Publications by authors named "Gareth J Sullivan"
Article Synopsis
- * Key findings reveal that expression of aquaporins (AQP8 and AQP9) increases during cell differentiation, but AQP8 protein levels decrease post-hypoxia despite increased mRNA levels after reoxygenation.
- * The research indicates that post-transcriptional mechanisms, rather than transcription changes, lead to reduced AQP8 protein concentration after hypoxia and reoxygenation events in liver cells.
Article Synopsis
- Mitochondrial diseases cause neuronal death and depletion of mitochondrial DNA (mtDNA), with astrocytes potentially playing a damaging role in neurodegeneration.
- Research using induced pluripotent stem cells (iPSCs) from patients with POLG mutations showed that the resulting astrocytes experienced significant mitochondrial dysfunction and developed a toxic phenotype.
- When these dysfunctioning astrocytes interacted with neurons, they induced neuronal death, highlighting a novel toxic contribution of astrocytes to the progression of POLG-related diseases.
Article Synopsis
- Recent research indicates that physical abnormalities within tumors, such as higher stiffness and fluid pressure, can contribute to tumor growth and development.
- These mechanical forces can influence cellular metabolism through pathways that sense and respond to physical changes, particularly involving mitochondria, which are key for energy production and adaptation to stress.
- The relationship between the mechanical properties of cancer cells and mitochondrial function is still not well understood, but recent studies suggest that understanding this connection could reveal how mitochondria may influence tumor formation.
Article Synopsis
- The study focuses on using parenteral nutrition (PN) for premature newborns, who are at risk for liver disease associated with PN, and aims to develop predictive models for this condition.
- Researchers utilized liver organoids derived from induced pluripotent stem cells to simulate the liver environment and assess the effects of different lipid treatments used in PN.
- Results indicated that both lipid treatments led to lipid accumulation in liver cells and decreased liver function markers, suggesting that liver organoids could serve as a useful platform for testing new, less harmful PN solutions.
Article Synopsis
- A 3D brain organoid model is created to investigate POLG-related encephalopathy, a mitochondrial disease caused by POLG mutations, using patient-derived induced pluripotent stem cells (iPSCs).
- The generated cortical organoids display key disease features like abnormal structure, neuron loss, and depleted mitochondrial DNA, along with changes in critical neuronal development pathways and increased NOTCH and JAK-STAT signaling.
- Metformin treatment improved several issues found in the organoids, but did not resolve problems with inhibitory dopamine-glutamate neurons, making this model a useful tool for studying POLG disorders and related diseases linked to mitochondrial dysfunction.
Article Synopsis
- Alpers' syndrome is a severe neurodegenerative disorder often caused by mutations in the POLG gene, leading to issues like intractable epilepsy and developmental regression, with no current effective treatments.
- Researchers created patient-specific induced pluripotent stem cells (iPSCs) from an Alpers' patient to study neural dysfunction and observed that organoids replicated key molecular changes seen in actual patient brain tissue.
- The study found that the NAD precursor nicotinamide riboside (NR) improved mitochondrial function, suggesting it could be a potential treatment for Alpers' syndrome and other similar mitochondrial disorders.*
Article Synopsis
- The OXR1 gene plays a crucial role in various biological processes, and mutations in this gene have been linked to conditions like cerebellar atrophy and epilepsy in affected patients.
- A novel mutation in OXR1 has been identified, leading to severe developmental issues, including cognitive disabilities and sensitivity to oxidative stress, which can be partially rescued by replacing the affected domain.
- The study highlights the importance of OXR1 in regulating gene expression during neurodevelopment and its potential role in spatial-temporal histone arginine methylation in the brain.
Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and biomedicine. Notably, it has become clear that liver function can only be sustained in 3D culture systems at physiologically relevant cell densities. Additionally, drug metabolism and drug-induced cellular toxicity often follow distinct spatial micropatterns of the metabolic zones in the liver acinus, calling for models that capture this zonation.
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- The development of organoid models, especially for the liver, addresses the limitations of traditional 2D cell culture by creating more physiologically relevant systems that better mimic native tissue.
- The new approach eliminates the need for 2D patterning and extracellular matrices, using small molecules to replicate embryonic liver development, resulting in liver-like organoids with complex cellular structures.
- These liver organoids demonstrate critical functions such as drug metabolism and protein production, and can be transplanted into mice, maintaining their functionality and offering potential for applications in therapy, drug testing, and disease modeling.
Article Synopsis
- Mutations in the POLG gene lead to mitochondrial diseases by disrupting the maintenance of mitochondrial DNA (mtDNA), yet effective treatments are lacking.
- The study examined neural stem cells derived from POLG patients and found that while mtDNA depletion occurred similarly in all cells, recovery was slower in cells with compound heterozygous mutations.
- Supplementing with deoxyribonucleosides (dNs) improved mtDNA recovery in patient cells, suggesting that dNs might be a promising therapeutic approach for mitochondrial diseases linked to POLG mutations.
Article Synopsis
- Increased electromagnetic radiation has raised health concerns, but the biological effects of magnetic fields are still not well understood.
- Research aimed at identifying how these fields affect cellular functions is ongoing, yet results are often conflicting.
- In this study, we tested whether HeLa cells' autofluorescence is sensitive to magnetic fields but found no evidence of such sensitivity, suggesting that new approaches are necessary to explore cellular responses to magnetic fields.
Article Synopsis
- Aagenaes syndrome is an autosomal recessive condition that includes symptoms like neonatal cholestasis, lymphedema, and giant cell hepatitis, with its genetic cause previously unknown.
- Researchers studied 26 patients and their parents using techniques like whole-genome sequencing and CRISPR to pinpoint genetic variants affecting the disease.
- The study identified a specific variant (c.-98G>T) in the UNC45A gene present in all patients, indicating it as the genetic cause of Aagenaes syndrome, and showed reduced expression of the UNC45A protein in affected individuals.
Article Synopsis
- * Using an induced pluripotent stem cell (iPSC) model, researchers discovered that compound heterozygous neural stem cells (NSCs) showed greater mitochondrial dysfunction than homozygous NSCs, indicated by issues like reduced ATP production and increased levels of reactive oxygen species (ROS).
- * The study's findings highlight significant downregulation of key metabolic pathways in compound heterozygous NSCs, suggesting this iPSC model could aid in better understanding the relationship between genotypes and disease phenotypes in mitochondrial disorders, potentially
Article Synopsis
- - The bleeding problems in hereditary coagulation disorders stem from low or absent activity of hemostasis proteins due to genetic changes, with most of these factors produced in the liver.
- - Current models using human or animal cells fail to accurately replicate the liver's biology and the specific genetic background of patients, limiting research on these disorders.
- - Induced Pluripotent Stem Cell (iPSC) technology, combined with CRISPR/Cas9, allows for the creation of patient-specific liver organoids, providing a more accurate platform for studying coagulation proteins and developing potential therapies for these inherited disorders.
Article Synopsis
- Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) differ in origin, with ESCs coming from pre-implanted embryos and iPSCs being reprogrammed from somatic cells, but both are crucial for studying human neurological development.
- The research compares mitochondrial function and mitochondrial DNA (mtDNA) in ESCs and iPSCs across three developmental stages: pluripotent, neural progenitor, and astrocyte, revealing key differences in mitochondrial activity during differentiation.
- Findings indicate that while ESCs and iPSCs are similar at the pluripotent stage, iPSC-derived neural stem cells have lower ATP production than ESC-derived counterparts, whereas iPSC-derived astrocy
Article Synopsis
- * To find non-surgical treatments, it's crucial to understand the cellular and molecular processes behind this calcification, and various imaging techniques like echocardiography and MRI are used for evaluation.
- * The overview discusses cell culture models for research, emphasizing that while animal models exist, they don't fully mimic human conditions; also, it touches on additional techniques related to aortic valve calcification, such as identifying biomarkers.
Article Synopsis
- Mutations in mitochondrial genes result in significant alterations in mitochondrial functions, affecting neural stem cells (NSCs) and their differentiation into neurons and astrocytes.
- In research comparing POLG-mutated and control stem cells, it was found that while overall mitochondrial changes were similar, key processes like mtDNA replication and mitochondrial respiratory chain complex I did not function properly in the mutated cells.
- Specifically, the study noted that POLG mutations hindered the expected increases in mitochondrial membrane potential and ATP production during the differentiation of neuronal cells, while astrocyte differentiation remained unaffected, indicating a complex relationship between mutations and mitochondrial remodeling in early neural development.
Early events during development leading to exit from a pluripotent state and commitment toward a specific germ layer still need in-depth understanding. Autophagy has been shown to play a crucial role in both development and differentiation. This study employs human embryonic and induced pluripotent stem cells to understand the early events of lineage commitment with respect to the role of autophagy in this process.
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- The study focuses on the regulation of self-renewal and differentiation in stem cells, emphasizing the importance of mitochondrial remodeling and metabolic shifts between glycolysis and oxidative phosphorylation (OXPHOS) in maintaining stem cell properties.
- It suggests that the metabolic switch from glycolysis to OXPHOS is specific to different germ layers, with glycolysis remaining active in early ectoderm commitment, but decreasing when transitioning to mesoderm and endoderm lineages.
- The researchers found that while mitochondrial activity and ATP-linked respiration increase during the differentiation of human pluripotent stem cells into cardiac cells, mitochondrial content actually decreases, challenging the assumption that more OXPHOS activity corresponds with greater mitochondrial quantity.
Article Synopsis
- - Mitophagy is crucial for removing damaged mitochondria to ensure proper brain function, and its impairment is linked to neurodegenerative diseases related to mutations.
- - In a study with astrocytes derived from iPSCs, researchers found gene downregulation related to mitophagy, confirming reduced autophagosome formation and various protein level changes under stress, all regulated by specific cellular pathways.
- - Treatment with nicotinamide riboside (NR) and metformin showed promise in correcting mitophagy defects and mitochondrial dysfunction in astrocytes with POLG mutations, highlighting potential therapies for these mitochondrial diseases.
Article Synopsis
- * The understanding of DILI's mechanisms is limited, primarily due to discrepancies between animal and human responses in drug testing and the absence of accurate models that mirror human liver conditions.
- * This Consensus Statement outlines the need for more realistic human-based systems for hepatotoxicity assessment and discusses recent advancements in research methods that may enhance our ability to predict drug safety and liver injury outcomes.
Article Synopsis
- Induced pluripotent stem cells (iPSCs) can be differentiated into various liver cell types, providing a unique opportunity to study liver development, toxicity, and diseases with patient-specific contexts, overcoming limitations imposed by the availability of primary tissues.
- Current research focuses on 3D or organotypic differentiation of iPSCs, creating more realistic models that mimic liver tissue architecture and cell interactions, which could potentially replace animal models in clinical settings.
- A variety of liver organoid models exist, from simple single-cell structures to complex systems that include multiple cell types, enhancing functionality for drug metabolism and disease studies; however, more advanced organotypic models are needed for better disease modeling and therapeutic development.
Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes.
View Article and Find Full Text PDFBrain organoids closely recapitulate many features and characteristics of brain tissue. This technology in turn allows unprecedented possibilities to investigate brain development and function in the dish. Several brain organoid protocols have been established, and the studies have focused on validating the architecture, cellular composition, and function of the organoids.
View Article and Find Full Text PDFThe inability to reliably replicate mitochondrial DNA (mtDNA) by mitochondrial DNA polymerase gamma (POLG) leads to a subset of common mitochondrial diseases associated with neuronal death and depletion of neuronal mtDNA. Defining disease mechanisms in neurons remains difficult due to the limited access to human tissue. Using human induced pluripotent stem cells (hiPSCs), we generated functional dopaminergic (DA) neurons showing positive expression of dopaminergic markers TH and DAT, mature neuronal marker MAP2 and functional synaptic markers synaptophysin and PSD-95.
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