A5078249129- Adenosine and Purinergic Signaling
- Corneal Surgery and Treatments
- Epigenetics and DNA Methylation
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Corneal surgery and disorders
- Immune Cell Function and Interaction
- Systemic Lupus Erythematosus Research
- Enzyme Structure and Function
- Melanoma and MAPK Pathways
- Liver Diseases and Immunity
- Synthesis of heterocyclic compounds
- Amino Acid Enzymes and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Plant tissue culture and regeneration
- Platelet Disorders and Treatments
- Ferrocene Chemistry and Applications
- Lymphoma Diagnosis and Treatment
- HER2/EGFR in Cancer Research
- Chronic Lymphocytic Leukemia Research
- Immune Response and Inflammation
- Ocular Surface and Contact Lens
- Advanced Glycation End Products research
University of California, San Francisco
2019-2024
Howard Hughes Medical Institute
2019-2021
University of Oxford
2016-2018
Genomics (United Kingdom)
2018
Discovery Institute
2018
Genomics England
2018
Prolonged drug residence times may result in longer-lasting efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high dissociation rates. However, few strategies have been elaborated to rationally modulate time thereby integrate this key property into the development process. Herein, we show that interaction between a halogen moiety on an inhibitor aromatic residue target protein can significantly increase time. By using of serine/threonine kinase...
B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and trafficking. P2RY8 a receptor with established roles in germinal center (GC) migration inhibition growth regulation. Somatic variants are common GC-derived lymphomas. Here, we identify germline novel or rare missense lupus kindreds the related antiphospholipid syndrome, “de novo” variant child severe nephritis. All decreased protein expression, F-actin abundance, GPCR-RhoA...
Abstract Missense variants can have pleiotropic effects on protein function and predicting these be difficult. We performed near-saturation deep mutational scanning of P2RY8, a G-protein-coupled receptor that promotes germinal center B cell confinement. assayed the effect each variant surface expression, migration, proliferation. delineated affected both expression function, independently discrepantly migration also used cryo-electron microscopy to determine structure activated, ligand-bound...
The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. targeted by several clinically approved inhibitors, inhibition has been reported to protect from doxorubicin-induced cardiomyopathy. On other hand, unintended targeting linked severe adverse effects such as development cutaneous squamous carcinoma. Therefore, both specific inhibitors ZAK, well anticancer drugs lacking off-target activity against may provide therapeutic...
Abstract SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study to elucidate its substrate specificity functional characteristics. In contrast orthologs from great apes, human SLC22A10, tagged green fluorescent protein, not expressed on the plasma membrane. Cells expressing ape exhibit significant accumulation estradiol-17β-glucuronide, unlike those SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which leucine apes. Replacing...
This work establishes how P2RY8 ligand is exported and degraded to regulate lymphocyte behavior in lymphoid follicles bone marrow.
Mononuclear phagocytes (MP) have central importance in innate immunity, inflammation, and fibrosis. Recruited MPs, such as macrophages, are plastic cells can switch from an inflammatory to a restorative phenotype during the healing process. However, role of MPs corneal wound is not completely understood. The purpose this study characterize kinetics recruited evaluate macrophage metalloelastase (MMP12) process, using vivo chemical injury model. Unwounded wounded corneas wild-type (WT)...
Abstract: Major advances in genomics have dramatically increased our understanding of Fuchs endothelial corneal dystrophy (FECD) and identified diverse genetic causes associations. Biomarkers derived from these studies the potential to inform both clinical treatment yield novel therapeutics for this dystrophy.
Abstract Längere Verweilzeiten vom Wirkstoff am Zielmolekül (Target) können zu länger anhaltender Arzneimittelwirksamkeit, verbesserten pharmakodynamischen Eigenschaften und kinetischer Selektivität gegenüber Antitargets mit schnellen Dissoziationsraten führen. Bisher wurden nur wenige Strategien gefunden, um die Verweilzeit des Wirkstoffs rational modulieren dadurch diese Schlüsseleigenschaft in den Medikamentenentwicklungsprozess integrieren. Die Wechselwirkung zwischen einem Halogenrest...
ABSTRACT Prolonged drug residence times may result in longer lasting efficacy, improved pharmacodynamic properties and “kinetic selectivity” over off-targets with fast dissociation rates. However, few strategies have been elaborated to rationally modulate time thereby integrate this key property into the development process. Here, we show that interaction between a halogen moiety on an inhibitor aromatic residue target protein can significantly increase time. By using of serine/threonine...
Exaggerated PI3K/AKT signaling abrogates B cell tolerance and results in autoimmunity. P2RY8 is a repressor of AKT-mediated activation that also restrains migration. Here we identified de novo, novel missense variant child with severe lupus nephritis, an ultrarare proband antiphospholipid syndrome, less rare six patients. These variants impaired protein expression function, leading to increased AKT ERK activity migration, diminished follicular confinement. By contrast, overexpression...