6 results on '"Kit-Yi Leung"'
Search Results
2. Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels
- Author
-
John G. Sled, Lena Serghides, Tanvi Sanghvi, Evelyn Y. Laurette, Oscar Tejada, Paul Delgado-Olguin, Haneesha Mohan, Kit-Yi Leung, Monica S. Guzman Lenis, Nicholas D. E. Greene, Lindsay S. Cahill, and Andrew J. Copp more...
- Subjects
0301 basic medicine ,Letter ,lcsh:Medicine ,Physiology ,HIV Infections ,Microphthalmia ,Piperazines ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Odds Ratio ,Neural Tube Defects ,lcsh:R5-920 ,General Medicine ,Immunohistochemistry ,3. Good health ,Phenotype ,medicine.anatomical_structure ,Maternal Exposure ,030220 oncology & carcinogenesis ,Toxicity ,Dolutegravir ,Gestation ,Female ,Disease Susceptibility ,lcsh:Medicine (General) ,Heterocyclic Compounds, 3-Ring ,Research Paper ,medicine.drug ,Pyridones ,Emtricitabine ,Risk Assessment ,General Biochemistry, Genetics and Molecular Biology ,Congenital Abnormalities ,03 medical and health sciences ,Placenta ,Oxazines ,medicine ,Animals ,HIV Integrase Inhibitors ,Fetus ,business.industry ,lcsh:R ,medicine.disease ,Disease Models, Animal ,Regimen ,030104 developmental biology ,chemistry ,business - Abstract
Background Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential. Methods Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5 mg/kg-peak plasma concentration ~3000 ng/ml – therapeutic level), or 5x-DTG (12.5 mg/kg-peak plasma concentration ~12,000 ng/ml – supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50 mg/kg tenofovir+33.3 mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry. Findings 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group. Interpretation Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake. Funding This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I. more...
- Published
- 2021
- Full Text
- View/download PDF
Catalog
3. Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis
- Author
-
Selina Wray, Brian H. Anderton, Malcolm Saxton, Kit-Yi Leung, Anjan Seereeram, Diane P. Hanger, Helen Byers, Malcolm Ward, and C. Hugh Reynolds
- Subjects
Molecular Sequence Data ,tau Proteins ,macromolecular substances ,Models, Biological ,Biochemistry ,MAP2K7 ,Glycogen Synthase Kinase 3 ,Alzheimer Disease ,GSK-3 ,Casein Kinase I ,mental disorders ,Casein kinase 2, alpha 1 ,Animals ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Glycogen synthase ,Molecular Biology ,MAPK14 ,Neurons ,Glycogen Synthase Kinase 3 beta ,biology ,Chemistry ,Brain ,Cell Biology ,Molecular biology ,Recombinant Proteins ,Rats ,Casein Kinase Idelta ,biology.protein ,Casein kinase 1 ,Casein kinase 2 ,Protein Binding - Abstract
Tau in Alzheimer disease brain is highly phosphorylated and aggregated into paired helical filaments comprising characteristic neurofibrillary tangles. Here we have analyzed insoluble Tau (PHF-tau) extracted from Alzheimer brain by mass spectrometry and identified 11 novel phosphorylation sites, 10 of which were assigned unambiguously to specific amino acid residues. This brings the number of directly identified sites in PHF-tau to 39, with an additional six sites indicated by reactivity with phosphospecific antibodies to Tau. We also identified five new phosphorylation sites in soluble Tau from control adult human brain, bringing the total number of reported sites to nine. To assess which kinases might be responsible for Tau phosphorylation, we used mass spectrometry to determine which sites were phosphorylated in vitro by several kinases. Casein kinase 1delta and glycogen synthase kinase-3beta were each found to phosphorylate numerous sites, and each kinase phosphorylated at least 15 sites that are also phosphorylated in PHF-tau from Alzheimer brain. A combination of casein kinase 1delta and glycogen synthase kinase-3beta activities could account for over three-quarters of the serine/threonine phosphorylation sites identified in PHF-tau, indicating that casein kinase 1delta may have a role, together with glycogen synthase kinase-3beta, in the pathogenesis of Alzheimer disease. more...
- Published
- 2007
- Full Text
- View/download PDF
4. Analysis of CLN3-protein interactions using the yeasttwo-hybrid system
- Author
-
Patricia B. Munroe, Kit-Yi Leung, Nicholas D. E. Greene, and Sara E. Mole
- Subjects
Batten disease ,Protein subunit ,Two-hybrid screening ,Saccharomyces cerevisiae ,Biology ,Protein–protein interaction ,Neuronal Ceroid-Lipofuscinoses ,Two-Hybrid System Techniques ,medicine ,Humans ,Child ,Membrane Glycoproteins ,Proteins ,General Medicine ,Mitochondrial Proton-Translocating ATPases ,medicine.disease ,biology.organism_classification ,Fusion protein ,Mitochondria ,Proton-Translocating ATPases ,Biochemistry ,CLN3 ,Pediatrics, Perinatology and Child Health ,Neuronal ceroid lipofuscinosis ,Neurology (clinical) ,Molecular Chaperones - Abstract
Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a childhood neurodegenerative disease that is caused by mutations in the CLN3 gene. The protein encoded by CLN3 has no homology with any proteins of known function and its cellular role remains elusive. In order to investigate the role played by the CLN3 protein we aimed to identify interacting proteins. Here, we describe the yeast two-hybrid system as the approach taken to investigate such protein-protein interactions. CLN3 was expressed as a fusion protein with a DNA-binding domain and used to screen a library of human fetal brain cDNAs fused to a transcriptional activation domain. Owing to low level expression of the full length CLN3 fusion protein, truncated regions corresponding to the predicted hydrophilic regions were also tested. No proteins that interact with CLN3 were detected, nor was there any evidence for CLN3-CLN3 interactions. Potential interaction of CLN3 with subunit c of mitochondrial ATP synthase, the major component of the storage material that accumulates in Batten disease patients, was also tested. No interaction was detected suggesting that the accumulation of subunit c does not result from loss of a process that requires a direct interaction with CLN3. We conclude that either CLN3 does not interact with other proteins or such interactions cannot be detected using the two-hybrid system. more...
- Published
- 2001
- Full Text
- View/download PDF
5. 06-P024 Identification of Lmnb1 as a possible modifier gene for neural tube defects in the mouse
- Author
-
Dawn Savery, Nicholas D. E. Greene, Peter Gustavsson, Andrew J. Copp, Kit-Yi Leung, and Sandra C. P. De Castro
- Subjects
Embryology ,medicine.anatomical_structure ,Neural tube ,medicine ,Identification (biology) ,Computational biology ,Biology ,Gene ,Developmental Biology - Published
- 2009
- Full Text
- View/download PDF
6. P3-244 Modulating GSK-3 phosphorylation regulates axonal transport of tau
- Author
-
Helen Byers, Kit-Yi Leung, Malcom Ward, Diane P. Hanger, Brian H. Anderton, and Inmaculada Cuchillo-Ibañez
- Subjects
Aging ,Chemistry ,GSK-3 ,General Neuroscience ,Axoplasmic transport ,Phosphorylation ,Neurology (clinical) ,Geriatrics and Gerontology ,Developmental Biology ,Cell biology - Published
- 2004
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.