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The centriolar complex isolated from starfish spermatozoa.
Centrioles from spermatozoa of the starfish, Asterina pectinifera, were isolated and partially purified by solubilization of chromatin followed by sucrose density-gradient centrifugation. The ultrastructure of the isolated centriolar complex was investigated in whole mount preparations by electron microscopy. The complex unit was composed of a pair of centrioles and a pericentriolar structure, which associated with the distal end of the distal centriole by 9 spoke-like satellites extending radially to a marginal ring. Each satellite bifurcated at a dense node forming 2 fan-like shapes with a periodic striated pattern. The tubular structure of the centrioles easily disintegrated, leaving the pericentriolar structure or axonemal microtubules intact. The distal centriole in a spermatozoon served as an initiating site for flagellar microtubule assembly; that is, a number of "9 + 2' axonemal tubules were observed adhering just beneath the distal end of the basal body. In experiments in vitro, polymerization of microtubule proteins purified from porcine brain was initiated by the structure at the ends of both proximal and distal centrioles, but not from the satellites or the marginal ring. Also, few if any microtubules were formed from the sides of each centriole, even in the presence of a high concentration of exogenous tubulin. On the other hand, centrioles of spermatozoa, when they were in mature ooplasm, could initiate the formation of sperm asters by microtubules. Therefore, centrioles in spermatozoa seem to be able to initiate microtubules in a 2 ways. A possible explanation of the difference between the 2 types of microtubule organization in vivo, i.e. in the sperm cell itself and in the ooplasm, it discussed.
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A Novel Acetylcholine Nanosensor for Single Vesicle Storage and Sub-Quantal Exocytosis in Living Neurons and Organoids.
Acetylcholine (ACh) is a critical neurotransmitter that regulates diverse physiological functions, such as cognition and muscle contraction, through synaptic transmission. However, in situ quantitative chemical analysis of single-vesicle storage and release dynamics at single-cell level remains a major technical challenge, hindering mechanistic understanding of cholinergic synaptic plasticity across physiological and pathological states. To address this, we developed an Ti3C2Tx MXene/enzyme-functionalized (M@E@CF) nanosensor, enabling real-time monitoring of vesicular ACh storage and exocytotic release in primary cholinergic neurons and human spinal cord organoids. Our findings reveal a sub-quantal release mode in both mouse and human-derived neurons. To further elucidate the regulatory principles of exocytosis kinetics, we classified single-vesicle exocytosis patterns based on signal peak shapes using a 1D convolutional neural network (1D-CNN) deep learning model, uncovering significant differences in the number of released molecules and kinetic parameters across modes. Critically, in Down syndrome models, we observed significantly reduced single vesicle ACh storage and release alongside an elevated release fraction, concurrent with shortened fusion pore durations during exocytosis. Thus, the M@E@CF nanosensor platform establishes a versatile tool for spatiotemporal investigation of neurotransmitter storage and release dynamics, providing a critical technical foundation for exploring physiological functions and pathological mechanisms of the cholinergic system.
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A nomenclature consensus for nervous system organoids and assembloids.
Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.
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Calcium accumulation in intracellular compartments of frog retinal rod photoreceptors.
The accumulation of calcium in the rod cells of isolated frog retinas was studied by methods involving the pretreatment of tissue with saponin, which reduces the permeability barrier posed by the plasma membrane, and the inclusion of a Ca2+ trapping agent, oxalate, in incubation media. X-ray microanalysis using an analytical transmission electron microscope was employed to verify the presence of calcium in the deposits produced by these methods. Ca2+ was found to accumulate in the rough endoplasmic reticulum (ER) and the agranular reticulum of the myoid region and in the presynaptic terminals of the rods. At least one aspect of this accumulation appears to depend upon the presence of ATP.
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A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling.
Failure of neural tube closure during embryonic development can result in anencephaly, one of the most common birth defects in humans. A family with recurrent anencephalic fetuses was investigated to understand its etiology and pathogenesis. Exome sequencing revealed a recessive germline 21-bp in-frame deletion in NUAK2 segregating with the disease. In vitro kinase assays demonstrated that the 7-amino acid truncation in NUAK2, a serine/threonine kinase, completely abrogated its catalytic activity. Patient-derived disease models including neural progenitor cells and cerebral organoids showed that loss of NUAK2 activity led to decreased Hippo signaling via cytoplasmic YAP retention. In neural tube-like structures, endogenous NUAK2 colocalized apically with the actomyosin network, which was disrupted in patient cells, causing impaired nucleokinesis and apical constriction. Our results establish NUAK2 as an indispensable kinase for brain development in humans and suggest that a NUAK2-Hippo signaling axis regulates cytoskeletal processes that govern cell shape during neural tube closure.
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Ultrastructure of a new microtubule-neurofilament coupler in nerves.
A new structure associated with the surfaces of neuronal microtubules is described which connects microtubules to neurofilaments in the axonal processes of cultured chick sensory ganglia. These couplers consist of a spherical core particle (15 nm in diameter) from which radiate several thin filaments (4 nm in diameter). Connection of adjacent microtubules and neurofilaments is achieved by thin filaments radiating from core particles positioned between these cytoskeletal elements. Couplers are most conspicuous in regions of axonal processes containing widely separated microtubules and neurofilaments. The structure and distribution of these couplers suggests that they are directly involved in intra-axonal organelle movements, possibly by modulating the spatial separation of adjacent microtubules and neurofilaments, thereby allowing the passage of transported organelles.
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Biofabrication of neural microphysiological systems using magnetic spheroid bioprinting.
The high attrition rate of neuro-pharmaceuticals as they proceed to market necessitates the development of clinically-relevant in vitro neural microphysiological systems that can be utilized during the preclinical screening phase to assess the safety and efficacy of potential compounds. Historically, proposed models have adhered to two distinct approaches; those that are biologically relevant (e.g.-organoids, spheroids) or those that provide engineering control (e.g.-bioprinting, microfluidics). Separately, these approaches fail to fully recapitulate the complex hierarchical structure of the nervous system, limiting their clinical applications. Furthermore, the reliance on manual implementation present in many models fails to effectively scale up or satisfy the consistency standards required for widespread industry adoption. This work serves as a proof-of-concept for merging the two approaches to create a neural microphysiological system that overcomes their individual limitations. Spinal cord spheroids, fabricated using magnetic nanoparticles, are positioned in a three-dimensional hydrogel construct using magnetic bioprinting. Resulting constructs demonstrate both localized cell-cell interactions and long-distance projections that mimic in vivo structure. The use of magnetic nanoparticles for spheroid formation provides batch-to-batch consistency in size and shape and reduces the reliance on trained experimenters for accurate placing for culture. Taken together, this combination approach provides the first steps towards developing a simple approach for integrating spheroid, hydrogel culture, and bioprinting as an alternative to more specialized and expensive processes.
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Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer's Disease.
Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer's disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies.
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iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder.
Bipolar disorder (BD) is increasingly recognized as a disease with both mitochondrial dysfunction and heightened inflammatory reactivity, yet contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a more physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. The effect of a Bioactive Flavonoid Extract (BFE), a potential therapeutic, was also explored and yielded a partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.
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High-throughput dissection of inter-organ genetic networks: A multi-omic systems biology approach.
The existing multi-omic analyses are frequently confined to individual tissues, and the regulatory picture of the systemic regulator of complex physiology and disease is hidden. To fill this gap, we have created a unified systems biology model of the high-throughput dissection of inter-organ genetic networks. Our model incorporates transcriptomic, epigenomic and proteomic analysis of five major organs (liver, kidney, heart, lung, brain) using the Multi-Omics Factor Analysis (MOFA+) tool, specifically, cross-tissue coordination. We characterized 27 evidence-heavy cross-tissue modules (FDR < 0.05) that are major hubs such as *HNF4Aenda NRF2cheng8loadmasterregulatingconstitutionembryonicstemcellularinfoncogenes recognize them. One notable observation was liver-kidney metabolic axis, significant cross-talks in hepatocyte organoids are confirmed with CRISPR knockdown, which suppresses the expression of transporters expressed by the kidney. Our work offers a scalable validated framework that goes beyond organ-centric perspectives, which can be used as a potent tool of systemic disease modelling and precision medicine.