratios.

Methods: Four Dutch cohorts were included, comprising 10,834 individuals.

Epigenetic signatures of asthma: a comprehensive study of DNA methylation and clinical markers.

Background: Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma.

Methods: The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood from 319 participants from 94 families.

Correction of Griscelli Syndrome Type 2 causing mutations in the gene with CRISPR/Cas9.

Background/aim: Griscelli Syndrome Type 2 (GS-2) is a rare, inherited immune deficiency caused by a mutation in the gene. The current treatment consists of hematopoietic stem cell transplantation, but a lack of suitable donors warrants the development of alternative treatment strategies, including gene therapy. The development of mutation-specific clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing technology has opened the way for custom-designed gene correction of patient-derived stem cells.

Assessment of non-myelotoxic agents as a preparatory regimen for hematopoietic stem cell gene therapy.

RAG2 deficiency is characterized by a lack of B and T lymphocytes, causing severe lethal infections. Currently, RAG2 deficiency is treated with a Hematopoietic Stem Cell transplantation (HSCT). Most conditioning regimens used before HSCT consist of alkylating myelotoxic agents with or without irradiation and affect growth and development of pediatric patients.

Border-ownership tuning determines the connectivity between V4 and V1 in the macaque visual system.

Cortical feedback connections are extremely numerous but the logic of connectivity between higher and lower areas remains poorly understood. Feedback from higher visual areas to primary visual cortex (V1) has been shown to enhance responses on perceptual figures compared to backgrounds, an effect known as figure-background modulation (FBM). A likely source of this feedback are border-ownership (BO) selective cells in mid-tier visual areas (e.

Activity dependent modulation of glial gap junction coupling in the thalamus.

Astrocytes and oligodendrocytes in the ventrobasal thalamus are electrically coupled through gap junctions. We have previously shown that these cells form large panglial networks, which have a key role in the transfer of energy substrates to postsynapses for sustaining neuronal activity. Here, we show that the efficiency of these transfer networks is regulated by synaptic activity: preventing the generation and propagation of action potentials resulted in reduced glial coupling.

Polyconnectomic scoring of functional connectivity patterns across eight neuropsychiatric and three neurodegenerative disorders.

Background: Neuropsychiatric and neurodegenerative disorders involve diverse changes in brain functional connectivity. As an alternative to approaches searching for specific mosaic patterns of affected connections and networks, we used polyconnectomic scoring to quantify disorder-related whole-brain connectivity signatures into interpretable, personalized scores.

Methods: The polyconnectomic score (PCS) measures the extent to which an individual's functional connectivity (FC) mirrors the whole-brain circuitry characteristics of a trait.

Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer's Disease Therapeutics.

Therapeutic research and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and neurodegeneration. There is growing interest in drug repositioning and repurposing strategies for FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA drug efavirenz has been investigated as a candidate drug for repurposing as an AD medication.

Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study.

Background: Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD.