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Page 127 of 546-
[Development of capillaries in the human brain].
The development of capillaries in auditory, motor and visual areas of the cortex in males (ranging in age from 6-8 months of embryonic development to 60-80 years) was studied, using Gomory's method of alkaline phosphatase activity assessment and electron microscopy. It was found that cerebral capillaries formation continues in the course of man's entire life. It is noteworthy that the rate of capillary growth decreases with age, this feature being particularly prominent by the age of 60 to 80 years.
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New findings concerning the pathogenesis of acute carbon monoxide (CO) poisoning.
The pathomechanism of carbon monoxide (CO) poisoning was studied by means of cardiopathological and neuropathological investigations in experimental CO intoxication. It has been shown that besides CO-hemoglobin association, the binding of CO to cytochromes is a significant factor. The latter is thought to be responsible for the cytotoxic phenomena. Combined ultrastructural and cytochemical studies have enabled differentiation between toxic, hypoxic, and mixed alternations.
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High-throughput screening of human induced pluripotent stem cell-derived brain organoids.
BACKGROUND: The need for scalable high-throughput screening (HTS) approaches for 3D human stem cell platforms remains a central challenge for disease modeling and drug discovery. We have developed a workflow to screen cortical organoids across platforms. NEW METHOD: We used serum-free embryoid bodies (SFEBs) derived from human induced pluripotent stem cells (hiPSCs) and employed high-content imaging (HCI) to assess neurite outgrowth and cellular composition within SFEBs. We multiplexed this screening assay with both multi-electrode arrays (MEAs) and single-cell calcium imaging. RESULTS: HCI was used to assess the number of excitatory neurons (VGlut+) in experimental replicates of hiPSC-derived SFEBs, demonstrating experiment-to-experiment consistency. Neurite detection using HCI was applied to assess neurite morphology. MEA analysis showed that firing and burst rates in SFEBs decreased with blockade of NMDARs and AMPARs and increased with GABAR blockade. We also demonstrate effective combination of both MEA and HCI to analyze VGlut+ populations surrounding electrodes within MEAs. HCI-based (Ca2+) transient analysis revealed firing in individual cells surrounding active MEA electrodes. COMPARISON WITH EXISTING METHODS: Current methods to generate neural organoids show high degrees of variability, and often require sectioning or special handling for analysis. The protocol outlined in this manuscript generates SFEBs with high degree of consistency making them amenable to complex assays combining HTS and electrophysiology allowing for an in-depth, unbiased analysis. CONCLUSIONS: SFEBs can be used in combination with HTS to compensate for experimental variability common in 3D cultures, while significantly decreasing processing speed, making this an efficient starting point for phenotypic drug screening.
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ICU patient-on-a-chip emulating orchestration of mast cells and cerebral organoids in neuroinflammation.
Propofol and midazolam are the current standard of care for prolonged sedation in Intensive Care Units (ICUs). However, the effects and mechanism of these sedatives in brain tissue are unclear. Herein, the development of an ICU patient-on-a-chip platform to elucidate those effects is reported. The humanized neural tissue compartment combines mast cells differentiated from human induced pluripotent stem cells (hiPSCs) with cerebral organoids in a three-dimensional (3D) matrix, which is covered with a membrane populated with human cerebral microvascular endothelial cells (hCMEC/D3) that separates the tissue chamber from the vascular lumen, where sedatives were infused for four days to evaluate neurotoxicity and cell-mediated immune responses. Subsequent to propofol administration, gene expressions of CD40 and TNF-α in mast cells, AIF1 in microglia and GFAP/S100B/OLIG2/MBP in macroglia were elevated, as well as NOS2, CD80, CD40, CD68, IL6 and TNF-α mediated proinflammation is noted in cerebral organoids, which resulted in higher expressions of GJB1, GABA-A and NMDAR1 in the tissue construct of the platform. Besides, midazolam administration stimulated expression of CD40 and CD203c+ reactivated mast cell proliferation and compromised BBB permeability and decreased TEER values with higher barrier disruption, whereas increased populations of CD11b+ microglia, higher expressions of GFAP/DLG4/GJB1 and GABA-A-/NMDAR1- identities, as well as glutamate related neurotoxicity and IL1B, IFNG, IFNA1, IL6 genes mediated proinflammation, resulting in increased apoptotic zones are observed in cerebral organoids. These results suggest that different sedatives cause variations in cell type activation that modulate different pathways related to neuroinflammation and neurotoxicity in the ICU patient-on-chip platform.
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Uncovering cell biology in the third dimension.
Developmental biology has long benefited from studies of classic model organisms. These model systems have provided the fundamental understanding of general principles of development, as well as insight into genes and signaling pathways that control unique aspects of cell fate specification and tissue morphogenesis. Because human brain development cannot be studied in vivo, scientists have relied on these model systems to study basic principles underlying the development of this complex organ as many of these genes and signaling pathways play conserved roles in human development. However, recent studies have shown species-specific signatures in neurodevelopment such as the transcriptome of outer-radial glia, suggesting use of a human-derived model remains imperative. Over the past decade, human stem cell-derived brain organoids have emerged as a biologically relevant model system to study normal human brain development and neurological diseases. Here, we provide a historical perspective of this emerging model system, discuss current systems and limitations, and propose that new mechanistic insight into cell biology can be revealed using these three-dimensional brain structures.
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Vesicular and synaptoplasmic synthesis of acetylcholine.
The synthesis and distribution of acetylcholine has been studied in the isolated synaptosome. Binding or contamination of [(14)C]acetylcholine in the synaptic vesicle fraction represents 1.5 percent of the total amount found in the synaptoplasm (synaptosomal cytoplasm). However, when the [(14)C]acetylcholine is derived solely by synthesis from labeled choline, then the labeled acetylcholine in the synaptic vesicle is 15 percent of the amount of acetylcholine synthesized in the synaptoplasm. The results suggest that the [(14)C]acetylcholine found in the vesicle fraction of synaptosomes incubated with labeled choline is due to vesicular synthesis.
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Peering into the mind: unraveling schizophrenia's secrets using models.
Schizophrenia (SCZ) is a complex mental disorder characterized by a range of symptoms, including positive and negative symptoms, as well as cognitive impairments. Despite the extensive research, the underlying neurobiology of SCZ remain elusive. To overcome this challenge, the use of diverse laboratory modeling techniques, encompassing cellular and animal models, and innovative approaches like induced pluripotent stem cell (iPSC)-derived neuronal cultures or brain organoids and genetically engineered animal models, has been crucial. Immortalized cellular models provide controlled environments for investigating the molecular and neurochemical pathways involved in neuronal function, while iPSCs and brain organoids, derived from patient-specific sources, offer significant advantage in translational research by facilitating direct comparisons of cellular phenotypes between patient-derived neurons and healthy-control neurons. Animal models can recapitulate the different psychopathological aspects that should be modeled, offering valuable insights into the neurobiology of SCZ. In addition, invertebrates' models are genetically tractable and offer a powerful approach to dissect the core genetic underpinnings of SCZ, while vertebrate models, especially mammals, with their more complex nervous systems and behavioral repertoire, provide a closer approximation of the human condition to study SCZ-related traits. This narrative review provides a comprehensive overview of the diverse modeling approaches, critically evaluating their strengths and limitations. By synthesizing knowledge from these models, this review offers a valuable source for researchers, clinicians, and stakeholders alike. Integrating findings across these different models may allow us to build a more holistic picture of SCZ pathophysiology, facilitating the exploration of new research avenues and informed decision-making for interventions.
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COVID and the brain: researchers zero in on how damage occurs.
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Next-Gen Stroke Models: The Promise of Assembloids and Organ-on-a-Chip Systems.
The complexity of stroke pathophysiology, involving intricate neurovascular interactions and dynamic cellular responses, has long challenged the development of effective preclinical models. Traditional 2D cultures and animal models often fail to fully recapitulate human-specific features, limiting translational success. Emerging 3D systems, particularly brain assembloids and organ-on-a-chip platforms, are offering new opportunities to create more physiologically relevant stroke models. Assembloids, which integrate multiple brain-region-specific organoids, enable the study of interregional connectivity and complex cellular responses under ischemic conditions. Organ-on-a-chip platforms, by mimicking key tissue interfaces such as the blood-brain barrier and incorporating controlled fluid dynamics, enable a dynamic and highly customizable microenvironment with real-time monitoring capabilities. This review introduces and characterizes these two cutting-edge platforms (assembloids and organ-on-chip technologies), exploring their potential in stroke research while also discussing current challenges that need to be addressed for their broader adoption in translational applications.
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From immunoneurology to immunopsychiatry: neuromodulating activity of anti-brain antibodies.