Temperature Dependence of the Mechanical Dissipation of Gallium Bonds for Use in Gravitational Wave Detectors.

The mirror suspensions in gravitational wave detectors demand low mechanical loss jointing to ensure good enough detector performance and to enable the detection of gravitational waves. Hydroxide catalysis bonds have been used in the fused silica suspensions of the GEO600, Advanced LIGO, and Advanced Virgo detectors. Future detectors may use cryogenic cooling of the mirror suspensions and this leads to a potential change of mirror material and suspension design.

Titania Mixed with Silica: A Low Thermal-Noise Coating Material for Gravitational-Wave Detectors.

Coating thermal noise is one of the dominant noise sources in current gravitational wave detectors and ultimately limits their ability to observe weaker or more distant astronomical sources. This Letter presents investigations of TiO_{2} mixed with SiO_{2} (TiO_{2}:SiO_{2}) as a coating material. We find that, after heat treatment for 100 h at 850 °C, thermal noise of a highly reflective coating comprising of TiO_{2}:SiO_{2} and SiO_{2} reduces to 76% of the current levels in the Advanced LIGO and Advanced Virgo detectors-with potential for reaching 45%, if we assume the mechanical loss of state-of-the-art SiO_{2} layers.

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

Amorphous dielectric optical coatings deposited by plasma ion-assisted electron beam evaporation for gravitational wave detectors.

Coating thermal noise (CTN) in amorphous coatings is a drawback hindering their application in precision experiments such as gravitational wave detectors (GWDs). Mirrors for GWDs are Bragg's reflectors consisting of a bilayer-based stack of high- and low-refractive-index materials showing high reflectivity and low CTN. In this paper, we report the characterization of morphological, structural, optical, and mechanical properties of high-index materials such as scandium sesquioxide and hafnium dioxide and a low-index material such as magnesium fluoride deposited by plasma ion-assisted electron beam evaporation.

Tantalum oxide and silicon oxide mixture coatings deposited using microwave plasma assisted co-sputtering for optical mirror coatings in gravitational wave detectors.

This work presents the characterization of the optical and mechanical properties of thin films based on ( ) ( ) mixed oxides deposited by microwave plasma assisted co-sputtering, including post-annealing treatments. The deposition of low mechanical loss materials (3×10) with a high refractive index (1.93) while maintaining low processing costs was achieved and the following trends were demonstrated: The energy band gap increased as the concentration was increased in the mixture, and the disorder constant decreased when the annealing temperatures increased.

Demonstration of the Multimaterial Coating Concept to Reduce Thermal Noise in Gravitational-Wave Detectors.

Thermal noise associated with the mechanical loss of current highly reflective mirror coatings is a critical limit to the sensitivity of gravitational-wave detectors. Several alternative coating materials show potential for reducing thermal noise, but cannot be used due to their high optical absorption. Multimaterial coatings have been proposed to enable the use of such materials to reduce thermal noise while minimizing their impact on the total absorption of the mirror coating.

Integrating the Impact of Lipophilicity on Potency and Pharmacokinetic Parameters Enables the Use of Diverse Chemical Space during Small Molecule Drug Optimization.

Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations.

Advances in the study of drug metabolism - symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).

The 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the "" symposium, as it engaged attendees with diverse backgrounds.

Mirror Coating Solution for the Cryogenic Einstein Telescope.

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.

Interpretation of Metabolic Stability Studies for Racemic Mixtures.

In early drug discovery, where chiral syntheses may not yet have been elucidated or enantiomeric separation is not feasible, screening of racemates in metabolic stability assays may offer a pragmatic approach. To assess the risk of incorrectly deprioritizing enantiomers due to misclassification of apparent intrinsic clearance (CLint), we evaluated (1) theoretical simulations; (2) literature on enantiomeric CLint differences; (3) historic MSD data; and (4) new data on enantiomers with high eudysmic ratios and low predicted three-dimensional similarity. Overall, the results suggested minimal risk of not progressing an enantiomer due to an appreciably different (>3-fold) racemate CLint.

Microbial biotransformation - an important tool for the study of drug metabolism.

Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes.

Analyzing the Potential Root Causes of Variability of Pharmacokinetics in Preclinical Species.

The purpose of this research was to assess variability in pharmacokinetic profiles (PK variability) in preclinical species and identify the risk factors associated with the properties of a drug molecule that contribute to the variability. Exposure data in mouse, rat, dog, and monkey for a total of 16,592 research compounds studied between 1999 and 2013 were included in the analysis. Both in vivo study parameters and in silico/experimental physicochemical properties of the molecules were analyzed.

Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A.

A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes.

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose.

A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy.

Asteroid modeling for testing spacecraft approach and landing.

Spacecraft exploration of asteroids presents autonomous-navigation challenges that can be aided by virtual models to test and develop guidance and hazard-avoidance systems. Researchers have extended and applied graphics techniques to create high-resolution asteroid models to simulate cameras and other spacecraft sensors approaching and descending toward asteroids. A scalable model structure with evenly spaced vertices simplifies terrain modeling, avoids distortion at the poles, and enables triangle-strip definition for efficient rendering.

Investigation of the Young's modulus and thermal expansion of amorphous titania-doped tantala films.

The current generation of advanced gravitational wave detectors utilize titania-doped tantala/silica multilayer stacks for their mirror coatings. The properties of the low-refractive-index silica are well known; however, in the absence of detailed direct measurements, the material parameters of Young's modulus and coefficient of thermal expansion (CTE) of the high refractive index material, titania-doped tantala, have been assumed to be equal to values measured for pure tantala coatings. In order to ascertain the true values necessary for thermal noise calculations, we have undertaken measurements of Young's modulus and CTE through the use of nanoindentation and thermal-bending measurements.

Cell interactions at the nanoscale: piezoelectric stimulation.

Nanometric movements of the substrate on which endothelial cells are growing, driven by periodic sinusoidal vibration from 1 Hz to 50 Hz applied by piezo actuators, upregulate endothelin-1 and Kruppel-like factor 2 expression, and increase cell adhesion. These movements are in the z (vertical) axis and ranges from 5 to 50 nm and are similar in vertical extent to protrusions from the cells themselves already reported in the literature. White noise vibrations do not to produce these effects.

Preeclampsia is associated with compromised maternal synthesis of long-chain polyunsaturated fatty acids, leading to offspring deficiency.

Obesity and excessive lipolysis are implicated in preeclampsia (PE). Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with PE (n=62) or intrauterine growth restriction (n=23) compared with healthy pregnancies (n=164).

Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain.

Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.

Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap.

We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ketone using a combination of electronic and steric effects.

Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB1 antagonists.

The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.