Precision Doppler shift measurements with a frequency comb calibrated laser heterodyne radiometer.

We report precision atmospheric spectroscopy of CO2 using a laser heterodyne radiometer (LHR) calibrated with an optical frequency comb. Using the comb calibrated LHR, we record spectra of atmospheric CO2 near 1572.33 nm with a spectral resolution of 200 MHz, using sunlight as a light source. The measured CO2 spectra exhibit frequency shifts by approximately 11 MHz over the course of the 5-h measurement, and we show that these shifts are caused by Doppler effects due to wind along the spectrometer line of sight. The measured frequency shifts are in excellent agreement with an atmospheric model, and we show that our measurements track the wind-induced Doppler shifts with a relative frequency precision of 2 MHz (3 m·s-1) for a single 10 s measurement, improving to 100 kHz (15 cm·s-1) after averaging (equivalent to a fractional precision of a few parts in 1010). These results demonstrate that frequency comb calibrated LHR enables precision velocimetry that can be of use in applications ranging from climate science to astronomy.

Targeting a Conserved Lysine in the Hydrophobic Pocket of HIV-1 gp41 Improves Small Molecule Antiviral Activity.

Human Immunodeficiency virus (HIV-1) fusion is mediated by glycoprotein-41, a protein that has not been widely exploited as a drug target. Small molecules directed at the gp41 ectodomain have proved to be poorly drug-like, having moderate efficacy, high hydrophobicity and/or high molecular weight. We recently investigated conversion of a fairly potent hydrophobic inhibitor into a covalent binder, by modifying it to react with a lysine residue on the protein. We demonstrated a 10-fold improvement in antiviral efficacy. Here, we continue this study, utilizing instead molecules with better inherent drug-like properties. Molecules possessing low to no antiviral activity as equilibrium binders were converted into µM inhibitors upon addition of an electrophilic warhead in the form of a sulfotetrafluorophenyl (STP) activated ester. We confirmed specificity for gp41 and for entry. The small size of the inhibitors described here offers an opportunity to expand their reach into neighboring pockets while retaining drug-likeness. STP esterification of equilibrium binders is a promising avenue to explore for inhibiting HIV-1 entry. Many gp41 targeting molecules studied over the years possess carboxylic acid groups which can be easily converted into the corresponding STP ester. It may be worth the effort to evaluate a library of such inhibitors as a way forward to small molecule inhibition of fusion of HIV and possibly other enveloped viruses.

Large regional shortwave forcing by anthropogenic methane informed by Jovian observations.

Recently, it was recognized that widely used calculations of methane radiative forcing systematically underestimated its global value by 15% by omitting its shortwave effects. We show that shortwave forcing by methane can be accurately calculated despite considerable uncertainty and large gaps in its shortwave spectroscopy. We demonstrate that the forcing is insensitive, even when confronted with much more complete methane absorption spectra extending to violet light wavelengths derived from observations of methane-rich Jovian planets. We undertake the first spatially resolved global calculations of this forcing and find that it is dependent on bright surface features and clouds. Localized annual mean forcing from preindustrial to present-day methane increases approaches +0.25 W/m2, 10 times the global annualized shortwave forcing and 43% of the total direct CH4 forcing. Shortwave forcing by anthropogenic methane is sufficiently large and accurate to warrant its inclusion in historical analyses, projections, and mitigation strategies for climate change.