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The ultrastructure of rat conductive tissue; an electron microscopic study of the atrioventricular node and the bundle of His.
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Imposter syndrome?
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Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations.
OBJECTIVE: We utilized human midbrain-like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn- and Lewy body-related pathologies and the process of neurodegeneration in the hMLO model. METHODS: We generated and characterized hMLOs from GBA1-/- and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body-like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol-b-epoxide-treated SNCA triplication hMLOs. RESULTS: We identified for the first time that the loss of glucocerebrosidase, coupled with wild-type α-syn overexpression, results in a substantial accumulation of detergent-resistant, β-sheet-rich α-syn aggregates and Lewy body-like inclusions in hMLOs. These Lewy body-like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α-syn with ubiquitin, and can also be formed in Parkinson disease patient-derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body-like inclusions in hMLOs derived from patients carrying the SNCA triplication. INTERPRETATION: Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild-type α-syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490-505.
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Tanycytes in the medial habenular nucleus of the rat.
Tanycytes with foot processes contacting capillary basal membranes were identified in the rat medial habenular nucleus. They constitute a relatively small but constant population of cells among the conventional ependymal cells. In contrast to tanycytes in most circumventricular organs, habenular tanycytes possess cilia. Superimposed upon the cells are nerve fibers belonging to the serotonergic supraependymal axon plexus. Their ultrastructure differs in many respects from that of hypothalamic tanycytes.
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Ultrastructure of the pineal gland in the adult rat.
The ultrastructure of the rat pineal gland was studied from 75 days until 10 months of age. Type I pinealocytes of young adults showed nuclei with dispersed chromatin, numerous infoldings of the nuclear envelope and well developed nucleoli. The cytoplasm displayed many mitochondria and clusters of smooth endoplasmic reticulum. With increasing age, there was a clear increase in the number of dense bodies or lysosomes in the Type I pinealocyte. The changes in the Type II pinealocytes with age were mainly in nuclear shape and in the appearance of lipofuscin granules.
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[Ultrastructural characteristics of the specialized ependyma of the 3d cerebral ventricle in rats].
The ultrastructure of the specialized ependyma of the third cerebrals ventricle was studied in males of albino Wistar rats, 160--180 g of weight. The ependyma lining the inferolateral walls (alpha-tanycytes) was found to differ ultrastructurally from that of the floor of the third ventricle or of the median eminence (beta-tanycytes). These differences are assumed to reflect a specific functional differentiation of the different types of tanycytes. Various types of microvesicles and a system of peculiar membranous cavities are described in the alpha-and beta-tanycytes. These structures are supposed to be associated with the transport and secretory function of tanycytes.
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A dyad of human-specific NBPF14 and NOTCH2NLB orchestrates cortical progenitor abundance crucial for human neocortex expansion.
We determined the roles of two coevolved and coexpressed human-specific genes, NBPF14 and NOTCH2NLB, on the abundance of the cortical progenitors that underlie the evolutionary expansion of the neocortex, the seat of higher cognitive abilities in humans. Using automated microinjection into apical progenitors (APs) of embryonic mouse neocortex and electroporation of APs in chimpanzee cerebral organoids, we show that NBPF14 promotes the delamination of AP progeny, by promoting oblique cleavage plane orientation during AP division, leading to increased abundance of the key basal progenitor type, basal radial glia. In contrast, NOTCH2NLB promotes AP proliferation, leading to expansion of the AP pool. When expressed together, NBPF14 and NOTCH2NLB exert coordinated effects, resulting in expansion of basal progenitors while maintaining self-renewal of APs. Hence, these two human-specific genes orchestrate the behavior of APs, and the lineages of their progeny, in a manner essential for the evolutionary expansion of the human neocortex.
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Engineering functional ventral midbrain dopaminergic neurons in human organoids through WNT modulation and bioreactor culture.
Human midbrain organoids (hMOs) derived from induced pluripotent stem cells provide a powerful system to model disorders involving dopamine (DA) dysfunction, including Parkinson's disease (PD) and neuropsychiatric conditions. However, current differentiation protocols still fall short in recapitulating early specification, substantia nigra pars compacta (SNpc)-like identity, and the functional maturation of vulnerable DA neurons. Here, we established a differentiation strategy that combines tri-phasic WNT modulation with dynamic bioreactor culture to generate hMOs enriched in SNpc-like DA neurons. This approach significantly increases the yield of TH⁺/GIRK2⁺ and TH⁺/ALDH1A1⁺ DA neurons and promotes enhanced synaptic maturation, robust electrophysiological activity, and elevated DA release. Single-cell transcriptomics revealed that this strategy drives the emergence of SOX6+/GIRK2+ SNpc-like neurons, accompanied by upregulation of synaptic, metabolic, and maturation programs, alongside reduced cell stress and apoptotic signaling. Importantly, hMOs demonstrated vulnerability upon exposure to α-synuclein preformed fibrils, resulting in aggregate formation and DA neuron degeneration, supporting their use as a human model of PD-relevant pathology. Overall, this system provides a scalable and physiologically relevant approach to investigate molecular mechanisms underlying neurodegeneration and DA-related disorders.
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Calcium homeostasis in a clonal pituitary cell line of mouse corticotropes.
Calcium homeostasis was studied following a depolarization-induced transient increase in [Ca2+]i in single cells of the clonal pituitary cell line of corticotropes, AtT-20 cells. The KCl-induced increase in [Ca2+]i was blocked in (i) extracellular calcium-deficient solutions, (ii) external cobalt (2.0 mM), (iii) cadmium (200 microM), and (iv) nifedipine (2.0 microM). The mean increase in [Ca2+]i in single cells in the presence of an uncoupler of mitochondrial function [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, FCCP, 1 microM] was 54 +/- 13 nM (n = 9). The increase in [Ca2+]i produced by FCCP was greater either during or following a KCl-induced [Ca2+]i load. However, FCCP did not significantly alter the clearance of calcium during a KCl-induced rise in [Ca2+]i. Fifty percent of the cells responded to caffeine (10 mM) with an increase in [Ca2+]i (191 +/- 24 nM; n = 21) above resting levels; this effect was blocked by ryanodine (10 microM). Thapsigargin (2 microM) and 2,5 di(-t-butyl)-1,4 hydroquinone (BuBHQ, 10 microM) produced increases in [Ca2+]i (47 +/- 11 nM, n = 6 and 22 +/- 4 nM, n = 8, respectively) that increased cell excitability. These results support a role for mitochondria and sarco-endoplasmic reticulum calcium stores in cytosolic [Ca2+]i regulation; however, none of these organelles are primarily responsible for the return of [Ca2+]i to resting levels following this KCl-induced [Ca2+]i load.
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[Effect of exogenous somatotropin on the ultrastructure of somatotropic cells in hyperthyroid rats].
Marked ultrastructural changes indicating a decrease in the cell functional activity occur in the somatotropic cells of rats after chronic hyperthyroidism with 1-thyroxin. Exogenous somatotropin produces no effect on these ultrastructural changes.