38 results on '"RICHARDS"'
Search Results
2. Functional Genomics in Psoriasis.
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Rossi, Stefano, Richards, Ellie Louise, Orozco, Gisela, and Eyre, Stephen
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FUNCTIONAL genomics , *GENOME-wide association studies , *PSORIASIS , *MOLECULAR biology , *GENE expression - Abstract
Psoriasis is an autoimmune cutaneous condition that significantly impacts quality of life and represents a burden on society due to its prevalence. Genome-wide association studies (GWASs) have pinpointed several psoriasis-related risk loci, underlining the disease's complexity. Functional genomics is paramount to unveiling the role of such loci in psoriasis and disentangling its complex nature. In this review, we aim to elucidate the main findings in this field and integrate our discussion with gold-standard techniques in molecular biology—i.e., Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—and high-throughput technologies. These tools are vital to understanding how disease risk loci affect gene expression in psoriasis, which is crucial in identifying new targets for personalized treatments in advanced precision medicine. [ABSTRACT FROM AUTHOR]
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- 2024
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3. An Overview of Epigenetic Changes in the Parkinson's Disease Brain.
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Klokkaris, Anthony and Migdalska-Richards, Anna
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PARKINSON'S disease , *BRAIN diseases , *EPIGENETICS , *RNA modification & restriction , *DNA methylation - Abstract
Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells
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Yegambaram, Manivannan, primary, Sun, Xutong, additional, Flores, Alejandro Garcia, additional, Lu, Qing, additional, Soto, Jamie, additional, Richards, Jaime, additional, Aggarwal, Saurabh, additional, Wang, Ting, additional, Gu, Haiwei, additional, Fineman, Jeffrey R., additional, and Black, Stephen M., additional
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- 2023
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5. Interrogating the Role of miR-125b and Its 3′isomiRs in Protection against Hypoxia
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Wong, Lee Lee, primary, Fadzil, Azizah Binti, additional, Chen, Qiying, additional, Rademaker, Miriam T., additional, Charles, Christopher J., additional, Richards, Arthur Mark, additional, and Wang, Peipei, additional
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- 2023
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6. Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)
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Richards, Cathy E., primary, Elamin, Yasir Y., additional, Carr, Aoife, additional, Gately, Kathy, additional, Rafee, Shereen, additional, Cremona, Mattia, additional, Hanrahan, Emer, additional, Smyth, Robert, additional, Ryan, Daniel, additional, Morgan, Ross K., additional, Kennedy, Susan, additional, Hudson, Lance, additional, Fay, Joanna, additional, O’Byrne, Kenneth, additional, Hennessy, Bryan T., additional, and Toomey, Sinead, additional
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- 2023
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7. Physical Mapping of QTLs for Root Traits in a Population of Recombinant Inbred Lines of Hexaploid Wheat
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Li, Xiaoqing, primary, Wasson, Anton P., additional, Zwart, Alexander B., additional, Whan, Alex, additional, Ryan, Peter R., additional, Forrest, Kerrie, additional, Hayden, Matthew, additional, Chin, Sabrina, additional, Richards, Richard, additional, and Delhaize, Emmanuel, additional
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- 2023
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8. DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson’s Individuals with GBA1 Mutations
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Smith, Adam R., primary, Richards, David M., additional, Lunnon, Katie, additional, Schapira, Anthony H. V., additional, and Migdalska-Richards, Anna, additional
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- 2023
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9. Comparison of SPEED, S-Trap, and In-Solution-Based Sample Preparation Methods for Mass Spectrometry in Kidney Tissue and Plasma
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Templeton, Evelyn M., primary, Pilbrow, Anna P., additional, Kleffmann, Torsten, additional, Pickering, John W., additional, Rademaker, Miriam T., additional, Scott, Nicola J. A., additional, Ellmers, Leigh J., additional, Charles, Christopher J., additional, Endre, Zoltan H., additional, Richards, A. Mark, additional, Cameron, Vicky A., additional, and Lassé, Moritz, additional
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- 2023
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10. Influence of Butyrate on Impaired Gene Expression in Colon from Patients with High Blood Pressure
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Li, Jing, primary, Richards, Elaine M., additional, Handberg, Eileen M., additional, Pepine, Carl J., additional, Alakrad, Eyad, additional, Forsmark, Chris E., additional, and Raizada, Mohan K., additional
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- 2023
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11. Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction
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Lim, Xiong Chang, primary, Huang, Chenyuan, additional, Yatim, Siti Maryam J. M., additional, Chong, Suet Yen, additional, Tan, Sock Hwee, additional, Yang, Xiaoxun, additional, Heldt, Caryn L., additional, Pedersen, Jodi, additional, Talanker, Michael, additional, Modh, Harshvardhan, additional, Wacker, Matthias G., additional, Pastorin, Giorgia, additional, Chan, Siew Pang, additional, Richards, A. Mark, additional, Charles, Chris J., additional, Chan, Mark Y., additional, and Wang, Jiong-Wei, additional
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- 2022
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12. Influence of Butyrate on Impaired Gene Expression in Colon from Patients with High Blood Pressure
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Jing Li, Elaine M. Richards, Eileen M. Handberg, Carl J. Pepine, Eyad Alakrad, Chris E. Forsmark, and Mohan K. Raizada
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Inorganic Chemistry ,gut organoid ,hypertension ,drug–gene interaction ,Organic Chemistry ,colonic transcriptome ,General Medicine ,Physical and Theoretical Chemistry ,butyrate ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Hypertension (HTN) is associated with gut dysbiosis and the depletion of butyrate-producing bacteria in animal models and people. Furthermore, fecal material transfer from donor hypertensive patients increases blood pressure in normotensive recipient animals and ameliorates HTN-associated pathophysiology. These observations have implications in the impaired interactions between the gut and gut microbiota in HTN. Although this concept is supported in animal models, little is known about human HTN. Therefore, our objective for this study was to compare gene expression with transcriptomics and its potential to influence microbiota in subjects with normal and high blood pressure (HBP). Colon samples from reference subjects with normal blood pressure (REF) and HBP were used for RNA-seq to analyze their transcriptomes. We observed the significant downregulation of gene sets governing immune responses (e.g., SGK1 and OASL), gut epithelial function (e.g., KRT20 and SLC9A3R1), gut microbiota (e.g., PPARG and CIDEC) and genes associated with cardiovascular and gut diseases (e.g., PLAUR and NLN) in HBP subjects; the expression of genes within these pathways correlated with blood pressure. Potential drug targets in the gut epithelium were identified using the Drug Gene International Database for possible use in HTN. They include peroxisome proliferator-activated receptor gamma (PPRG), active serum/glucocorticoid regulated kinase 1 (SGK1) and 3 beta-hydroxysteroid isomerase type II inhibitor (HSD3B). Finally, butyrate, a microbiota-derived short-chain fatty acid, restored the disrupted expression of certain functional genes in colonic organoids from HBP subjects. Patients with HBP exhibit a unique transcriptome that could underlie impaired gut–microbiota interactions. Targeting these interactions could provide a promising new therapeutic intervention for hypertension management.
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- 2023
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13. Phylogeography of Sub-Saharan Mitochondrial Lineages Outside Africa Highlights the Roles of the Holocene Climate Changes and the Atlantic Slave Trade
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Sá, Luísa, primary, Almeida, Mafalda, additional, Azonbakin, Simon, additional, Matos, Erica, additional, Franco-Duarte, Ricardo, additional, Gómez-Carballa, Alberto, additional, Salas, Antonio, additional, Laleye, Anatóle, additional, Rosa, Alexandra, additional, Brehm, António, additional, Richards, Martin B., additional, Soares, Pedro, additional, and Rito, Teresa, additional
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- 2022
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14. Hydrogen Sulfide and Substance P Levels in Patients with Escherichia coli and Klebsiella pneumoniae Bacteraemia
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Manandhar, Sumeet, primary, Scott-Thomas, Amy, additional, Harrington, Michael, additional, Sinha, Priyanka, additional, Pilbrow, Anna, additional, Richards, Arthur Mark, additional, Cameron, Vicky, additional, Bhatia, Madhav, additional, and Chambers, Stephen T., additional
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- 2022
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15. DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson’s Individuals with GBA1 Mutations
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Adam R. Smith, David M. Richards, Katie Lunnon, Anthony H. V. Schapira, and Anna Migdalska-Richards
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Inorganic Chemistry ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated.
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- 2023
16. Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC).
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Richards, Cathy E., Elamin, Yasir Y., Carr, Aoife, Gately, Kathy, Rafee, Shereen, Cremona, Mattia, Hanrahan, Emer, Smyth, Robert, Ryan, Daniel, Morgan, Ross K., Kennedy, Susan, Hudson, Lance, Fay, Joanna, O'Byrne, Kenneth, Hennessy, Bryan T., and Toomey, Sinead
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NON-small-cell lung carcinoma , *PHOSPHOPROTEIN phosphatases , *SOMATIC mutation , *MITOGEN-activated protein kinases , *SQUAMOUS cell carcinoma , *PROTEIN-tyrosine phosphatase - Abstract
PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Hydrogen Sulfide and Substance P Levels in Patients with
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Sumeet, Manandhar, Amy, Scott-Thomas, Michael, Harrington, Priyanka, Sinha, Anna, Pilbrow, Arthur Mark, Richards, Vicky, Cameron, Madhav, Bhatia, and Stephen T, Chambers
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Klebsiella pneumoniae ,Escherichia coli ,Animals ,Humans ,Bacteremia ,Hydrogen Sulfide ,Substance P ,Escherichia coli Infections - Abstract
Hydrogen sulfide (H
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- 2022
18. Helena’s Many Daughters: More Mitogenome Diversity behind the Most Common West Eurasian mtDNA Control Region Haplotype in an Extended Italian Population Sample
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Bodner, Martin, primary, Amory, Christina, additional, Olivieri, Anna, additional, Gandini, Francesca, additional, Cardinali, Irene, additional, Lancioni, Hovirag, additional, Huber, Gabriela, additional, Xavier, Catarina, additional, Pala, Maria, additional, Fichera, Alessandro, additional, Schnaller, Lisa, additional, Gysi, Mario, additional, Sarno, Stefania, additional, Pettener, Davide, additional, Luiselli, Donata, additional, Richards, Martin B., additional, Semino, Ornella, additional, Achilli, Alessandro, additional, Torroni, Antonio, additional, and Parson, Walther, additional
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- 2022
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19. Coronary Artery Ectasia: Review of the Non-Atherosclerotic Molecular and Pathophysiologic Concepts
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Richards, Gavin H. C., primary, Hong, Kathryn L., additional, Henein, Michael Y., additional, Hanratty, Colm, additional, and Boles, Usama, additional
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- 2022
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20. Comparison of SPEED, S-Trap, and In-Solution-Based Sample Preparation Methods for Mass Spectrometry in Kidney Tissue and Plasma
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Evelyn M. Templeton, Anna P. Pilbrow, Torsten Kleffmann, John W. Pickering, Miriam T. Rademaker, Nicola J. A. Scott, Leigh J. Ellmers, Christopher J. Charles, Zoltan H. Endre, A. Mark Richards, Vicky A. Cameron, and Moritz Lassé
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Inorganic Chemistry ,mass spectrometry ,kidney ,plasma ,sample preparation techniques ,proteomics ,renal ,suspension trap ,SPEED ,quantitative proteomics ,SWATH-MS ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC); suspension trapping (S-Trap)) with the recently developed sample preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250; S-Trap 1202; SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150; SDC 148; SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85–0.90) and plasma (SPEED R2 = 0.84; SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.
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- 2023
21. Reduced Glx and GABA Inductions in the Anterior Cingulate Cortex and Caudate Nucleus Are Related to Impaired Control of Attention in Attention-Deficit/Hyperactivity Disorder
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Ping C. Mamiya, Todd L. Richards, Richard A. E. Edden, Adrian K. C. Lee, Mark A. Stein, and Patricia K. Kuhl
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Adult ,neurotransmitter ,anterior cingulate cortex ,striatum ,basal ganglia ,executive function ,Organic Chemistry ,Glutamic Acid ,General Medicine ,behavioral disciplines and activities ,Gyrus Cinguli ,Magnetic Resonance Imaging ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,nervous system ,Attention Deficit Disorder with Hyperactivity ,mental disorders ,Humans ,Physical and Theoretical Chemistry ,Caudate Nucleus ,Molecular Biology ,Spectroscopy ,gamma-Aminobutyric Acid ,Genome-Wide Association Study - Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31–51 years) and 16 adults without ADHD (28–54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry.
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- 2022
22. Reduced Glx and GABA Inductions in the Anterior Cingulate Cortex and Caudate Nucleus Are Related to Impaired Control of Attention in Attention-Deficit/Hyperactivity Disorder
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Mamiya, Ping C., primary, Richards, Todd L., additional, Edden, Richard A. E., additional, Lee, Adrian K. C., additional, Stein, Mark A., additional, and Kuhl, Patricia K., additional
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- 2022
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23. Pathophysiological Link between Insulin Resistance and Adrenal Incidentalomas
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Higgs, Jordan A., primary, Quinn, Alyssa P., additional, Seely, Kevin D., additional, Richards, Zeke, additional, Mortensen, Shad P., additional, Crandall, Cody S., additional, and Brooks, Amanda E., additional
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- 2022
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24. Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure
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Templeton, Evelyn, primary, Lassé, Moritz, additional, Kleffmann, Torsten, additional, Ellmers, Leigh, additional, Palmer, Suetonia, additional, Davidson, Trent, additional, Scott, Nicola, additional, Pickering, John, additional, Charles, Christopher, additional, Endre, Zoltan, additional, Cameron, Vicky, additional, Richards, A., additional, Rademaker, Miriam, additional, and Pilbrow, Anna, additional
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- 2022
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25. Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction.
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Lim, Xiong Chang, Huang, Chenyuan, Yatim, Siti Maryam J. M., Chong, Suet Yen, Tan, Sock Hwee, Yang, Xiaoxun, Heldt, Caryn L., Pedersen, Jodi, Talanker, Michael, Modh, Harshvardhan, Wacker, Matthias G., Pastorin, Giorgia, Chan, Siew Pang, Richards, A. Mark, Charles, Chris J., Chan, Mark Y., and Wang, Jiong-Wei
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MYOCARDIAL infarction ,VENTRICULAR remodeling ,EXTRACELLULAR vesicles ,VON Willebrand factor ,PROTEINS ,PLASMINOGEN ,DESMOPRESSIN - Abstract
The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. Protein concentrations of von Willebrand factor (VWF), SerpinC1 and plasminogen were determined in LDL-EVs extracted from plasma samples obtained at baseline (within 72 h post-AMI), 1 month and 6 months post-AMI from 198 patients. Patients were categorized as exhibiting adverse (n = 98) or reverse (n = 100) LV remodeling based on changes in LV end-systolic volume (increased or decreased ≥15) over a 6-month period. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess predictive value for LV remodeling independent of baseline differences. At baseline, protein levels of VWF, SerpinC1 and plasminogen in LDL-EVs did not differ between patients with adverse versus reverse LV remodeling. At 1 month post-AMI, protein levels of VWF and SerpinC1 decreased whilst plasminogen increased in patients with adverse LV remodeling. In contrast, VWF and plasminogen decreased whilst SerpinC1 remained unchanged in patients with reverse LV remodeling. Overall, compared with patients with adverse LV remodeling, higher levels of SerpinC1 and VWF but lower levels of plasminogen resulted in higher ratios of VWF:Plasminogen and SerpinC1:Plasminogen at both 1 month and 6 months post-AMI in patients with reverse LV remodeling. More importantly, ratios VWF:Plasminogen (AUC = 0.674) and SerpinC1:Plasminogen (AUC = 0.712) displayed markedly better prognostic power than NT-proBNP (AUC = 0.384), troponin-I (AUC = 0.467) or troponin-T (AUC = 0.389) (p < 0.001) to predict reverse LV remodeling post-AMI. Temporal changes in the ratios of coagulation to fibrinolysis pathway proteins in LDL-EVs outperform current standard plasma biomarkers in predicting post-AMI reverse LV remodeling. Our findings may provide clinical cues to uncover the cellular mechanisms underpinning post-AMI reverse LV remodeling. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure
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Evelyn M. Templeton, Moritz Lassé, Torsten Kleffmann, Leigh J. Ellmers, Suetonia C. Palmer, Trent Davidson, Nicola J. A. Scott, John W. Pickering, Christopher J. Charles, Zoltan H. Endre, Vicky A. Cameron, A. Mark Richards, Miriam T. Rademaker, and Anna P. Pilbrow
- Subjects
Proteomics ,acute decompensated heart failure ,QH301-705.5 ,SWATH–MS ,Platelet Membrane Glycoproteins ,acute renal failure ,Article ,Catalysis ,Inorganic Chemistry ,Animals ,Humans ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Heart Failure ,acute kidney injury ,biomarker ,proteomics ,heart failure ,CCT6A ,TRiC ,CCT ,Sheep ,Organic Chemistry ,General Medicine ,Acute Kidney Injury ,Prognosis ,Computer Science Applications ,Chemistry ,Disease Models, Animal ,Biomarkers - Abstract
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.
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- 2022
27. Functional Genomics in Psoriasis
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Stefano Rossi, Ellie Louise Richards, Gisela Orozco, and Stephen Eyre
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psoriasis ,functional genomics ,GWAS ,inflammation ,precision medicine ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Psoriasis is an autoimmune cutaneous condition that significantly impacts quality of life and represents a burden on society due to its prevalence. Genome-wide association studies (GWASs) have pinpointed several psoriasis-related risk loci, underlining the disease’s complexity. Functional genomics is paramount to unveiling the role of such loci in psoriasis and disentangling its complex nature. In this review, we aim to elucidate the main findings in this field and integrate our discussion with gold-standard techniques in molecular biology—i.e., Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—and high-throughput technologies. These tools are vital to understanding how disease risk loci affect gene expression in psoriasis, which is crucial in identifying new targets for personalized treatments in advanced precision medicine.
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- 2024
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28. An Overview of Epigenetic Changes in the Parkinson’s Disease Brain
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Anthony Klokkaris and Anna Migdalska-Richards
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epigenetics ,Parkinson’s disease ,DNA methylation ,DNA hydroxymethylation ,histone modifications ,non-coding RNAs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Parkinson’s disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson’s have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson’s disease. We will also discuss the limitations of current epigenetic research in Parkinson’s disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.
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- 2024
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29. In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice
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Susanne Paukner, Sandra Kimber, Charlotte Cumper, Tina Rea-Davies, Lorena Sueiro Ballesteros, Christopher Kirkham, Adam Hargreaves, Steven P. Gelone, Claire Richards, and Wolfgang W. Wicha
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acute respiratory distress syndrome (ARDS) ,acute lung injury (ALI) ,community-acquired pneumonia ,lefamulin ,oseltamivir ,azithromycin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant ‘low’ dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
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- 2024
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30. Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells
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Manivannan Yegambaram, Xutong Sun, Alejandro Garcia Flores, Qing Lu, Jamie Soto, Jaime Richards, Saurabh Aggarwal, Ting Wang, Haiwei Gu, Jeffrey R. Fineman, and Stephen M. Black
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mitofusin ,mitochondrial function ,glycolysis ,metabolomics ,pulmonary hypertension ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.
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- 2023
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31. Interrogating the Role of miR-125b and Its 3′isomiRs in Protection against Hypoxia
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Lee Lee Wong, Azizah Binti Fadzil, Qiying Chen, Miriam T. Rademaker, Christopher J. Charles, Arthur Mark Richards, and Peipei Wang
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microRNA ,isomiR ,miR-125b ,hypoxia ,and apoptosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5′ or 3′ addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3′isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3′ isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs’ metabolism and function will contribute to better miRNA therapeutic drug design.
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- 2023
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32. Physical Mapping of QTLs for Root Traits in a Population of Recombinant Inbred Lines of Hexaploid Wheat
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Xiaoqing Li, Anton P. Wasson, Alexander B. Zwart, Alex Whan, Peter R. Ryan, Kerrie Forrest, Matthew Hayden, Sabrina Chin, Richard Richards, and Emmanuel Delhaize
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bread wheat ,root morphology ,traits ,genetics ,candidate genes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Root architecture is key in determining how effective plants are at intercepting and absorbing nutrients and water. Previously, the wheat (Triticum aestivum) cultivars Spica and Maringa were shown to have contrasting root morphologies. These cultivars were crossed to generate an F6:1 population of recombinant inbred lines (RILs) which was genotyped using a 90 K single nucleotide polymorphisms (SNP) chip. A total of 227 recombinant inbred lines (RILs) were grown in soil for 21 days in replicated trials under controlled conditions. At harvest, the plants were scored for seven root traits and two shoot traits. An average of 7.5 quantitative trait loci (QTL) were associated with each trait and, for each of these, physical locations of the flanking markers were identified using the Chinese Spring reference genome. We also compiled a list of genes from wheat and other monocotyledons that have previously been associated with root growth and morphology to determine their physical locations on the Chinese Spring reference genome. This allowed us to determine whether the QTL discovered in our study encompassed genes previously associated with root morphology in wheat or other monocotyledons. Furthermore, it allowed us to establish if the QTL were co-located with the QTL identified from previously published studies. The parental lines together with the genetic markers generated here will enable specific root traits to be introgressed into elite wheat lines. Moreover, the comprehensive list of genes associated with root development, and their physical locations, will be a useful resource for researchers investigating the genetics of root morphology in cereals.
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- 2023
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33. Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)
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Cathy E. Richards, Yasir Y. Elamin, Aoife Carr, Kathy Gately, Shereen Rafee, Mattia Cremona, Emer Hanrahan, Robert Smyth, Daniel Ryan, Ross K. Morgan, Susan Kennedy, Lance Hudson, Joanna Fay, Kenneth O’Byrne, Bryan T. Hennessy, and Sinead Toomey
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Shp2 ,PTPN11 ,lung cancer ,somatic mutations ,PI3K signalling pathway ,MAPK signalling pathway ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.
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- 2023
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34. Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction
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Xiong Chang Lim, Chenyuan Huang, Siti Maryam J. M. Yatim, Suet Yen Chong, Sock Hwee Tan, Xiaoxun Yang, Caryn L. Heldt, Jodi Pedersen, Michael Talanker, Harshvardhan Modh, Matthias G. Wacker, Giorgia Pastorin, Siew Pang Chan, A. Mark Richards, Chris J. Charles, Mark Y. Chan, and Jiong-Wei Wang
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extracellular vesicles ,coagulation ,fibrinolysis ,acute myocardial infarction ,ventricular remodeling ,heart failure ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. Protein concentrations of von Willebrand factor (VWF), SerpinC1 and plasminogen were determined in LDL-EVs extracted from plasma samples obtained at baseline (within 72 h post-AMI), 1 month and 6 months post-AMI from 198 patients. Patients were categorized as exhibiting adverse (n = 98) or reverse (n = 100) LV remodeling based on changes in LV end-systolic volume (increased or decreased ≥15) over a 6-month period. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess predictive value for LV remodeling independent of baseline differences. At baseline, protein levels of VWF, SerpinC1 and plasminogen in LDL-EVs did not differ between patients with adverse versus reverse LV remodeling. At 1 month post-AMI, protein levels of VWF and SerpinC1 decreased whilst plasminogen increased in patients with adverse LV remodeling. In contrast, VWF and plasminogen decreased whilst SerpinC1 remained unchanged in patients with reverse LV remodeling. Overall, compared with patients with adverse LV remodeling, higher levels of SerpinC1 and VWF but lower levels of plasminogen resulted in higher ratios of VWF:Plasminogen and SerpinC1:Plasminogen at both 1 month and 6 months post-AMI in patients with reverse LV remodeling. More importantly, ratios VWF:Plasminogen (AUC = 0.674) and SerpinC1:Plasminogen (AUC = 0.712) displayed markedly better prognostic power than NT-proBNP (AUC = 0.384), troponin-I (AUC = 0.467) or troponin-T (AUC = 0.389) (p < 0.001) to predict reverse LV remodeling post-AMI. Temporal changes in the ratios of coagulation to fibrinolysis pathway proteins in LDL-EVs outperform current standard plasma biomarkers in predicting post-AMI reverse LV remodeling. Our findings may provide clinical cues to uncover the cellular mechanisms underpinning post-AMI reverse LV remodeling.
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- 2022
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35. Phylogeography of Sub-Saharan Mitochondrial Lineages Outside Africa Highlights the Roles of the Holocene Climate Changes and the Atlantic Slave Trade
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Luísa Sá, Mafalda Almeida, Simon Azonbakin, Erica Matos, Ricardo Franco-Duarte, Alberto Gómez-Carballa, Antonio Salas, Anatóle Laleye, Alexandra Rosa, António Brehm, Martin B. Richards, Pedro Soares, and Teresa Rito
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phylogeography ,mitochondrial DNA ,founder analysis ,Holocene ,slave trade influence ,computational approach ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Despite the importance of ancient DNA for understanding human prehistoric dispersals, poor survival means that data remain sparse for many areas in the tropics, including in Africa. In such instances, analysis of contemporary genomes remains invaluable. One promising approach is founder analysis, which identifies and dates migration events in non-recombining systems. However, it has yet to be fully exploited as its application remains controversial. Here, we test the approach by evaluating the age of sub-Saharan mitogenome lineages sampled outside Africa. The analysis confirms that such lineages in the Americas date to recent centuries—the time of the Atlantic slave trade—thereby validating the approach. By contrast, in North Africa, Southwestern Asia and Europe, roughly half of the dispersal signal dates to the early Holocene, during the “greening” of the Sahara. We elaborate these results by showing that the main source regions for the two main dispersal episodes are distinct. For the recent dispersal, the major source was West Africa, but with two exceptions: South America, where the fraction from Southern Africa was greater, and Southwest Asia, where Eastern Africa was the primary source. These observations show the potential of founder analysis as both a supplement and complement to ancient DNA studies.
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- 2022
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36. Helena’s Many Daughters: More Mitogenome Diversity behind the Most Common West Eurasian mtDNA Control Region Haplotype in an Extended Italian Population Sample
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Martin Bodner, Christina Amory, Anna Olivieri, Francesca Gandini, Irene Cardinali, Hovirag Lancioni, Gabriela Huber, Catarina Xavier, Maria Pala, Alessandro Fichera, Lisa Schnaller, Mario Gysi, Stefania Sarno, Davide Pettener, Donata Luiselli, Martin B. Richards, Ornella Semino, Alessandro Achilli, Antonio Torroni, and Walther Parson
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massively parallel sequencing ,next-generation sequencing ,forensics ,most common haplotype ,power of discrimination ,mtDNA haplogroup H ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The high number of matching haplotypes of the most common mitochondrial (mt)DNA lineages are considered to be the greatest limitation for forensic applications. This study investigates the potential to solve this constraint by massively parallel sequencing a large number of mitogenomes that share the most common West Eurasian mtDNA control region (CR) haplotype motif (263G 315.1C 16519C). We augmented a pilot study on 29 to a total of 216 Italian mitogenomes that represents the largest set of the most common CR haplotype compiled from a single country. The extended population sample confirmed and extended the huge coding region diversity behind the most common CR motif. Complete mitogenome sequencing allowed for the detection of 163 distinct haplotypes, raising the power of discrimination from 0 (CR) to 99.6% (mitogenome). The mtDNAs were clustered into 61 named clades of haplogroup H and did not reveal phylogeographic trends within Italy. Rapid individualization approaches for investigative purposes are limited to the most frequent H clades of the dataset, viz. H1, H3, and H7.
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- 2022
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37. Coronary Artery Ectasia: Review of the Non-Atherosclerotic Molecular and Pathophysiologic Concepts
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Gavin H. C. Richards, Kathryn L. Hong, Michael Y. Henein, Colm Hanratty, and Usama Boles
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coronary artery ectasia ,coronary artery aneurysm ,CAD ,cytokine ,lipidome ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Coronary artery ectasia (CAE) is frequently encountered in clinical practice, conjointly with atherosclerotic CAD (CAD). Given the overlapping cardiovascular risk factors for patients with concomitant CAE and atherosclerotic CAD, a common underlying pathophysiology is often postulated. However, coronary artery ectasia may arise independently, as isolated (pure) CAE, thereby raising suspicions of an alternative mechanism. Herein, we review the existing evidence for the pathophysiology of CAE in order to help direct management strategies towards enhanced detection and treatment.
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- 2022
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38. Pathophysiological Link between Insulin Resistance and Adrenal Incidentalomas
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Jordan A. Higgs, Alyssa P. Quinn, Kevin D. Seely, Zeke Richards, Shad P. Mortensen, Cody S. Crandall, and Amanda E. Brooks
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adrenal incidentaloma ,insulin resistance ,autonomous cortisol secretion ,differential diagnosis of adrenal masses ,subclinical hypercortisolism ,adrenalectomy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Adrenal incidentalomas are incidentally discovered adrenal masses greater than one centimeter in diameter. An association between insulin resistance and adrenal incidentalomas has been established. However, the pathophysiological link between these two conditions remains incompletely characterized. This review examines the literature on the interrelationship between insulin resistance and adrenal masses, their subtypes, and related pathophysiology. Some studies show that functional and non-functional adrenal masses elicit systemic insulin resistance, whereas others conclude the inverse. Insulin resistance, hyperinsulinemia, and the anabolic effects on adrenal gland tissue, which have insulin and insulin-like growth factor-1 receptors, offer possible pathophysiological links. Conversely, autonomous adrenal cortisol secretion generates visceral fat accumulation and insulin resistance. Further investigation into the mechanisms and timing of these two pathologies as they relate to one another is needed and could be valuable in the prevention, detection, and treatment of both conditions.
- Published
- 2022
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