Neuroprotective role of sialic-acid-binding immunoglobulin-like lectin-11 in humanized transgenic mice.

Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes -2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer's disease, although its role in inflammation and neurodegeneration remains poorly understood.

Human neural stem cells directly programmed from peripheral blood show functional integration into the adult mouse brain.

Transplantation of induced pluripotent stem cell-derived neural cells represents a promising strategy for treating neurodegenerative diseases. However, reprogramming of somatic cells and their subsequent neural differentiation is complex and time-consuming, thereby impeding autologous applications. Recently, direct transcription factor-based conversion of blood cells into induced neural stem cells (iNSCs) has emerged as a potential alternative.

Distinct and Overlapping Metabolites Associated with Visual Impairment and Cognitive Impairment.

Background: Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown.

Objective: We aim to compare the metabolite associations of VI and cognitive impairment.

Methods: The study population with comprehensive measurements was derived from the UK Biobank study.

Automated CRISPR/Cas9-based genome editing of human pluripotent stem cells using the StemCellFactory.

CRISPR/Cas9 genome editing is a rapidly advancing technology that has the potential to accelerate research and development in a variety of fields. However, manual genome editing processes suffer from limitations in scalability, efficiency, and standardization. The implementation of automated systems for genome editing addresses these challenges, allowing researchers to cover the increasing need and perform large-scale studies for disease modeling, drug development, and personalized medicine.

Decreased sialylation elicits complement-related microglia response and bipolar cell loss in the mouse retina.

Sialylation plays an important role in self-recognition, as well as keeping the complement and innate immune systems in check. It is unclear whether the reduced sialylation seen during aging and in mice heterozygous for the null mutant of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (Gne+/-), an essential enzyme for sialic acid biosynthesis, contributes to retinal inflammation and degeneration. We found a reduction of polysialic acid and trisialic acid expression in several retinal layers in Gne+/- mice at 9 months of age compared to Gne+/+ wildtype (WT) mice, which was associated with a higher microglial expression of the lysosomal marker CD68.

Author Correction: BCL7A-containing SWI/SNF/BAF complexes modulate mitochondrial bioenergetics during neural progenitor differentiation.

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Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.

Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death.

The impact of the mesoprefrontal dopaminergic system on the maturation of interneurons in the murine prefrontal cortex.

The prefrontal cortex (PFC) undergoes a protracted maturation process. This is true both for local interneurons and for innervation from midbrain dopaminergic (mDA) neurons. In the striatum, dopaminergic (DA) neurotransmission is required for the maturation of medium spiny neurons during a critical developmental period.

Revealing Genetic Dynamics: scRNA-seq Unravels Modifications in Human PDL Cells across In Vivo and In Vitro Environments.

The periodontal ligament (PDL) is a highly specialized fibrous tissue comprising heterogeneous cell populations of an intricate nature. These complexities, along with challenges due to cell culture, impede a comprehensive understanding of periodontal pathophysiology. This study aims to address this gap, employing single-cell RNA sequencing (scRNA-seq) technology to analyze the genetic intricacies of PDL both in vivo and in vitro.

Epigenetic and Transcriptional Shifts in Human Neural Stem Cells after Reprogramming into Induced Pluripotent Stem Cells and Subsequent Redifferentiation.

Induced pluripotent stem cells (iPSCs) and their derivatives have been described to display epigenetic memory of their founder cells, as well as de novo reprogramming-associated alterations. In order to selectively explore changes due to the reprogramming process and not to heterologous somatic memory, we devised a circular reprogramming approach where somatic stem cells are used to generate iPSCs, which are subsequently re-differentiated into their original fate. As somatic founder cells, we employed human embryonic stem cell-derived neural stem cells (NSCs) and compared them to iPSC-derived NSCs derived thereof.

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases.

Sialic acids, commonly found as the terminal carbohydrate on the glycocalyx of mammalian cells, are pivotal checkpoint inhibitors of the innate immune system, particularly within the central nervous system (CNS). Sialic acid-binding immunoglobulin-like lectins (SIGLECs) expressed on microglia are key players in maintaining microglial homeostasis by recognizing intact sialylation. The finely balanced sialic acid-SIGLEC system ensures the prevention of excessive and detrimental immune responses in the CNS.

Paroxysmal dystonia results from the loss of RIM4 in Purkinje cells.

Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell type-specific role in cerebellar Purkinje cells that is essential for normal motor function.

A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1.

Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations.

6'-sialyllactose ameliorates the ototoxic effects of the aminoglycoside antibiotic neomycin in susceptible mice.

Sialic acids are terminal sugars of the cellular glycocalyx and are highly abundant in the nervous tissue. Sialylation is sensed by the innate immune system and acts as an inhibitory immune checkpoint. Aminoglycoside antibiotics such as neomycin have been shown to activate tissue macrophages and induce ototoxicity.

Cell type specificity for circuit output in the midbrain dopaminergic system.

Midbrain dopaminergic neurons are a relatively small group of neurons in the mammalian brain controlling a wide range of behaviors. In recent years, increasingly sophisticated tracing, imaging, transcriptomic, and machine learning approaches have provided substantial insights into the anatomical, molecular, and functional heterogeneity of dopaminergic neurons. Despite this wealth of new knowledge, it remains unclear whether and how the diverse features defining dopaminergic subclasses converge to delineate functional ensembles within the dopaminergic system.

Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.

Background: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations.

Methods: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks.

Loss of function of FIP200 in human pluripotent stem cell-derived neurons leads to axonal pathology and hyperactivity.

FIP200 plays important roles in homeostatic processes such as autophagy and signaling pathways such as focal adhesion kinase (FAK) signaling. Furthermore, genetic studies suggest an association of FIP200 mutations with psychiatric disorders. However, its potential connections to psychiatric disorders and specific roles in human neurons are not clear.

Stem cell programming - prospects for perinatal medicine.

Recreating human cell and organ systems has tremendous potential for disease modeling, drug discovery and regenerative medicine. The aim of this short overview is to recapitulate the impressive progress that has been made in the fast-developing field of cell programming during the past years, to illuminate the advantages and limitations of the various cell programming technologies for addressing nervous system disorders and to gauge their impact for perinatal medicine.

Association of polysialic acid serum levels with schizophrenia spectrum and bipolar disorder-related structural brain changes and hospitalization.

Expression of polysialic acid (polySia) in the adult brain is enriched in areas of continuous neurogenesis and plasticity such as the hippocampus. Genome-wide association studies identified variants of glycosylation enzyme-encoding genes, required for the generation of polySia, to be associated with the development of schizophrenia and bipolar disorder. Here, we report that serum levels of polySia are increased in patients with schizophrenia spectrum disorder compared to patients with major depressive disorders or demographically matched healthy controls.

Bringing to light the physiological and pathological firing patterns of human induced pluripotent stem cell-derived neurons using optical recordings.

Human induced pluripotent stem cells (hiPSCs) are a promising approach to study neurological and neuropsychiatric diseases. Most methods to record the activity of these cells have major drawbacks as they are invasive or they do not allow single cell resolution. Genetically encoded voltage indicators (GEVIs) open the path to high throughput visualization of undisturbed neuronal activity.

Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell-derived sensory neurons.

Induced pluripotent stem cells (iPSCs) have enabled the generation of various difficult-to-access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdNs) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdNs, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored.