Publications by authors named "Alysson Muotri"

Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple hiPSC lines.

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The brain integrates activity across networks of interconnected neurons to generate behavioral outputs. Several physiological and imaging-based approaches have been previously used to monitor responses of individual neurons. While these techniques can identify cellular responses greater than the neuron's action potential threshold, less is known about the events that are smaller than this threshold or are localized to subcellular compartments.

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Adenosine deaminases acting on RNA (ADARs) impact diverse cellular processes and pathological conditions, but their functions in early cell-fate specification remain less understood. To gain insights here, we began by charting time-course RNA editing profiles in human organs from fetal to adult stages. Next, we utilized hPSC differentiation to experimentally probe ADARs, harnessing brain organoids as neural specific, and teratomas as pan-tissue developmental models.

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Single-cell proteomics has emerged as a powerful technology for unraveling the complexities of cellular heterogeneity, enabling insights into individual cell functions and pathologies. One of the primary challenges in single-cell proteomics is data generation, where low mass spectral signals often preclude the triggering of MS2 events. This challenge is addressed by Data Independent Acquisition (DIA), a data acquisition strategy that does not depend on peptide ion isotopic signatures to generate an MS2 event.

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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.

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Article Synopsis
  • Microglia, although typically known for their immune functions in the central nervous system, also play crucial roles in brain development that are not yet fully understood, especially in humans.
  • Researchers used human microglia-like cells with a deleted MECP2 gene to study its impact, discovering that this disruption led to significant issues in cell functions like phagocytosis and synapse formation.
  • A drug called ADH-503 was found to enhance phagocytosis and restore normal synapse formation, offering potential new treatment options for conditions linked to MECP2 abnormalities in mice.
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To support complex cognition, neuronal circuits must integrate information across multiple temporal scales, ranging from milliseconds to decades. Neuronal timescales describe the duration over which activity within a network persists, posing a putative explanatory mechanism for how information might be integrated over multiple temporal scales. Little is known about how timescales develop in human neural circuits or other model systems, limiting insight into how the functional dynamics necessary for cognition emerge.

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Article Synopsis
  • VAPB is an ER membrane protein linked to familial ALS, specifically the mutation VAPB P56S, the exact mechanism of how it causes motor neuron disease is unclear.
  • In studies using iPSC-derived motor neurons, VAPB P56S was found to reduce neuronal firing, mitochondrial-ER contact, and caused aging-related drops in mitochondrial function while increasing sensitivity to ER stress.
  • Elevated levels of ATF4, a stress response marker, and reduced protein synthesis were observed in VAPB P56S neurons, with inhibition of the Integrated Stress Response (ISR) using ISRIB improving ALS symptoms, suggesting ISR as a therapeutic target.
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Background: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.

Methods: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject).

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Temporal development of neural electrophysiology follows genetic programming, similar to cellular maturation and organization during development. The emergent properties of this electrophysiological development, namely neural oscillations, can be used to characterize brain development. Recently, we utilized the innate programming encoded in the human genome to generate functionally mature cortical organoids.

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The CRISPR-Cas9 technology has the potential to revolutionize the treatment of various diseases, including Rett syndrome, by enabling the correction of genes or mutations in human patient cells. However, several challenges need to be addressed before its widespread clinical application. These challenges include the low delivery efficiencies to target cells, the actual efficiency of the genome-editing process, and the precision with which the CRISPR-Cas system operates.

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Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice.

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Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26-28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in WS.

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Three Prime Repair Exonuclease 1 (TREX1) gene mutations have been associated with Aicardi-Goutières Syndrome (AGS) - a rare, severe pediatric autoimmune disorder that primarily affects the brain and has a poorly understood etiology. Microglia are brain-resident macrophages indispensable for brain development and implicated in multiple neuroinflammatory diseases. However, the role of TREX1 - a DNase that cleaves cytosolic nucleic acids, preventing viral- and autoimmune-related inflammatory responses - in microglia biology remains to be elucidated.

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The complexity of the human brain creates a spectrum of sophisticated behavioral repertoires, such as language, tool use, self-awareness, symbolic thought, cultural learning, and consciousness. Understanding how the human brain achieves that has been a longstanding challenge for neuroscientists and may bring insights into the evolution of human cognition and disease states. Human pluripotent stem cells could differentiate into specialized cell types and tissues in vitro.

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Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue.

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Article Synopsis
  • The human brain is an incredibly efficient computing system, operating on just 20 watts of power, and is unmatched in processing information and learning.
  • Recent advancements in stem cell technology have led to the creation of three-dimensional brain organoids that better mimic human brain functions, paving the way for Organoid Intelligence (OI).
  • The first Organoid Intelligence Workshop at Johns Hopkins University aimed to foster a community focused on establishing OI as a new discipline, exploring its potential to revolutionize fields like computing, neuroscience, and drug development.
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Pinson . () concluded that the modern human gene is responsible for an increased number of cortical neurons. We show that the "putative Neanderthal variant" of is present in modern human backgrounds.

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LINE-1 (L1) elements are a class of transposons, comprising approximately 19% and 21% of the mouse and human genomes, respectively. L1 retrotransposons can reverse transcribe their own RNA sequence into a de novo DNA copy integrated into a new genomic location. This activity, known as retrotransposition, may induce genomic alterations, such as insertions and deletions.

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The new science called aims to identify the dynamic patterns that endow living systems with the capacity to feel and become conscious. One of the most promising fields of investigation in is the development and 'education' of human brain organoids to become sentient and useful for the promotion of human health in the (also new) field of Regenerative Neuromedicine. Here, we discuss the type of informational-rich input necessary to make a brain organoid sentient in experimental settings.

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The rapidly evolving stem cell field puts much stress on developing educational resources. The ISSCR Education Committee has created a flexible stem cell syllabus rooted in core concepts to facilitate stem cell literacy. The free syllabus will be updated regularly to maintain accuracy and relevance.

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Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice.

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