Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 456
Страница 114 из 546-
Effects of acute low-moderate dose ionizing radiation to human brain organoids.
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. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses.
-
Modeling genetic epileptic encephalopathies using brain organoids.
Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain-containing oxidoreductase (WWOX) are associated with a relatively mild autosomal recessive spinocerebellar ataxia-12 (SCAR12) and a more severe early infantile WWOX-related epileptic encephalopathy (WOREE). In this study, we generated an in vitro model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR-engineered human ES cells and from patient-derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.
-
Proteomic dataset of MECP2-deficient and wild-type human brain organoids under spaceflight and ground conditions.
This dataset contains mass spectrometry-based proteomic profiles of human brain organoids cultured on Earth for 30 days, then maintained aboard the International Space Station (ISS) for an additional 30 days, with matched ground controls that remained on Earth for the equivalent duration. Brain organoids were derived from induced pluripotent stem cell (iPSC) lines: Q83X, carrying a nonsense mutation in MECP2 from a male patient with Rett syndrome, and WT83, derived from the patient's unaffected familial control. Rett syndrome is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in MECP2, which encodes Methyl-CpG-binding protein 2, a critical epigenetic regulator. The spaceflight experiment was conducted using cryovials with automated control maintenance. Deep proteome coverage with approximately 6,000 protein groups was inferred from 56,639 peptides. This dataset provides unique insights into how the space environment affects human neural tissue and MECP2-related pathologies, serving as a resource for understanding spaceflight-induced neurological changes and as a steppingstone for future space missions.
-
Compartmentalized Devices as Tools for Investigation of Human Brain Network Dynamics.
Neuropsychiatric disorders have traditionally been difficult to study due to the complexity of the human brain and limited availability of human tissue. Induced pluripotent stem (iPS) cells provide a promising avenue to further our understanding of human disease mechanisms, but traditional 2D cell cultures can only provide a limited view of the neural circuits. To better model complex brain neurocircuitry, compartmentalized culturing systems and 3D organoids have been developed. Early compartmentalized devices demonstrated how neuronal cell bodies can be isolated both physically and chemically from neurites. Soft lithographic approaches have advanced this approach and offer the tools to construct novel model platforms, enabling circuit-level studies of disease, which can accelerate mechanistic studies and drug candidate screening. In this review, we describe some of the common technologies used to develop such systems and discuss how these lithographic techniques have been used to advance our understanding of neuropsychiatric disease. Finally, we address other in vitro model platforms such as 3D culture systems and organoids and compare these models with compartmentalized models. We ask important questions regarding how we can further harness iPS cells in these engineered culture systems for the development of improved in vitro models. Developmental Dynamics 248:65-77, 2019. © 2018 Wiley Periodicals, Inc.
-
Changes in amount of colchicine-binding protein (tubulin) in rabbit brain during development.
-
Probing human brain evolution and development in organoids.
Expansion of the neocortex is thought to underpin the higher cognitive abilities of a number of mammalian lineages, such as cetaceans, elephants, and primates, with humans exhibiting a particularly enlarged and dense cerebral cortex. However, the evolutionary and developmental mechanisms that led to this expansion are not well-understood and limited to correlative observations. Historically, this has been due to technical and ethical limitations owing to the intractability of various species for functional studies. Nonetheless, comparative neuroanatomical observations have revealed probable cell-biological mechanisms that may have driven reorganization of neocortical architecture and cortical expansion. Furthermore, new in vitro neural differentiation technologies are allowing, for the first time, functional studies to test existing hypotheses and identify new mechanisms. Here, we introduce three-dimensional neural organoids as a powerful new tool for these types of evolutionary-neurodevelopmental studies.
-
The ethical and legal challenges of human foetal brain tissue-derived organoids : At the intersection of science, ethics, and regulation.
The recent generation of brain organoids from human foetal tissue highlights the need for nuanced ethical considerations and international coordination to navigate the complexities of this research and its broader implications for developmental neuroscience and ethical debates. [Image: see text]
-
Super resolution microscopy and deep learning identify Zika virus reorganization of the endoplasmic reticulum.
The endoplasmic reticulum (ER) is a complex subcellular organelle composed of diverse structures such as tubules, sheets and tubular matrices. Flaviviruses such as Zika virus (ZIKV) induce reorganization of ER membranes to facilitate viral replication. Here, using 3D super resolution microscopy, ZIKV infection is shown to induce the formation of dense tubular matrices associated with viral replication in the central ER. Viral non-structural proteins NS4B and NS2B associate with replication complexes within the ZIKV-induced tubular matrix and exhibit distinct ER distributions outside this central ER region. Deep neural networks trained to distinguish ZIKV-infected versus mock-infected cells successfully identified ZIKV-induced central ER tubular matrices as a determinant of viral infection. Super resolution microscopy and deep learning are therefore able to identify and localize morphological features of the ER and allow for better understanding of how ER morphology changes due to viral infection.
-
Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids.
The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.
-
Human coronavirus OC43 infection in human cerebral organoids: novel insights on pathogenesis and potential therapeutic interventions.
BACKGROUND: Since the COVID-19 pandemic, there has been a documented rise in the incidence of neurological manifestations among individuals complicated with encephalitis or myelitis. The spectrum of neurological symptoms associated with HCoVs infections is expanding. However, the infection characteristics and pathogenesis of seasonal HCoVs to the central nervous system remain obscure. No pharmacological agents have demonstrated the capacity to specifically and efficaciously mitigate the neurological symptoms induced by HCoVs infections to date. METHODS: We developed human cerebral organoids (HCOs) derived from human induced pluripotent stem cells and established a blood-brain barrier (BBB) HCOs co-culture model. We subjected these models to seasonal human coronavirus (HCoV) infections to investigate the viral characteristics within the central nervous system (CNS). Utilizing RNA sequencing, we conducted a preliminary exploration of the mechanisms underlying virus-induced inflammatory responses in the CNS. Furthermore, we assessed the efficacy of antiviral and anti-inflammatory drugs using the HCO model. RESULTS: Our results showed that among seasonal coronaviruses, HCoV-OC43 replicates efficiently within the organoids, primarily targeting neurons and astrocytes, and disrupts the barrier function of the BBB. RNA sequencing analysis revealed that HCoV-OC43 infection triggers an inflammatory response through the TNF and NF-κB signaling pathways, leading to cell death, impaired neuronal function, and disrupted interneuron signaling. Interestingly, Bardoxolone methyl (CDDO-Me) demonstrated antiviral effects comparable to remdesivir, reducing both inflammation and cell death. CONCLUSIONS: Conclusively, HCOs infected with HCoV-OC43 offer valuable insights into the pathogenesis of HCoVs in central nervous system (CNS), and might serve as a tool for developing novel therapeutic strategies for HCoVs infections, including COVID-19, especially on exploring treatment candidates.