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Agilent Technologies
Company•Santa Clara, California, United States•
About: Agilent Technologies is a company organization based out in Santa Clara, California, United States. It is known for research contribution in the topics: Signal & Mass spectrometry. The organization has 7398 authors who have published 11518 publications receiving 262410 citations. The organization is also known as: Agilent Technologies, Inc..
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TL;DR: It is shown that synaptic TCR–pMHC binding dynamics differ significantly from TCR’s binding in solution, and TCR affinity for pMHC was significantly elevated as the result of a large (about 100-fold) increase in the association rate, a likely consequence of complementary molecular orientation and clustering.
Abstract: The use of a novel FRET-based imaging system provides an in situ view of the kinetics of T-cell receptor (TCR) binding to peptide MHC complexes in their natural environment, the immunological synapse. Previously the mater of how containment in this environment would affect the molecular interactions that drive cell–cell interactions has been a matter of speculation. Now that they have been measured, both expected effects (enhanced association rate due to optimal orientation) and unexpected (a very active cytoskeletal component destabilizing TCR binding) are revealed. This work is of relevance to T-cell immunology and to in cell–cell interactions more generally. T lymphocytes, which are an integral part of most adaptive immune responses, recognize foreign antigens through the binding of antigenic peptide–major histocompatibility complex (pMHC) molecules on other cells to specific T-cell antigen receptors (TCRs). Using single-molecule microscopy and fluorescence resonance energy transfer, the kinetics of TCR–pMHC binding are now measured in situ, revealing accelerated kinetics and increased affinity when compared with solution measurements. The recognition of foreign antigens by T lymphocytes is essential to most adaptive immune responses. It is driven by specific T-cell antigen receptors (TCRs) binding to antigenic peptide–major histocompatibility complex (pMHC) molecules on other cells1. If productive, these interactions promote the formation of an immunological synapse2,3. Here we show that synaptic TCR–pMHC binding dynamics differ significantly from TCR–pMHC binding in solution. We used single-molecule microscopy and fluorescence resonance energy transfer (FRET) between fluorescently tagged TCRs and their cognate pMHC ligands to measure the kinetics of TCR–pMHC binding in situ. When compared with solution measurements, the dissociation of this complex was increased significantly (4–12-fold). Disruption of actin polymers reversed this effect, indicating that cytoskeletal dynamics destabilize this interaction directly or indirectly. Nevertheless, TCR affinity for pMHC was significantly elevated as the result of a large (about 100-fold) increase in the association rate, a likely consequence of complementary molecular orientation and clustering. In helper T cells, the CD4 molecule has been proposed to bind cooperatively with the TCR to the same pMHC complex. However, CD4 blockade had no effect on the synaptic TCR affinity, nor did it destabilize TCR–pMHC complexes, indicating that the TCR binds pMHC independently of CD4.
479 citations
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University of California, San Francisco1, Memorial Sloan Kettering Cancer Center2, Université Paris-Saclay3, University of South Florida4, University of California, Los Angeles5, Harvard University6, Princess Margaret Cancer Centre7, University of Sydney8, Westmead Hospital9, Macquarie University10, Mayo Clinic11, University of Pennsylvania12, University of Pittsburgh13, Agilent Technologies14, Merck & Co.15
TL;DR: PD-L 1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.
Abstract: PurposeExpression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti–programmed death 1 (PD-1). This study explored the relationship between anti–PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827).Patients and MethodsSix hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 t...
477 citations
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TL;DR: MAGE will help microarray data producers and users to exchange information by providing a common platform for data exchange, and MAGE-STK will make the adoption of MAGE easier.
Abstract: Background
Meaningful exchange of microarray data is currently difficult because it is rare that published data provide sufficient information depth or are even in the same format from one publication to another. Only when data can be easily exchanged will the entire biological community be able to derive the full benefit from such microarray studies.
474 citations
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472 citations
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TL;DR: A specially designed cantilever tip is created that allows these interaction forces to be measured with good (sub-microsecond) temporal resolution and material properties to be determined and mapped in detail with nanoscale spatial resolution.
Abstract: Tapping-mode atomic force microscopy (AFM), in which the vibrating tip periodically approaches, interacts and retracts from the sample surface, is the most common AFM imaging method. The tip experiences attractive and repulsive forces that depend on the chemical and mechanical properties of the sample, yet conventional AFM tips are limited in their ability to resolve these time-varying forces. We have created a specially designed cantilever tip that allows these interaction forces to be measured with good (sub-microsecond) temporal resolution and material properties to be determined and mapped in detail with nanoscale spatial resolution. Mechanical measurements based on these force waveforms are provided at a rate of 4 kHz. The forces and contact areas encountered in these measurements are orders of magnitude smaller than conventional indentation and AFM-based indentation techniques that typically provide data rates around 1 Hz. We use this tool to quantify and map nanomechanical changes in a binary polymer blend in the vicinity of its glass transition. Phase changes and chemical compositional variations in materials on the nanoscale have been studied using various scanning force microscopy techniques. In these techniques, a force-sensing cantilever with a sharp tip is placed in continuous contact with the sample surface. Dynamical properties of the cantilever are adjusted depending on the material in contact with the tip. Examples of these techniques include ultrasonic force microscopy 1 , force modulation microscopy 2 , shear modulation force microscopy and lateral force microscopy 3,4 .T hese
469 citations
Authors
Showing all 7402 results
Name | H-index | Papers | Citations |
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Hongjie Dai | 197 | 570 | 182579 |
Zhuang Liu | 149 | 535 | 87662 |
Jie Liu | 131 | 1531 | 68891 |
Thomas Quertermous | 103 | 405 | 52437 |
John E. Bowers | 102 | 1767 | 49290 |
Roy G. Gordon | 89 | 449 | 31058 |
Masaru Tomita | 76 | 677 | 40415 |
Stuart Lindsay | 74 | 347 | 22224 |
Ron Shamir | 74 | 319 | 23670 |
W. Richard McCombie | 71 | 144 | 64155 |
Tomoyoshi Soga | 71 | 392 | 21209 |
Michael R. Krames | 65 | 321 | 18448 |
Shabaz Mohammed | 64 | 188 | 17254 |
Geert Leus | 62 | 609 | 19492 |
Giuseppe Gigli | 61 | 541 | 15159 |