Enantioselective Synthesis of Enantioisotopomers with Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy

Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge. Here, we report the first highly enantioselective metal-catalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples oft he enantioisotopomer

A Lithium Depletion Age for the Carina Association

The dispersed remnants of stellar nurseries, stellar associations provide unparalleled samples of coeval stars critical for studies of stellar and planetary formation and evolution. The Carina Stellar Association is one of the closest stellar associations to Earth, and yet measurements of its age have varied from 13 to 45 Myr. We aim to update the age of Carina using the Lithium Depletion Boundary method. We obtain new measurements of the Li 6708 Angstrom, absorption feature in likely members using optical spectra from the Goodman HTS on SOAR and NRES on LCO. We detect the depletion boundary at M_K ~= 6.8 (M5), which corresponds to an age of 41(+3,-5) Myr. The age is consistent within uncertainties across six different models, including those that account for magnetic fields and spots. We also estimate the age through analysis of the group's overall variability, and by comparing the association members' CMD to stellar evolutionary models using a Gaussian Mixture Model, recovering ages consistent with the LDB. The resulting age agrees with the older end of previous age measurements and is consistent with the lithium depletion age for the neighboring Tucana-Horologium Moving Group.Comment: 9 pages, 6 figures, accepted to AJ on 10/17/202

Evidence for a Mass Dependent Step-Change in the Scaling of Efficiency in Terrestrial Locomotion

A reanalysis of existing data suggests that the established tenet of increasing efficiency of transport with body size in terrestrial locomotion requires re-evaluation. Here, the statistical model that described the data best indicated a dichotomy between the data for small (<1 kg) and large animals (>1 kg). Within and between these two size groups there was no detectable difference in the scaling exponents (slopes) relating metabolic (Emet) and mechanical costs (Emech, CM) of locomotion to body mass (Mb). Therefore, no scaling of efficiency (Emech, CM/Emet) with Mb was evident within each size group. Small animals, however, appeared to be generally less efficient than larger animals (7% and 26% respectively). Consequently, it is possible that the relationship between efficiency and Mb is not continuous, but, rather, involves a step-change. This step-change in the efficiency of locomotion mirrors previous findings suggesting a postural cause for an apparent size dichotomy in the relationship between Emet and Mb. Currently data for Emech, CM is lacking, but the relationship between efficiency in terrestrial locomotion and Mb is likely to be determined by posture and kinematics rather than body size alone. Hence, scaling of efficiency is likely to be more complex than a simple linear relationship across body sizes. A homogenous study of the mechanical cost of terrestrial locomotion across a broad range of species, body sizes, and importantly locomotor postures is a priority for future research

Farmers’ Perceptions of and Adaptations to Climate Change in Southeast Asia: The Case Study from Thailand and Vietnam

The perceptions of climate change and adaptation choices made by farmers are important considerations in the design of adaptation strategies by policy makers and agricultural extension services. This paper seeks to determine these perceptions and choices by farmers in already poor environmental regions of Thailand and Vietnam especially vulnerable to climate change. Overall findings were that farmers do perceive climate change, but describe it in quite distinct ways and that location influences how farmers recognize climate change. Our 2007 and 2013 surveys show that farmers are adapting, but it is difficult to determine if specific practices are “climate smart”. Further, adaptation measures are informed by perception and, at least in the case of Vietnam, perceptions are shaped by the respondent’s characteristics, location variables and recent climate related shocks. Finally, the three climate variables of rainfall, temperature, and wind are the most important factors in explaining specific adaptation measures chosen by farmers. Farmer participation is an essential part of public actions designed to allow adaptation to climate change. Our research can also contribute to understanding farmer constraints and tailoring good overall strategies to the local heterogeneity of vulnerable locations

Whole Body Mechanics of Stealthy Walking in Cats

The metabolic cost associated with locomotion represents a significant part of an animal's metabolic energy budget. Therefore understanding the ways in which animals manage the energy required for locomotion by controlling muscular effort is critical to understanding limb design and the evolution of locomotor behavior. The assumption that energetic economy is the most important target of natural selection underlies many analyses of steady animal locomotion, leading to the prediction that animals will choose gaits and postures that maximize energetic efficiency. Many quadrupedal animals, particularly those that specialize in long distance steady locomotion, do in fact reduce the muscular contribution required for walking by adopting pendulum-like center of mass movements that facilitate exchange between kinetic energy (KE) and potential energy (PE) [1]–[4]. However, animals that are not specialized for long distance steady locomotion may face a more complex set of requirements, some of which may conflict with the efficient exchange of mechanical energy. For example, the “stealthy” walking style of cats may demand slow movements performed with the center of mass close to the ground. Force plate and video data show that domestic cats (Felis catus, Linnaeus, 1758) have lower mechanical energy recovery than mammals specialized for distance. A strong negative correlation was found between mechanical energy recovery and diagonality in the footfalls and there was also a negative correlation between limb compression and diagonality of footfalls such that more crouched postures tended to have greater diagonality. These data show a previously unrecognized mechanical relationship in which crouched postures are associated with changes in footfall pattern which are in turn related to reduced mechanical energy recovery. Low energy recovery was not associated with decreased vertical oscillations of the center of mass as theoretically predicted, but rather with posture and footfall pattern on the phase relationship between potential and kinetic energy. An important implication of these results is the possibility of a tradeoff between stealthy walking and economy of locomotion. This potential tradeoff highlights the complex and conflicting pressures that may govern the locomotor choices that animals make

Evolution of hindlimb muscle anatomy across the tetrapod water-to-land transition, including comparisons with forelimb anatomy

Tetrapod limbs are a key innovation implicated in the evolutionary success of the clade. Although musculoskeletal evolution of the pectoral appendage across the fins‐to‐limbs transition is fairly well documented, that of the pelvic appendage is much less so. The skeletal elements of the pelvic appendage in some tetrapodomorph fish and the earliest tetrapods are relatively smaller and/or qualitatively less similar to those of crown tetrapods than those of the pectoral appendage. However, comparative and developmental works have suggested that the musculature of the tetrapod forelimb and hindlimb was initially very similar, constituting a “similarity bottleneck” at the fins‐to‐limbs transition. Here we used extant phylogenetic bracketing and phylogenetic character optimization to reconstruct pelvic appendicular muscle anatomy in several key taxa spanning the fins‐to‐limbs and water‐to‐land transitions. Our results support the hypothesis that transformation of the pelvic appendages from fin‐like to limb‐like lagged behind that of the pectoral appendages. Compared to similar reconstructions of the pectoral appendages, the pelvic appendages of the earliest tetrapods had fewer muscles, particularly in the distal limb (shank). In addition, our results suggest that the first tetrapods had a greater number of muscle‐muscle topological correspondences between the pectoral and pelvic appendages than tetrapodomorph fish had. However, ancestral crown‐group tetrapods appear to have had an even greater number of similar muscles (both in terms of number and as a percentage of the total number of muscles), indicating that the main topological similarity bottleneck between the paired appendages may have occurred at the origin of the tetrapod crown group

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines