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Nerve-ending specializations in the central ganglia of Planorbis corneus.
The neuropile in the central ganglia of Planorbis corneus was studied by electron microscopy, using different fixatives. Several types of specialization were observed in the membranes of adjacent axonal processes, varying from only slight membrane thickenings to structures resembling desmosomes. Specialized structures similar to the 'spinule complexes' in mammalian brain are widely distributed in certain areas of neuropile. They consist of a small projection which invaginates a neighbouring neurone; the membranes are closely apposed and there is associated electron-dense material. The problem of identifying chemical synapses in this tissue is discussed. Many axonal processes are varicose, and it is suggested that varicosities may also be sites of transmitter release.
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Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids.
Mutations in N-glycanase 1 (NGLY1), which deglycosylates misfolded glycoproteins for degradation, can cause NGLY1 deficiency in patients and their abnormal fetal development in multiple organs, including microcephaly and other neurological disorders. Using cerebral organoids (COs) developed from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), we investigate how NGLY1 dysfunction disturbs early brain development. While NGLY1 loss had limited impact on the undifferentiated cells, COs developed from NGLY1-deficient hESCs showed defective formation of SATB2-positive upper-layer neurons, and attenuation of STAT3 and HES1 signaling critical for sustaining radial glia. Bulk and single-cell transcriptomic analysis revealed premature neuronal differentiation accompanied by downregulation of secreted and transcription factors, including TTR, IGFBP2, and ID4 in NGLY1-deficient COs. NGLY1 malfunction also dysregulated ID4 and enhanced neuronal differentiation in CO transplants developed in vivo. NGLY1-deficient CO cells were more vulnerable to multiple stressors; treating the deficient cells with recombinant TTR reduced their susceptibility to stress from proteasome inactivation, likely through LRP2-mediated activation of MAPK signaling. Expressing NGLY1 led to IGFBP2 and ID4 upregulation in CO cells developed from NGLY1-deficiency patient's hiPSCs. In addition, treatment with recombinant IGFBP2 enhanced ID4 expression, STAT3 signaling, and proliferation of NGLY1-deficient CO cells. Overall, our discoveries suggest that dysregulation of stress responses and neural precursor differentiation underlies the brain abnormalities observed in NGLY1-deficient individuals.
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Liver organoids in domestic animals: an expected promise for metabolic studies.
The liver is one of the most important organs, both in terms of the different metabolic processes (energy, lipid, ferric, uric, etc.) and of its central role in the processes of detoxification of substances of food origin or noxious substances (alcohol, drugs, antibiotics, etc.). The development of a relevant model that reproduces some of the functions of this tissue has become a challenge, in particular for human medicine. Thus, in recent years, most studies aimed at producing hepatocytes in vitro with the goal of developing hepatic 3D structures have been carried out in the human model. However, the tools and protocols developed using this unique model can also be considered to address physiological questions specific to this tissue in other species, such as the pig, chicken, and duck. Different strategies are presently being considered to carry out in vitro studies of the hepatic metabolism of these agronomic species.
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Molecular mechanisms of neurotransmitter storage and release: a comparison of the adrenergic and cholinergic systems.
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[The ultrastructure of a strain of rat ependymoblastoma subjected to long-term passage].
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oFlowSeq: a quantitative approach to identify protein coding mutations affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids.
Cerebral organoids are comprised of diverse cell types found in the developing human brain, and can be leveraged in the identification of critical cell types perturbed by genetic risk variants in common, neuropsychiatric disorders. There is great interest in developing high-throughput technologies to associate genetic variants with cell types. Here, we describe a high-throughput, quantitative approach (oFlowSeq) by utilizing CRISPR-Cas9, FACS sorting, and next-generation sequencing. Using oFlowSeq, we found that deleterious mutations in autism-associated gene KCTD13 resulted in increased proportions of Nestin+ cells and decreased proportions of TRA-1-60+ cells within mosaic cerebral organoids. We further identified that a locus-wide CRISPR-Cas9 survey of another 18 genes in the 16p11.2 locus resulted in most genes with > 2% maximum editing efficiencies for short and long indels, suggesting a high feasibility for an unbiased, locus-wide experiment using oFlowSeq. Our approach presents a novel method to identify genotype-to-cell type imbalances in an unbiased, high-throughput, quantitative manner.
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Extracerebral leptomeningeal astrocytoma mimicking a meningioma.
A 49-year-old woman with a two-year history of headaches that became progressively more frequent was found on computerized tomographic scan to have a dense, enhancing right frontoparietal mass. The tumor mimicked a meningioma in that it indented the inner table of the skull, was well demarcated from the underlying brain, and microscopically lacked the fibrillated cell processes and background that characterize astrocytomas. The 80- to 100-A cytofilaments were sparse and seen in few cells. It was only by the immunoperoxidase stain for glial acidic protein that the diagnosis of an extra-axial leptomeningeal astrocytoma was established.
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Precipitation of proteins by vinblastine and calcium ions.
We have found that vinblastine sulfate can precipitate a number of proteins in addition to microtubule protein. Those proteins which precipitate with vinblastine sulfate, all of which were derived from structure, also precipitate with Ca(2+) ions. Our results suggest that vinblastine sulfate, presumably acting as a cation, precipitates proteins by combining with sites which can also combine with Ca(2+) ions.
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Organoids in gastrointestinal diseases: from experimental models to clinical translation.
We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
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From Bench to Motion: Unraveling Exercise Biology Through 3D Human Organoids.
Despite extensive research, the systemic biological mechanisms underlying exercise-induced physiological adaptations remain incompletely understood. While animal models (e.g., rodents, non-human primates) have been instrumental in elucidating exercise-mediated benefits in aging and disease, interspecies differences in genomics, epigenetics, and metabolic regulation limit their translational relevance. The advent of induced pluripotent stem cell (iPSC)-derived 3D organoids revolutionizes exercise biology research by enabling human-specific modeling of tissue architecture and donor genomic/epigenetic profiles. This review highlights three transformative strategies: (1) Athlete-derived organoids preserving exercise-induced epigenetic memory to study muscle/neural adaptations; (2) Engineered systems integrating optogenetics and microfluidics to simulate mechanical forces (e.g., muscle contraction) and systemic signals (e.g., cytokines); (3) multi-omics mapping revealing exercise-responsive pathways like mitochondrial biogenesis. Collectively, these patient-specific models bridge pathophysiology with high-throughput screening, advancing precision medicine-from personalized training regimens to therapies counteracting sedentary-related diseases.