Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) ...candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.
With the capacity to produce and record data electronically, Scientific research and the data associated with it have grown at an unprecedented rate. However, despite a decent amount of data now ...existing in an electronic form, it is still common for scientific research to be recorded in an unstructured text format with inconsistent context (vocabularies) which vastly reduces the potential for direct intelligent analysis. Research has demonstrated that the use of semantic technologies such as ontologies to structure and enrich scientific data can greatly improve this potential. However, whilst there are many ontologies that can be used for this purpose, there is still a vast quantity of scientific terminology that does not have adequate semantic representation. A key area for expansion identified by the authors was the pharmacokinetic/pharmacodynamic (PK/PD) domain due to its high usage across many areas of Pharma. As such we have produced a set of these terms and other bioassay related terms to be incorporated into the BioAssay Ontology (BAO), which was identified as the most relevant ontology for this work. A number of use cases developed by experts in the field were used to demonstrate how these new ontology terms can be used, and to set the scene for the continuation of this work with a look to expanding this work out into further relevant domains. The work done in this paper was part of Phase 1 of the SEED project (Semantically Enriching electronic laboratory notebook (eLN) Data).
Planned cryogenic gravitational-wave detectors will require improved coatings with a strain thermal noise reduced by a factor of 25 compared to Advanced LIGO. We present investigations of HfO_{2} ...doped with SiO_{2} as a new coating material for future detectors. Our measurements show an extinction coefficient of k=6×10^{-6} and a mechanical loss of ϕ=3.8×10^{-4} at 10 K, which is a factor of 2 below that of SiO_{2}, the currently used low refractive-index coating material. These properties make HfO_{2} doped with SiO_{2} ideally suited as a low-index partner material for use with a-Si in the lower part of a multimaterial coating. Based on these results, we present a multimaterial coating design which, for the first time, can simultaneously meet the strict requirements on optical absorption and thermal noise of the cryogenic Einstein Telescope.
We report on the mechanical loss from bulk and shear stresses in thin film, ion beam deposited, titania-doped tantala. The numerical values of these mechanical losses are necessary to fully calculate ...the Brownian thermal noise in precision optical cavities, including interferometric gravitational wave detectors like LIGO. We found the values from measuring the normal mode mechanical quality factors, Q's, in the frequency range of about 2000-10,000 Hz, of silica disks coated with titania-doped tantala coupled with calculating the elastic energy in shear and bulk stresses in the coating using a finite element model. We fit the results to both a frequency independent and frequency dependent model and find ϕshear=(8.3±1.1)×10−4, ϕbulk=(6.6±3.8)×10−4 with a frequency independent model and ϕshear(f)=(5.0±0.7)×10−4+(5.4±1.1)×10−8f, ϕbulk(f)=(11±2.8)×10−4−(8.7±4.7)×10−8f with a frequency dependent (linear) model. The ratio of these values suggest that modest improvement in the coating thermal noise may be possible in future gravitational wave detector optics made with titania-doped tantala as the high index coating material by optimizing the coating design to take advantage of the two different mechanical loss angles.
•Mechanical quality factors for a sample with coating material titania doped tantala, used by LIGO, have been measured.•A finite element model has been developed to analyze the elastic energy distribution between shear and bulk stresses.•Two independent loss angles for the coating material titania doped tantala have been calculated.
Second-generation interferometric gravitational-wave detectors will operate at temperatures noticeably above room temperature. Study was done to determine what effect elevated temperatures would have ...on the
Q and coating thermal noise of the detector mirrors. Results show that increased temperature increases loss angle in a manner that is more significant at higher frequencies. Trends show that the increased temperature will have a negligible effect at the low (100 Hz) frequencies important to second-generation detectors.
May 15--A recent programming change by Kansas City's community radio station is being called a business decision, but it represents yet another setback for the local jazz and blues scene. According ...to that mission statement, KKFI 90.1 FM seeks to "stimulate, educate and entertain our audience, to reflect the diversity of the local and world community, and to provide a channel for individuals and groups, issues and music that have been overlooked, suppressed and under-represented by other media."
Just like graduates from high schools all around the area who are earning their diplomas this month, each GED recipient that I heard from last week was filled with the possibilities that a high ...school equivalency could bring them.
Greg Carroll, executive director of the American Jazz Museum, recently announced that the museum had received a major federal grant that will allow installation of a permanent exhibit called the John ...Baker Film Collection Exhibit. City Manager Wayne Cauthen told me that the city had received a $1.8 million economic development grant to make the vacant spaces in the latest phase of the development "tenant-ready."
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