Insights into pharmacogenetics, drug-gene interactions, and drug-drug-gene interactions.

This review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput in vitro approach to study the impact of genetic variation on protein function and/or expression in vitro. We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings.

Spatial hole burning in thin-disk lasers and twisted-mode operation.

Spatial hole burning prevents single-frequency operation of thin-disk lasers when the thin disk is used as a folding mirror. We present an evaluation of the saturation effects in the disk for disks acting as end mirrors and as folding mirrors, explaining one of the main obstacles toward single-frequency operation. It is shown that a twisted-mode scheme based on a multi-order quarter-wave plate combined with a polarizer provides an almost complete suppression of spatial hole burning and creates an additional wavelength selectivity that enforces efficient single-frequency operation.

A large octupole magnetic trap for research with atomic hydrogen.

We describe the design and performance of a large magnetic trap for storage and cooling of atomic hydrogen (H). The trap operates in the vacuum space of a dilution refrigerator at a temperature of 1.5 K. Aiming at a large volume of the trap, we implemented the octupole configuration of linear currents (Ioffe bars) for the radial confinement, combined with two axial pinch coils and a 3 T solenoid for the cryogenic H dissociator. The octupole magnet consists of eight race-track segments, which are compressed toward each other with magnetic forces. This provides a mechanically stable and robust construction with a possibility of replacement or repair of each segment. A maximum trap depth of 0.54 K (0.8 T) was reached, corresponding to an effective volume of 0.5 l for hydrogen gas at 50 mK. This is an order of magnitude larger than ever used for trapping atoms.

Is the proton radius a player in the redefinition of the International System of Units?

It is now recognized that the International System of Units (SI units) will be redefined in terms of fundamental constants, even if the date when this will occur is still under debate. Actually, the best estimate of fundamental constant values is given by a least-squares adjustment, carried out under the auspices of the Committee on Data for Science and Technology (CODATA) Task Group on Fundamental Constants. This adjustment provides a significant measure of the correctness and overall consistency of the basic theories and experimental methods of physics using the values of the constants obtained from widely differing experiments. The physical theories that underlie this adjustment are assumed to be valid, such as quantum electrodynamics (QED). Testing QED, one of the most precise theories is the aim of many accurate experiments. The calculations and the corresponding experiments can be carried out either on a boundless system, such as the electron magnetic moment anomaly, or on a bound system, such as atomic hydrogen. The value of fundamental constants can be deduced from the comparison of theory and experiment. For example, using QED calculations, the value of the fine structure constant given by the CODATA is mainly inferred from the measurement of the electron magnetic moment anomaly carried out by Gabrielse's group. (Hanneke et al. 2008 Phys. Rev. Lett. 100, 120801) The value of the Rydberg constant is known from two-photon spectroscopy of hydrogen combined with accurate theoretical quantities. The Rydberg constant, determined by the comparison of theory and experiment using atomic hydrogen, is known with a relative uncertainty of 6.6×10(-12). It is one of the most accurate fundamental constants to date. A careful analysis shows that knowledge of the electrical size of the proton is nowadays a limitation in this comparison. The aim of muonic hydrogen spectroscopy was to obtain an accurate value of the proton charge radius. However, the value deduced from this experiment contradicts other less accurate determinations. This problem is known as the proton radius puzzle. This new determination of the proton radius may affect the value of the Rydberg constant . This constant is related to many fundamental constants; in particular, links the two possible ways proposed for the redefinition of the kilogram, the Avogadro constant N(A) and the Planck constant h. However, the current relative uncertainty on the experimental determinations of N(A) or h is three orders of magnitude larger than the 'possible' shift of the Rydberg constant, which may be shown by the new value of the size of the proton radius determined from muonic hydrogen. The proton radius puzzle will not interfere in the redefinition of the kilogram. After a short introduction to the properties of the proton, we will describe the muonic hydrogen experiment. There is intense theoretical activity as a result of our observation. A brief summary of possible theoretical explanations at the date of writing of the paper will be given. The contribution of the proton radius puzzle to the redefinition of SI-based units will then be examined.

Optical heterodyning with a frequency difference of 1 THz in the 850-nm range.

We report our recent progress on detection of large frequency difference (up to 1.028 THz, Deltalambda = 2.5 nm) between two laser diodes at 852 nm, using a Schottky diode as harmonic mixer/detector. Using the 11th harmonic of a klystron operating at 93.5 GHz or the 991-GHz line of an optically pumped HCOOH far-infrared laser, we were able to observe a signal-to-noise ratio of 2 dB in a 1-MHz-resolution bandwidth.

Observation of a motional Stark effect to determine the second-order Doppler effect.

The high resolution two-photon spectroscopy of hydrogen is often limited by the second-order Doppler effect. To determine this effect, we apply a magnetic field perpendicular to the atomic beam. This field induces a quadratic motional Stark shift proportional, as the second-order Doppler effect, to v(2) (v atomic velocity). For some magnetic field, these two effects are opposite and the total shift due to the atomic velocity is reduced. We present the first observation of this effect for the 1S-3S transition in hydrogen.