1,041 results on '"Young, Lucy"'
Search Results
2. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
- Author
-
Young, Lucy C, Goldstein de Salazar, Ruby, Han, Sae-Won, Huang, Zi Yi Stephanie, Merk, Alan, Drew, Matthew, Darling, Joseph, Wall, Vanessa, Grisshammer, Reinhard, Cheng, Alice, Allison, Madeline R, Sale, Matthew J, Nissley, Dwight V, Esposito, Dominic, Ognjenovic, Jana, and McCormick, Frank
- Subjects
Humans ,Neurofibromatosis 1 ,Neurofibromin 1 ,Dimerization ,Mutation ,Mutation ,Missense ,NFI ,cryo-EM ,neurofibromatosis type I ,Genetics ,Rare Diseases ,Neurosciences ,Neurofibromatosis ,Aetiology ,2.1 Biological and endogenous factors - Abstract
The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
- Published
- 2023
3. Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex
- Author
-
Kwon, Jason J, Hajian, Behnoush, Bian, Yuemin, Young, Lucy C, Amor, Alvaro J, Fuller, James R, Fraley, Cara V, Sykes, Abbey M, So, Jonathan, Pan, Joshua, Baker, Laura, Lee, Sun Joo, Wheeler, Douglas B, Mayhew, David L, Persky, Nicole S, Yang, Xiaoping, Root, David E, Barsotti, Anthony M, Stamford, Andrew W, Perry, Charles K, Burgin, Alex, McCormick, Frank, Lemke, Christopher T, Hahn, William C, and Aguirre, Andrew J
- Subjects
2.1 Biological and endogenous factors ,Underpinning research ,Aetiology ,1.1 Normal biological development and functioning ,Generic health relevance ,Cancer ,Amino Acid Motifs ,Binding Sites ,Cryoelectron Microscopy ,Guanosine Triphosphate ,Humans ,Intracellular Signaling Peptides and Proteins ,MAP Kinase Signaling System ,Multiprotein Complexes ,Mutation ,Missense ,Phosphorylation ,Protein Binding ,Protein Phosphatase 1 ,Protein Stability ,raf Kinases ,ras Proteins ,General Science & Technology - Abstract
Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .
- Published
- 2022
4. Tumors of the Retinal Pigment Epithelium
- Author
-
Ma, Kevin K., Albert, Daniel M., Young, Lucy H., O’Brien, Joan Marie, Section editor, Gragoudas, Evangelos S., Section editor, Gombos, Dan, Section editor, Aronow, Mary, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor
- Published
- 2022
- Full Text
- View/download PDF
5. CMV Retinitis
- Author
-
Ung, Cindy, Young, Lucy H., Sobrin, Lucia, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor
- Published
- 2022
- Full Text
- View/download PDF
6. Choroidal Effusions and Detachments
- Author
-
Waheed, Nadia K., Mendonça, Luísa S. M., Young, Lucy H., Husain, Deeba, Section editor, Gragoudas, Evangelos S., Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor
- Published
- 2022
- Full Text
- View/download PDF
7. Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex
- Author
-
Roehrig, Anne E, Klupsch, Kristina, Oses-Prieto, Juan A, Chaib, Selim, Henderson, Stephen, Emmett, Warren, Young, Lucy C, Surinova, Silvia, Blees, Andreas, Pfeiffer, Anett, Tijani, Maha, Brunk, Fabian, Hartig, Nicole, Muñoz-Alegre, Marta, Hergovich, Alexander, Jennings, Barbara H, Burlingame, Alma L, and Rodriguez-Viciana, Pablo
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Rare Diseases ,Neurofibromatosis ,Neurosciences ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,Cancer ,Cell Adhesion ,Cell Proliferation ,Chromatin ,Chromatin Assembly and Disassembly ,Contact Inhibition ,DNA Helicases ,DNA-Binding Proteins ,Gene Expression Regulation ,HEK293 Cells ,Humans ,Neoplasms ,Neurofibromin 2 ,Protein Binding ,Protein Interaction Maps ,Signal Transduction ,Tumor Suppressor Proteins ,General Science & Technology - Abstract
The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.
- Published
- 2021
8. KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation
- Author
-
Tran, Timothy H, Chan, Albert H, Young, Lucy C, Bindu, Lakshman, Neale, Chris, Messing, Simon, Dharmaiah, Srisathiyanarayanan, Taylor, Troy, Denson, John-Paul, Esposito, Dominic, Nissley, Dwight V, Stephen, Andrew G, McCormick, Frank, and Simanshu, Dhirendra K
- Subjects
Cancer ,Binding Sites ,Crystallography ,X-Ray ,Cysteine ,Humans ,Models ,Molecular ,Protein Binding ,Protein Conformation ,Protein Domains ,Protein Interaction Domains and Motifs ,Proto-Oncogene Proteins c-raf ,Proto-Oncogene Proteins p21(ras) ,ras Proteins - Abstract
The first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we present crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures reveal that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutations at the KRAS-CRD interface result in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.
- Published
- 2021
9. Biodiversity shows unique responses to land-use change across regional biomes
- Author
-
Bevan, Peggy, primary, Ferreira, Guilherme, additional, Ingram, Daniel, additional, Rowcliffe, Marcus, additional, Young, Lucy, additional, Freeman, Robin, additional, and Jones, Kate, additional
- Published
- 2024
- Full Text
- View/download PDF
10. Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
- Author
-
Sangaré, Lamba Omar, Yang, Ninghan, Konstantinou, Eleni K, Lu, Diana, Mukhopadhyay, Debanjan, Young, Lucy H, and Saeij, Jeroen PJ
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Biodefense ,Emerging Infectious Diseases ,Infectious Diseases ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Binding Sites ,Gene Expression ,Host-Pathogen Interactions ,Humans ,NF-kappa B ,Protein Binding ,Protozoan Proteins ,Signal Transduction ,Toxoplasma ,Toxoplasmosis ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,NF-kappa B pathway ,TRAF2 ,TRAF6 ,Toxoplasma gondii ,host-pathogen interactions ,NF-κB pathway ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
The protozoan parasite Toxoplasma gondii secretes proteins from specialized organelles, the rhoptries, and dense granules, which are involved in the modulation of host cell processes. Dense granule protein GRA15 activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. Exactly how GRA15 activates the NF-κB pathway is unknown. Here we show that GRA15 interacts with tumor necrosis factor receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. We identified several TRAF binding sites in the GRA15 amino acid sequence and showed that these are involved in NF-κB activation. Furthermore, a TRAF2 knockout cell line has impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.IMPORTANCE The parasite Toxoplasma can cause birth defects and severe disease in immunosuppressed patients. Strain differences in pathogenicity exist, and these differences are due to polymorphic effector proteins that Toxoplasma secretes into the host cell to coopt host cell functions. The effector protein GRA15 of some Toxoplasma strains activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. We show that GRA15 interacts with TNF receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. Deletion of TRAF-binding sites in GRA15 greatly reduces its ability to activate the NF-κB pathway, and TRAF2 knockout cells have impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.
- Published
- 2019
11. SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics
- Author
-
del Río, Isabel Boned, Young, Lucy C, Sari, Sibel, Jones, Greg G, Ringham-Terry, Benjamin, Hartig, Nicole, Rejnowicz, Ewa, Lei, Winnie, Bhamra, Amandeep, Surinova, Silvia, and Rodriguez-Viciana, Pablo
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,1.1 Normal biological development and functioning ,Underpinning research ,CRISPR-Associated Protein 9 ,CRISPR-Cas Systems ,Cell Line ,Tumor ,Gene Editing ,Gene Knockout Techniques ,Humans ,Intracellular Signaling Peptides and Proteins ,MAP Kinase Signaling System ,Phosphorylation ,Protein Multimerization ,raf Kinases ,ras Proteins ,SHOC2 ,RAF ,MRAS ,RAS ,ERK - Abstract
Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.
- Published
- 2019
12. Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration Age-Related Eye Disease Study 2 Report No. 17
- Author
-
Yu, Jeannette J, Agrón, Elvira, Clemons, Traci E, Domalpally, Amitha, van Asten, Freekje, Keenan, Tiarnan D, Cukras, Catherine, Chew, Emily Y, Ferris, Frederick L, SanGiovanni, John Paul, Clemons, Traci, Lindblad, Anne, Lindblad, Robert, Shah, Nilay, Sperduto, Robert, McBee, Wendy, Gensler, Gary, Harrington, Molly, Henning, Alice, Jones, Katrina, Thotapally, Kumar, Tull, Diana, Watson, Valerie, Williams, Kayla, Gentry, Christina, Kaufman, Francine, Morrison, Chris, Saverino, Elizabeth, Schenning, Sherrie, Blodi, Barbara, Danis, Ronald P, Davis, Matthew, Glander, Kathy, Guilfoil, Gregory, Hubbard, Larry D, Johnson, Kristine, Klein, Ronald, Nardi, Barbara, Neider, Michael, Robinson, Nancy, Rosensteel, Eileen, Wabers, Hugh, Zhang, Grace, Ruby, Alan J, Capone, Antonio, Dass, Bawa, Drenser, Kimberly, Garretson, Bruce R, Hassan, Tarek S, Trese, Michael, Williams, George A, Wolfe, Jeremy, Bell, Tina, Zajechowski, Mary, Bezaire, Dennis, McIver, Fran, Medina, Anthony, Pagett, Jackie, Smith, Stephanie Hatch, Swartz, Lynn, Treuter, Tom, Antoszyk, Andrew, Brown, Justin, Browning, David J, Holland, Walter, Karow, Angella, Stalford, Kelly, Price, Angela, Ennis, Sarah, Fredenberg, Sherry, Herby, Jenna, Balasubramaniam, Uma, Clark, Loraine, McClain, Donna, McOwen, Michael, Watson, Lynn, Klein, Michael, Bailey, Steven T, Hwang, Thomas J, Lauer, Andreas, Stout, J Timothy, McCollum, Patty, Johnson, Milt, Rice, Patrick B, Kim, Ivana, Loewenstein, John, Miller, Joan, Sobrin, Lucia, Young, Lucy, Sullivan, Jacqueline, Houlihan, Patricia, Merry, Linda, Lane, Ann Marie, Bator, Ursula Lord, Evans, Claudia, Brett, Sarah, and Callahan, Charleen
- Subjects
Prevention ,Clinical Research ,Neurodegenerative ,Clinical Trials and Supportive Activities ,Eye Disease and Disorders of Vision ,Macular Degeneration ,Aging ,Genetics ,Eye ,Aged ,Aged ,80 and over ,Disease Progression ,Female ,Follow-Up Studies ,Genetic Predisposition to Disease ,Humans ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Prospective Studies ,Proteins ,Retinal Detachment ,Retinal Drusen ,Retinal Pigment Epithelium ,Retrospective Studies ,Time Factors ,Visual Acuity ,Age-Related Eye Disease Study 2 Research Group ,Clinical Sciences ,Opthalmology and Optometry ,Public Health and Health Services ,Ophthalmology & Optometry - Abstract
PurposeTo investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD).DesignRetrospective analysis of a prospective cohort study.ParticipantsOf the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED.MethodsBaseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan-Meier analyses and multivariable proportional hazard regressions were performed.Main outcome measuresProgression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype.ResultsMean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98-2.82; P < 0.001); 67% of eyes progressed to late AMD 5 years after DPED detection. Drusenoid pigment epithelial detachment was associated with increased risk of ≥3 lines of VA loss (HR, 3.08; CI, 2.41-3.93; P < 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58-4.70; 2 vs. 0: HR, 3.16, CI, 1.60-6.21, P < 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66-40.45, P < 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2.ConclusionsThis study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.
- Published
- 2019
13. SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers
- Author
-
Jones, Greg G, del Río, Isabel Boned, Sari, Sibel, Sekerim, Aysen, Young, Lucy C, Hartig, Nicole, Areso Zubiaur, Itziar, El-Bahrawy, Mona A, Hynds, Rob E, Lei, Winnie, Molina-Arcas, Miriam, Downward, Julian, and Rodriguez-Viciana, Pablo
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Cancer ,Lung ,Lung Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Apoptosis ,Carcinoma ,Non-Small-Cell Lung ,Cell Line ,Tumor ,Drug Resistance ,Neoplasm ,Female ,HEK293 Cells ,Humans ,Intracellular Signaling Peptides and Proteins ,Lung Neoplasms ,MAP Kinase Signaling System ,Male ,Mice ,Knockout ,Mice ,Nude ,Mutation ,Neoplasm Transplantation ,Protein Kinase Inhibitors ,Protein Multimerization ,raf Kinases ,ras Proteins - Abstract
Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.
- Published
- 2019
14. Serotyping of Toxoplasma gondii Infection Using Peptide Membrane Arrays
- Author
-
Arranz-Solís, David, Cordeiro, Cynthia, Young, Lucy H, Dardé, Marie Laure, Commodaro, Alessandra G, Grigg, Michael E, and Saeij, Jeroen PJ
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Microbiology ,Clinical Sciences ,Medical Microbiology ,Biotechnology ,Emerging Infectious Diseases ,Prevention ,Genetics ,Vaccine Related ,Biodefense ,Infectious Diseases ,Foodborne Illness ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Amino Acid Sequence ,Epitopes ,Genome ,Protozoan ,Genotype ,Humans ,Peptides ,Protein Array Analysis ,Protozoan Proteins ,Sensitivity and Specificity ,Serotyping ,Toxoplasma ,Toxoplasmosis ,Whole Genome Sequencing ,serotyping ,strain type ,dense granule ,peptide ,microarrays ,Biochemistry and Cell Biology ,Medical microbiology - Abstract
The intracellular parasite Toxoplasma gondii can cause chronic infections in most warm-blooded animals, including humans. In the USA, strains belonging to four different Toxoplasma clonal lineages (types 1, 2, 3, and 12) are commonly isolated, whereas strains not belonging to these lineages are predominant in other continents such as South America. Strain type plays a pivotal role in determining the severity of Toxoplasma infection. Therefore, it is epidemiologically relevant to develop a non-invasive and inexpensive method for determining the strain type in Toxoplasma infections and to correlate the genotype with disease outcome. Serological typing is based on the fact that many host antibodies are raised against immunodominant parasite proteins that are highly polymorphic between strains. However, current serological assays can only reliably distinguish type 2 from non-type 2 infections. To improve these assays, mouse, rabbit, and human infection serum were reacted against 950 peptides from 62 different polymorphic Toxoplasma proteins by using cellulose membrane peptide arrays. This allowed us to identify the most antigenic peptides and to pinpoint the most relevant polymorphisms that determine strain specificity. Our results confirm the utility of previously described peptides and identify novel peptides that improve and increase the specificity of the assay. In addition, a large number of novel proteins showed potential to be used for Toxoplasma diagnosis. Among these, peptides derived from several rhoptry, dense granule, and surface proteins represented promising candidates that may be used in future experiments to improve Toxoplasma serotyping. Moreover, a redesigned version of the published GRA7 typing peptide performed better and specifically distinguished type 3 from non-type 3 infections in sera from mice, rabbits, and humans.
- Published
- 2019
15. MRAS: A Close but Understudied Member of the RAS Family
- Author
-
Young, Lucy C and Rodriguez-Viciana, Pablo
- Subjects
Medical Biochemistry and Metabolomics ,Medical Microbiology ,Medical Physiology ,Biomedical and Clinical Sciences ,Cancer ,Underpinning research ,1.1 Normal biological development and functioning ,Carcinogenesis ,Cell Differentiation ,Cell Movement ,Cell Polarity ,Gene Expression Regulation ,Humans ,Intracellular Signaling Peptides and Proteins ,MAP Kinase Signaling System ,Noonan Syndrome ,Protein Phosphatase 1 ,Signal Transduction ,ras Proteins ,Medical biochemistry and metabolomics ,Medical microbiology ,Medical physiology - Abstract
MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and transformation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings. Activating mutations in MRAS (as well as SHOC2 and PP1) do occur in the RASopathy Noonan syndrome, underscoring a key role for MRAS within the RAS-ERK pathway. MRAS also has unique roles in cell migration and differentiation and has properties consistent with a key role in the regulation of cell polarity. Further investigations should shed light on what remains a relatively understudied RAS family member.
- Published
- 2018
16. Progression of Geographic Atrophy in Age-related Macular Degeneration AREDS2 Report Number 16
- Author
-
Keenan, Tiarnan D, Agrón, Elvira, Domalpally, Amitha, Clemons, Traci E, van Asten, Freekje, Wong, Wai T, Danis, Ronald G, Sadda, SriniVas, Rosenfeld, Philip J, Klein, Michael L, Ratnapriya, Rinki, Swaroop, Anand, Ferris, Frederick L, Chew, Emily Y, SanGiovanni, John Paul, Clemons, Traci, Lindblad, Anne, Lindblad, Robert, Shah, Nilay, Sperduto, Robert, McBee, Wendy, Gensler, Gary, Harrington, Molly, Henning, Alice, Jones, Katrina, Thotapally, Kumar, Tull, Diana, Watson, Valerie, Williams, Kayla, Gentry, Christina, Kaufman, Francine, Morrison, Chris, Saverino, Elizabeth, Schenning, Sherrie, Blodi, Barbara, Danis, Ronald P, Davis, Matthew, Glander, Kathy, Guilfoil, Gregory, Hubbard, Larry D, Johnson, Kristine, Klein, Ronald, Nardi, Barbara, Neider, Michael, Robinson, Nancy, Rosensteel, Eileen, Wabers, Hugh, Zhang, Grace, Ruby, Alan J, Capone, Antonio, Dass, Bawa, Drenser, Kimberly, Garretson, Bruce R, Hassan, Tarek S, Trese, Michael, Williams, George A, Wolfe, Jeremy, Bell, Tina, Zajechowski, Mary, Bezaire, Dennis, McIver, Fran, Medina, Anthony, Pagett, Jackie, Smith, Stephanie Hatch, Swartz, Lynn, Treuter, Tom, Antoszyk, Andrew, Brown, Justin, Browning, David J, Holland, Walter, Karow, Angella, Stalford, Kelly, Price, Angela, Ennis, Sarah, Fredenberg, Sherry, Herby, Jenna, Balasubramaniam, Uma, Clark, Loraine, McClain, Donna, McOwen, Michael, Watson, Lynn, Klein, Michael, Bailey, Steven T, Hwang, Thomas J, Lauer, Andreas, Stout, J Timothy, McCollum, Patty, Johnson, Milt, Rice, Patrick B, Kim, Ivana, Loewenstein, John, Miller, Joan, Sobrin, Lucia, Young, Lucy, Sullivan, Jacqueline, and Houlihan, Patricia
- Subjects
Prevention ,Genetics ,Neurodegenerative ,Aging ,Eye Disease and Disorders of Vision ,Macular Degeneration ,Eye ,Aged ,Aged ,80 and over ,Disease Progression ,Docosahexaenoic Acids ,Drug Therapy ,Combination ,Eicosapentaenoic Acid ,Female ,Geographic Atrophy ,Humans ,Lutein ,Male ,Middle Aged ,Photography ,Prospective Studies ,Visual Acuity ,Zeaxanthins ,AREDS2 Research Group ,Clinical Sciences ,Opthalmology and Optometry ,Public Health and Health Services ,Ophthalmology & Optometry - Abstract
PurposeTo analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement.DesignProspective cohort study within a controlled clinical trial.ParticipantsAge-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years.MethodsBaseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype.Main outcome measures(1) Presence or development of GA; (2) change in the square root of GA area over time.ResultsAt baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes.ConclusionsAnalyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.
- Published
- 2018
17. SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.
- Author
-
Young, Lucy C, Hartig, Nicole, Boned Del Río, Isabel, Sari, Sibel, Ringham-Terry, Benjamin, Wainwright, Joshua R, Jones, Greg G, McCormick, Frank, and Rodriguez-Viciana, Pablo
- Subjects
Cell Line ,Humans ,Noonan Syndrome ,ras Proteins ,raf Kinases ,Intracellular Signaling Peptides and Proteins ,Carrier Proteins ,Sequence Alignment ,MAP Kinase Signaling System ,Phosphorylation ,Mutation ,Models ,Molecular ,Protein Phosphatase 1 ,HEK293 Cells ,MRAS ,Noonan syndrome ,PP1 ,RAS ,SHOC2 ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance - Abstract
Dephosphorylation of the inhibitory "S259" site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2's predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS's unique effector specificity for SHOC2-PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development.
- Published
- 2018
18. Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial
- Author
-
Emsley, Richard, Peat, George, Snow, Martyn, Campbell, Marion, Howell, Tessa, Johnson, Hilary, McDonnell, Stephen, Pinkney, Thomas, Williams, Mark, Campbell, Helen, Davies, Jackie, Li, Jiyang, Bagg, Christina, Haywood, Laura, Nicholson, Anne, Riches, Joanne, Symons, Sean, Vertue, Mark, Al Mouazzen, Louay, Bray, Rachel, Clark, Damian, Coulthard, James, Holland, Tim, Howells, Nick, Jones, Andrew, Kapur, Richard, Kiszely, Alastair, Krishnan, Harry, MacDonald-Taylor, Karen, Manara, Jon, Murray, James, Negrut, Corina, Pai, Vishai, Porteous, Andrew, Putnis, Sven, Robinson, James, Rupasinghe, Shav, Selvaratnam, Veenesh, Smith, James, Smith, Nick, Stevens, Jarrad, Taylor, Clare, Theodorides, Anthony, Vetharajan, Niraj, Vint, Helen, Young, Lucy, Bullock, Susan, Cook, Rebecca, Dodds, Alexander, Freeman-Hicks, Amanda, Hillout, Paula, Cornell, Thomas, Coutts, Abbie, Dean, Suzy, Devooght-Johnson, Nicki, Ferrell, Emma, Fletcher, Eve, Hall, Chrissie, Kent, Benjamin, Kessly, Sandra, Kincaid, Robin, Lazizi, Mohamed, Mostafa, Ahmed, Nisbett, Toby, Powell, Tim, Riddlestone, Peter, Roberton, Andrew, Summers, Jessica, Whitbread, Lucy, Wroath, Belinda, Fenlon, Emma, Hall, Andrew, Jeffrey, Helen, Thonse, Raghuram, Dunne, Debra, Metcalfe, Andy, McGowan, Kerri, Middleton, Simon, Shah, Feisal, Spalding, Tim, Marie Suddens, Charlie, Sweed, Tamar, Teuke, Joanna, Thompson, Peter, Wright, David, Amero, Justine, Brown, Emma, Chissell, Hugh, Croucher, Andrea, Dickinson, Gareth, Hawkes-Blackburn, Catherine, Peacocke, Alice, Smith, Graham, Snipe, Carol, Dearnley, Kim, Mayahi, Reza, Andrews, Barry, Barcelona, Massimo, Giles, Hazel, Gokturk, Abdulkerim, Harnett, Paul, Jeeves, Katie, Kadunyi, Joyce, Mendoza, Sheena, Reichert, Ines, Santamaria, Marta, Virdee, Harshinder, Anand, Sanjeev, Aslam-Pervez, Nayef, Draycott, Stephen, Howarth, Faye, Jina, Irfan, Maher, Niall, Ross, Denise, Worstenholme, Lindsey, Baig, Abdul, Bhaskaran, Arun, Banks, Daniel, Brear, Tracy, Christie, Carla, Cowen, Laura, Davis, Jack, Dixey, Ross, Esler, Colin, Essop-Adam, Amirah, Haines, Christina, Houchen-Wolloff, Linzy, Varachia, Husein, Wood, Richard, Gray, Glaxy, Nichols, Jessica, Panes, Alice, Partridge, Susan, Rogerson, Lawrie, Sharma, Pankaj, Triggs, David, Venables, Ian, Wilcock, Danielle, Buckley, Sarah, Darian, Thelma, Denis, Elizabeth, Duncan, Jo, Hirst, Charlotte, Newman, James, Richardson, Fern, Smith, Jon, Adcode, Megan, Cottingham, Megan, Foster, Eliza, Kelly, Andrew, McKay, Niamh, Rewbury, Jane, Whitcher, Alison, Williams, James, Zebracki, Esther, Davies, Llinos, Jayachandran, Jayadeep, Tardivel, Alison, Whitehead, Victoria, Batting, Martha, Bond, Amy, Deakin, Marc, Dodd, Christopher, Hudak, Alison, Hynes, Samantha, Jones, Luke, Lang, Gail, McKenna, David, Morris, Susan, Scott-Dempster, Clare, Sykes, Adam, Vichos, Iason, Wood, Simon, Clifton, Rupert, Diaz, Stephanie, Hendy, Craig, Modi, Nishil, O'Mahony, Brendan, O'Sullivan, Susan, Parker, Nicola, Pecheva, Mira, Rumonovic, Rowan, McLoughlin, Emma, Rushbrook, Jeremy, Thornhill, Anna, Parkinson, Valerie, Sales, Rafael, Van De Snepscheut-Jones, Katja, Wilcock, David, Wright, Daniel, Allison, Joanna, Baker, Simon, Beesley, Kate, Ferrari, Gill, Lankester, Benedict, Lewis, Alison, Lyons, Joanne, O'Callaghan, Jamie, Sutcliffe, Sarah, Wood, Dianne, Bannister, Emily, Brown, Chloe, Burden, Debbie, Campbell, Terence, Craig, Emma, Easow, Rashmi, Foxton, Julie, Hazlerigg, Alexandra, Jayabev, Chethan, Murdoch, Rosie, Parsons, Georgie, Brown, Harry, Carvelli, Paula, Montaser, Rugaia, Pepper, Ali, Sivarajan, Sinduja, Templeton-Ward, Oliver, Wilson, Eva, Cronin, Julie, Diment, Sarah, King, Victoria, Shean, Katharine, Vachtsevanos, Leonidas, Wilcocks, Katharine, Wilson, Ben, McNestry, Paul, Ollerenshaw, Joanna, Stoddard, James, Sutton, Paul, Anand, Sanjay, Bell, Judith, Chikate, Albert, Daniel, Diane, Davies, Timothy, Finnigan, Tom, Frasquet-Garcia, Antonio, Hopkins, Susan, Kerrison, Sharon, McGowan, Angela, Sands Johnson, David, Smith, Lara, Turner, Philip, Wilkinson, Helen, Allsop, Lynne, Anthony, Deborah, Boulton, Rebecca, Brown, Sarah, Desai, Vikram, Gill, Mandy, Heeley, Cheryl, Kulkarni, Sushrut, Lovegrove, Wayne, Nash, Dominic, Ann Sewell, Terri, Shelton, Sarah, Slack, Katie, Cartwright, James, Connor, Lynda, Davies, Andrew, Davies, Caroline, Gainard, Glyn, Graham-Woollard, Dave, Murphy, Carl, Quinn, Leanne, Thomas, Caradog, Travers, Jenny, Williams, Marie, Bell, Amanda, Deo, Sunny, Francis, Katharine, Jackson, Tracy, McCafferty, Laura, Navadgi, Basalingappa, Plank, Karan, Satish, Venkat, Thelwall, Claire, Knight, Rachel, Patel, Rahul, Paton, Bruce, Acharya, Ashutosh, Aland, Utuman, Areirobulos, Miltiades, de Feyter, Pascal, Ditchfield, Lisa, Iqbaz, Hafiz, Massey, Daniel, Stables, Gareth, Appleby, Sarah, Brown, Michael, Cable, Sarah, Damen, Alexander, Da Rocha, Joana, Foster, Louise, Hamilton, Elizabeth, Hatton, Catriona, Honeywell, Cassie, Kulkarni, Kunal, Markham, Lucy, Mohammed, Haadiya, O'Grady, John, Joshi, Yogesh, Mclintock, Heather, Morgan, Tania, Stockport, Jane, Agrawal, Pranshu, Armstrong, Jo, Briggs, Shannon, Coupe, Ben, Evans, Anne, Gilbert, Rob, Latham, Sandra, Mohammed, Aslam, Beard, David J, Davies, Loretta, Cook, Jonathan A, Stokes, Jamie, Leal, Jose, Fletcher, Heidi, Abram, Simon, Chegwin, Katie, Greshon, Akiko, Jackson, William, Bottomley, Nicholas, Dodd, Matt, Bourke, Henry, Shirkey, Beverly A, Paez, Arsenio, Lamb, Sarah E, Barker, Karen, Phillips, Michael, Brown, Mark, Lythe, Vanessa, Mirza, Burhan, Carr, Andrew, Monk, Paul, Morgado Areia, Carlos, O'Leary, Sean, Haddad, Fares, Wilson, Chris, and Price, Andrew
- Published
- 2022
- Full Text
- View/download PDF
19. A preliminary prospective study of health-related quality of life among Chinese-American breast cancer survivors
- Author
-
Ashing, Kimlin Tam, Yeung, Sophia, Lai, Lily, Young, Lucy, and Wong, Alison G.
- Published
- 2021
- Full Text
- View/download PDF
20. Exploring characteristics, predictors, and consequences of fear of cancer recurrence among Asian‐American breast cancer survivors
- Author
-
Ashing, Kimlin Tam, Cho, Dalnim, Lai, Lily, Yeung, Sophia, Young, Lucy, Yeon, Christina, and Fong, Yuman
- Subjects
Biomedical and Clinical Sciences ,Psychology ,Behavioral and Social Science ,Clinical Research ,Cancer ,Breast Cancer ,Good Health and Well Being ,Acculturation ,Adult ,Aged ,Aged ,80 and over ,Asian ,Breast Neoplasms ,Cancer Survivors ,Fear ,Female ,Health Status ,Humans ,Middle Aged ,Neoplasm Recurrence ,Local ,Phobic Disorders ,Prospective Studies ,Quality of Life ,Surveys and Questionnaires ,United States ,Asian-American cancer survivors ,cancer ,fear of cancer recurrence ,health care satisfaction ,health-related quality of life ,oncology ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biomedical and clinical sciences - Abstract
BackgroundTo address the fear of cancer recurrence (FCR) research gap, we used prospective data to explore FCR predictors and FCR associations with health-related quality of life among Asian-American breast cancer survivors (BCS).MethodsA total of 208 diverse Asian-American BCS completed T1 survey, and 137 completed T2 survey after 1 year.ResultsFear of cancer recurrence scores (range = 0-4) were 2.01 at T1 and 1.99 at T2 reflecting low-to-moderate FCR. Scores of FCR were stable over the 1-year period (t(126) = .144, P = .886). Multiple regression analyses showed that Chinese women reported lower FCR both at T1 (t(193) = -2.92, P = .004) and T2 (t(128) = -2.56, P = .012) compared to other Asian women. Also, more positive health care experience at T1 predicted lower FCR at T2 (β = -.18, P = .041). Controlling for other covariates, greater FCR at T1 predicted poorer outcomes 1 year later including lower physical (β = -.31, P
- Published
- 2017
21. Sympathetic Ophthalmia
- Author
-
Ung, Cindy, Young, Lucy H., Saxena, Sandeep, Series Editor, Spaide, Richard F., Series Editor, Souied, Eric H., Series Editor, Lai, Timothy Y.Y., Series Editor, and Yu, Hyeong Gon, editor
- Published
- 2020
- Full Text
- View/download PDF
22. Cat-Scratch Disease
- Author
-
Ung, Cindy, Young, Lucy H., Saxena, Sandeep, Series Editor, Spaide, Richard F., Series Editor, Souied, Eric H., Series Editor, Lai, Timothy Y.Y., Series Editor, and Yu, Hyeong Gon, editor
- Published
- 2020
- Full Text
- View/download PDF
23. Bending the Curve of Global Freshwater Biodiversity Loss : An Emergency Recovery Plan
- Author
-
TICKNER, DAVID, OPPERMAN, JEFFREY J., ABELL, ROBIN, ACREMAN, MIKE, ARTHINGTON, ANGELA H., BUNN, STUART E., COOKE, STEVEN J., DALTON, JAMES, DARWALL, WILL, EDWARDS, GAVIN, HARRISON, IAN, HUGHES, KATHY, JONES, TIM, LECLÈRE, DAVID, LYNCH, ABIGAIL J., LEONARD, PHILIP, MCCLAIN, MICHAEL E., MURUVEN, DEAN, OLDEN, JULIAN D., ORMEROD, STEVE J., ROBINSON, JAMES, THARME, REBECCA E., THIEME, MICHELE, TOCKNER, KLEMENT, WRIGHT, MARK, and YOUNG, LUCY
- Published
- 2020
24. Improvement in quality of life and psychological well-being associated with a culturally based psychosocial intervention for Chinese American breast cancer survivors
- Author
-
Lu, Qian, Chen, Lingjun, Shin, Lilian J., Wang, Carol, Dawkins-Moultin, Lenna, Chu, Qiao, Loh, Alice, Young, Lucy, and Wang, Carol
- Published
- 2021
- Full Text
- View/download PDF
25. Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina
- Author
-
Notomi, Shoji, Ishihara, Kenji, Efstathiou, Nikolaos E., Lee, Jong-Jer, Hisatomi, Toshio, Tachibana, Takashi, Konstantinou, Eleni K., Ueta, Takashi, Murakami, Yusuke, Maidana, Daniel E., Ikeda, Yasuhiro, Kume, Shinji, Terasaki, Hiroto, Sonoda, Shozo, Blanz, Judith, Young, Lucy, Sakamoto, Taiji, Sonoda, Koh-Hei, Saftig, Paul, Ishibashi, Tatsuro, Miller, Joan W., and Kroemer, Guido
- Published
- 2019
26. Linking global drivers of agricultural trade to on-the-ground impacts on biodiversity
- Author
-
Green, Jonathan M. H., Croft, Simon A., Durán, América P., Balmford, Andrew P., Burgess, Neil D., Fick, Steve, Gardner, Toby A., Godar, Javier, Suavet, Clément, Virah-Sawmy, Malika, Young, Lucy E., and West, Christopher D.
- Published
- 2019
27. The human immune response to Toxoplasma: Autophagy versus cell death.
- Author
-
Krishnamurthy, Shruthi, Konstantinou, Eleni K, Young, Lucy H, Gold, Daniel A, and Saeij, Jeroen PJ
- Subjects
Animals ,Humans ,Mice ,Toxoplasma ,Toxoplasmosis ,Cell Death ,Autophagy ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Published
- 2017
28. Ocular Siderosis.
- Author
-
Tran, Jennifer A. and Young, Lucy H.
- Subjects
- *
MACULAR degeneration , *CORNEAL transplantation , *VISION , *PUPILLOMETRY , *SLIT lamp microscopy , *FOREIGN bodies , *PARS plana - Abstract
This document provides information on the management and treatment of ocular siderosis, a condition caused by the presence of an intraocular foreign body (IOFB) in the eye. It emphasizes the importance of timely removal of the IOFB to prevent complications and discusses various surgical techniques for removal. The document also highlights the need for eye protection to prevent ocular injuries and recommends regular monitoring of patients with retained IOFBs. The visual prognosis depends on the extent of injury and characteristics of the foreign body. The document includes references to related medical articles and is copyrighted by Wolters Kluwer Health, Inc. [Extracted from the article]
- Published
- 2024
- Full Text
- View/download PDF
29. Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system
- Author
-
Kostrzewski, Tomasz, Snow, Sophie, Battle, Anya Lindström, Peel, Samantha, Ahmad, Zahida, Basak, Jayati, Surakala, Manasa, Bornot, Aurelie, Lindgren, Julia, Ryaboshapkina, Maria, Clausen, Maryam, Lindén, Daniel, Maass, Christian, Young, Lucy May, Corrigan, Adam, Ewart, Lorna, and Hughes, David
- Published
- 2021
- Full Text
- View/download PDF
30. Tumors of the Retinal Pigment Epithelium
- Author
-
Ma, Kevin K., primary, Albert, Daniel M., additional, and Young, Lucy H., additional
- Published
- 2021
- Full Text
- View/download PDF
31. Bending the curve of terrestrial biodiversity needs an integrated strategy
- Author
-
Leclère, David, Obersteiner, Michael, Barrett, Mike, Butchart, Stuart H. M., Chaudhary, Abhishek, De Palma, Adriana, DeClerck, Fabrice A. J., Di Marco, Moreno, Doelman, Jonathan C., Dürauer, Martina, Freeman, Robin, Harfoot, Michael, Hasegawa, Tomoko, Hellweg, Stefanie, Hilbers, Jelle P., Hill, Samantha L. L., Humpenöder, Florian, Jennings, Nancy, Krisztin, Tamás, Mace, Georgina M., Ohashi, Haruka, Popp, Alexander, Purvis, Andy, Schipper, Aafke M., Tabeau, Andrzej, Valin, Hugo, van Meijl, Hans, van Zeist, Willem-Jan, Visconti, Piero, Alkemade, Rob, Almond, Rosamunde, Bunting, Gill, Burgess, Neil D., Cornell, Sarah E., Di Fulvio, Fulvio, Ferrier, Simon, Fritz, Steffen, Fujimori, Shinichiro, Grooten, Monique, Harwood, Thomas, Havlík, Petr, Herrero, Mario, Hoskins, Andrew J., Jung, Martin, Kram, Tom, Lotze-Campen, Hermann, Matsui, Tetsuya, Meyer, Carsten, Nel, Deon, Newbold, Tim, Schmidt-Traub, Guido, Stehfest, Elke, Strassburg, Bernardo B. N., van Vuuren, Detlef P., Ware, Chris, Watson, James E. M., Wu, Wenchao, and Young, Lucy
- Published
- 2020
- Full Text
- View/download PDF
32. Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
- Author
-
Lloyd, Rebecca L., Wijnhoven, Paul W. G., Ramos-Montoya, Antonio, Wilson, Zena, Illuzzi, Giuditta, Falenta, Katarzyna, Jones, Gemma N., James, Neil, Chabbert, Christophe D., Stott, Jonathan, Dean, Emma, Lau, Alan, and Young, Lucy A.
- Published
- 2020
- Full Text
- View/download PDF
33. Toxoplasma gondii Superinfection and Virulence during Secondary Infection Correlate with the Exact ROP5/ROP18 Allelic Combination
- Author
-
Jensen, Kirk DC, Camejo, Ana, Melo, Mariane B, Cordeiro, Cynthia, Julien, Lindsay, Grotenbreg, Gijsbert M, Frickel, Eva-Maria, Ploegh, Hidde L, Young, Lucy, and Saeij, Jeroen PJ
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Biodefense ,Infectious Diseases ,Foodborne Illness ,Emerging Infectious Diseases ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Infection ,Alleles ,Animals ,Coinfection ,Mice ,Inbred C57BL ,North America ,Protozoan Proteins ,South America ,Superinfection ,Toxoplasma ,Toxoplasmosis ,Animal ,Virulence ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
UnlabelledThe intracellular parasite Toxoplasma gondii infects a wide variety of vertebrate species globally. Infection in most hosts causes a lifelong chronic infection and generates immunological memory responses that protect the host against new infections. In regions where the organism is endemic, multiple exposures to T. gondii likely occur with great frequency, yet little is known about the interaction between a chronically infected host and the parasite strains from these areas. A widely used model to explore secondary infection entails challenge of chronically infected or vaccinated mice with the highly virulent type I RH strain. Here, we show that although vaccinated or chronically infected C57BL/6 mice are protected against the type I RH strain, they are not protected against challenge with most strains prevalent in South America or another type I strain, GT1. Genetic and genomic analyses implicated the parasite-secreted rhoptry effectors ROP5 and ROP18, which antagonize the host's gamma interferon-induced immunity-regulated GTPases (IRGs), as primary requirements for virulence during secondary infection. ROP5 and ROP18 promoted parasite superinfection in the brains of challenged survivors. We hypothesize that superinfection may be an important mechanism to generate T. gondii strain diversity, simply because two parasite strains would be present in a single meal consumed by the feline definitive host. Superinfection may drive the genetic diversity of Toxoplasma strains in South America, where most isolates are IRG resistant, compared to North America, where most strains are IRG susceptible and are derived from a few clonal lineages. In summary, ROP5 and ROP18 promote Toxoplasma virulence during reinfection.ImportanceToxoplasma gondii is a widespread parasite of warm-blooded animals and currently infects one-third of the human population. A long-standing assumption in the field is that prior exposure to this parasite protects the host from subsequent reexposure, due to the generation of protective immunological memory. However, this assumption is based on clinical data and mouse models that analyze infections with strains common to Europe infections with strains common to Europe and North America. In contrast, we found that the majority of strains sampled from around the world, in particular those from South America, were able to kill or reinfect the brains of hosts previously exposed to T. gondii. The T. gondii virulence factors ROP5 and ROP18, which inhibit key host effectors that mediate parasite killing, were required for these phenotypes. We speculate that these results underpin clinical observations that pregnant women previously exposed to Toxoplasma can develop congenital infection upon reexposure to South American strains.
- Published
- 2015
34. Case 8: Extracapsular Cataract Extraction Wound Rupture
- Author
-
Dahrouj, Mohammad, van Zyl, Tavé, Young, Lucy H., Grob, Seanna, Grob, Seanna, editor, and Kloek, Carolyn, editor
- Published
- 2018
- Full Text
- View/download PDF
35. Characterization of Epiretinal Proliferation in Full-Thickness Macular Holes and Effects on Surgical Outcomes
- Author
-
Lee Kim, Esther, Weiner, Adam J., Ung, Cindy, Roh, Miin, Wang, Jay, Lee, Ivan J., Huang, Natalie T., Stem, Maxwell, Dahrouj, Mohammad, Eliott, Dean, Vavvas, Demetrios G., Young, Lucy H.Y., Williams, George A., Garretson, Bruce R., Kim, Ivana K., Hassan, Tarek S., Mukai, Shizuo, Ruby, Alan J., Faia, Lisa J., Capone, Antonio, Jr., Comander, Jason, Kim, Leo A., Wu, David M., Drenser, Kimberly A., Woodward, Maria A., Wolfe, Jeremy D., and Yonekawa, Yoshihiro
- Published
- 2019
- Full Text
- View/download PDF
36. Endogenous Endophthalmitis
- Author
-
Patel, Avni V., Young, Lucy H., Durand, Marlene L., editor, Miller, Joan W., editor, and Young, Lucy H., editor
- Published
- 2016
- Full Text
- View/download PDF
37. Novel uses of complement inhibitors in myasthenia gravis—Two case reports.
- Author
-
Zadeh, Sean, Price, Hayley, Drews, Reed, Bouffard, Marc A., Young, Lucy H., and Narayanaswami, Pushpa
- Abstract
Introduction/Aims: Myasthenia gravis (MG) is a rare, life‐threatening immune‐related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5‐complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. Methods: This was a retrospective review of two medical records. Results: Patient 1: An 80‐year‐old male with recurrent, non‐muscle invasive transitional cell carcinoma of the bladder developed ICI‐induced AChR ab positive MG (ICI‐MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58‐year‐old male had refractory thymoma‐associated AChR ab‐positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri‐infusion pulse prednisone. MG remained stable and he continues eculizumab. Discussion: In the first patient, eculizumab, followed by ravulizumab, improved ICI‐MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI‐induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
38. SP10.3 Colectomy for Inflammatory Bowel Disease (IBD) – use of the National Consultant Information Programme (NCIP) to highlight colorectal surgical practice in England
- Author
-
Galla, Aashlesha, primary, Maxwell-Armstrong, Charles, additional, Booth, Matthew, additional, Young, Lucy, additional, Bogovac, Marina, additional, and Williams, Norman, additional
- Published
- 2023
- Full Text
- View/download PDF
39. FTP2.12 The National Consultant Information Programme (NCIP) and its effect on current Colorectal surgical practice, specifically looking at Exenteration of Pelvis for Lower Gastrointestinal Cancer
- Author
-
Galla, Aashlesha, primary, Maxwell-Armstrong, Charles, additional, Booth, Matthew, additional, Young, Lucy, additional, Bogovac, Marina, additional, and Williams, Norman, additional
- Published
- 2023
- Full Text
- View/download PDF
40. CMV Retinitis
- Author
-
Ung, Cindy, primary and Young, Lucy H., additional
- Published
- 2020
- Full Text
- View/download PDF
41. Choroidal Effusions and Detachments
- Author
-
Waheed, Nadia K., primary, Mendonça, Luísa S. M., additional, and Young, Lucy H., additional
- Published
- 2020
- Full Text
- View/download PDF
42. CMV Retinitis
- Author
-
Patel, Avni, Young, Lucy, and Papaliodis, George N., editor
- Published
- 2017
- Full Text
- View/download PDF
43. Translational control of gene expression in response to DNA-damaging agents
- Author
-
Young, Lucy A.
- Subjects
572.865 - Abstract
In response to DNA damage, cells initiate a complex DNA-damage response (DDR) that includes mechanisms of DNA repair, cell cycle arrest, or in the cases of irreparable damage, apoptosis. Although regulation of the DDR has been extensively studied at the level of post-translational modifications and transcription, less is known about the role played by translational regulation. The data presented in this study describes the translational response and genome-wide translational profiles of human cells exposed to the DNA-damaging agents, ethyl methanesulphonate (EMS) and ionising radiation (IR). Exposure of HeLa cells to EMS caused a 60% decrease in global protein synthesis, mediated by phosphorylation of the a-subunit of eukaryotic initiation factor 2 (eIF2), whereas IR modulated global protein synthesis through changes in 4E-BP phosphorylation. Polysome profiling by cDNA micro array was used to identify on a genome-wide scale the differential translation of mRNAs following exposure to EMS or IR. Functional analysis of the data revealed translational regulation of distinct subsets of genes that, in the most part, were unique to EMS or IR exposure. An enrichment of genes involved in the ER stress response was identified following exposure to EMS, whereas genes involved in the mitochondrial oxidative phosphorylation pathway and ubiquitin-proteasome pathway were identified following exposure to IR. These data suggest that translation of distinct subsets of mRNAs may be necessary to initiate appropriate stress responses following exposure to different types of DNA-damaging agents, and in agreement with previous studies (powley et al., 2009) implicates translational control as an important mechanism of the DRR.
- Published
- 2011
44. Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways
- Author
-
Melo, Mariane B, Nguyen, Quynh P, Cordeiro, Cynthia, Hassan, Musa A, Yang, Ninghan, McKell, Renée, Rosowski, Emily E, Julien, Lindsay, Butty, Vincent, Dardé, Marie-Laure, Ajzenberg, Daniel, Fitzgerald, Katherine, Young, Lucy H, and Saeij, Jeroen PJ
- Subjects
Microbiology ,Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Emerging Infectious Diseases ,Biodefense ,Vaccine Related ,Infectious Diseases ,Prevention ,Biotechnology ,Genetics ,Foodborne Illness ,Aetiology ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Infection ,Animals ,Cells ,Cultured ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,HEK293 Cells ,Host-Parasite Interactions ,Humans ,Macrophages ,Mice ,Mice ,Inbred C57BL ,Multigene Family ,Signal Transduction ,Toxoplasma ,Immunology ,Virology ,Medical microbiology - Abstract
Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.
- Published
- 2013
45. Hydroxychloroquine retinopathy — implications of research advances for rheumatology care
- Author
-
Jorge, April, Ung, Cindy, Young, Lucy H., Melles, Ronald B., and Choi, Hyon K.
- Published
- 2018
- Full Text
- View/download PDF
46. pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry
- Author
-
Jones, Gemma N., Rooney, Claire, Griffin, Nicola, Roudier, Martine, Young, Lucy A., Garcia-Trinidad, Antonio, Hughes, Gareth D., Whiteaker, Jeffrey R., Wilson, Zena, Odedra, Rajesh, Zhao, Lei, Ivey, Richard G., Howat, William J., Harrington, Elizabeth A., Barrett, J. Carl, Ramos-Montoya, Antonio, Lau, Alan, Paulovich, Amanda G., Cadogan, Elaine B., and Pierce, Andrew J.
- Published
- 2018
- Full Text
- View/download PDF
47. Past, present, and future of the Living Planet Index
- Author
-
Ledger, Sophie E. H., primary, Loh, Jonathan, additional, Almond, Rosamunde, additional, Böhm, Monika, additional, Clements, Christopher F., additional, Currie, Jessica, additional, Deinet, Stefanie, additional, Galewski, Thomas, additional, Grooten, Monique, additional, Jenkins, Martin, additional, Marconi, Valentina, additional, Painter, Brett, additional, Scott-Gatty, Kate, additional, Young, Lucy, additional, Hoffmann, Michael, additional, Freeman, Robin, additional, and McRae, Louise, additional
- Published
- 2023
- Full Text
- View/download PDF
48. Data from Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma
- Author
-
Floc'h, Nicolas, primary, Ashton, Susan, primary, Ferguson, Douglas, primary, Taylor, Paula, primary, Carnevalli, Larissa S., primary, Hughes, Adina M., primary, Harris, Emily, primary, Hattersley, Maureen, primary, Wen, Shenghua, primary, Curtis, Nicola J., primary, Pilling, James E., primary, Young, Lucy A., primary, Maratea, Kim, primary, Pease, Elizabeth J., primary, and Barry, Simon T., primary
- Published
- 2023
- Full Text
- View/download PDF
49. Supplementary Tables 1-5 and figures 1-3 from Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma
- Author
-
Floc'h, Nicolas, primary, Ashton, Susan, primary, Ferguson, Douglas, primary, Taylor, Paula, primary, Carnevalli, Larissa S., primary, Hughes, Adina M., primary, Harris, Emily, primary, Hattersley, Maureen, primary, Wen, Shenghua, primary, Curtis, Nicola J., primary, Pilling, James E., primary, Young, Lucy A., primary, Maratea, Kim, primary, Pease, Elizabeth J., primary, and Barry, Simon T., primary
- Published
- 2023
- Full Text
- View/download PDF
50. Hydroxychloroquine Retinopathy in the Era of Advanced Imaging Modalities
- Author
-
Dahrouj, Mohammad and Young, Lucy
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.