Kinetics and Inhibition Studies of the L205R Mutant of cAMP-Dependent Protein Kinase Involved in Cushing’s Syndrome

Overproduction of cortisol by the hypothalamus–pituitary–adrenal hormone system results in the clinical disorder known as Cushing\u27s syndrome. Genomics studies have identified a key mutation (L205R) in the α‐isoform of the catalytic subunit of cAMP‐dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone‐independent Cushing\u27s syndrome. Here, we conducted kinetics and inhibition studies on the L205R‐PKACα mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12‐fold and 4.5‐fold, respectively. We have also determined the IC50 and Ki for the peptide substrate‐competitive inhibitor PKI(5–24) and the ATP‐competitive inhibitor H89. The L205R mutation had no effect on the potency of H89, but causes a \u3e 250‐fold loss in potency for PKI(5–24). Collectively, these data provide insights for the development of L205R‐PKACα inhibitors as potential therapeutics

High-Precision Entropy Values for Spanning Trees in Lattices

Shrock and Wu have given numerical values for the exponential growth rate of the number of spanning trees in Euclidean lattices. We give a new technique for numerical evaluation that gives much more precise values, together with rigorous bounds on the accuracy. In particular, the new values resolve one of their questions.Comment: 7 pages. Revision mentions alternative approach. Title changed slightly. 2nd revision corrects first displayed equatio

Applying the partial credit method of Rasch analysis: language testing and accountability

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68583/2/10.1177_026553228900600109.pd

A Limited Habitable Zone for Complex Life

The habitable zone (HZ) is commonly defined as the range of distances from a host star within which liquid water, a key requirement for life, may exist on a planet's surface. Substantially more CO2 than present in Earth's modern atmosphere is required to maintain clement temperatures for most of the HZ, with several bars required at the outer edge. However, most complex aerobic life on Earth is limited by CO2 concentrations of just fractions of a bar. At the same time, most exoplanets in the traditional HZ reside in proximity to M dwarfs, which are more numerous than Sun-like G dwarfs but are predicted to promote greater abundances of gases that can be toxic in the atmospheres of orbiting planets, such as carbon monoxide (CO). Here we show that the HZ for complex aerobic life is likely limited relative to that for microbial life. We use a 1D radiative-convective climate and photochemical models to circumscribe a Habitable Zone for Complex Life (HZCL) based on known toxicity limits for a range of organisms as a proof of concept. We find that for CO2 tolerances of 0.01, 0.1, and 1 bar, the HZCL is only 21%, 32%, and 50% as wide as the conventional HZ for a Sun-like star, and that CO concentrations may limit some complex life throughout the entire HZ of the coolest M dwarfs. These results cast new light on the likely distribution of complex life in the universe and have important ramifications for the search for exoplanet biosignatures and technosignatures.Comment: Revised including additional discussion. Published Gold OA in ApJ. 9 pages, 5 figures, 5 table

The accelerating influence of humans on mammalian macroecological patterns over the late Quaternary

The transition of hominins to a largely meat-based diet ~1.8 million years ago led to the exploitation of other mammals for food and resources. As hominins, particularly archaic and modern humans, became increasingly abundant and dispersed across the globe, a temporally and spatially transgressive extinction of large-bodied mammals followed; the degree of selectivity was unprecedented in the Cenozoic fossil record. Today, most remaining large-bodied mammal species are confined to Africa, where they coevolved with hominins. Here, using a comprehensive global dataset of mammal distribution, life history and ecology, we examine the consequences of “body size downgrading” of mammals over the late Quaternary on fundamental macroecological patterns. Specifically, we examine changes in species diversity, global and continental body size distributions, allometric scaling of geographic range size with body mass, and the scaling of maximum body size with area. Moreover, we project these patterns toward a potential future scenario in which all mammals currently listed as vulnerable on the IUCN\u27s Red List are extirpated. Our analysis demonstrates that anthropogenic impact on earth systems predates the terminal Pleistocene and has grown as populations increased and humans have become more widespread. Moreover, owing to the disproportionate influence on ecosystem structure and function of megafauna, past and present body size downgrading has reshaped Earth\u27s biosphere. Thus, macroecological studies based only on modern species yield distorted results, which are not representative of the patterns present for most of mammal evolution. Our review supports the concept of benchmarking the “Anthropocene” with the earliest activities of Homo sapiens

Features of energetic particle radial profiles inferred from geosynchronous responses to solar wind dynamic pressure enhancements

Determination of the radial profile of phase space density of relativistic electrons at constant adiabatic invariants is crucial for identifying the source for them within the outer radiation belt. The commonly used method is to convert flux observed at fixed energy to phase space density at constant first, second and third adiabatic invariants, which requires an empirical global magnetic field model and thus might produce some uncertainties in the final results. From a different perspective, in this paper we indirectly infer the shape of the radial profile of phase space density of relativistic electrons near the geosynchronous region by statistically examining the geosynchronous energetic flux response to 128 solar wind dynamic pressure enhancements during the years 2000 to 2003. We thus avoid the disadvantage of using empirical magnetic field models. Our results show that the flux response is species and energy dependent. For protons and low-energy electrons, the primary response to magnetospheric compression is an increase in flux at geosynchronous orbit. For relativistic electrons, the dominant response is a decrease in flux, which implies that the phase space density decreases toward increasing radial distance at geosynchronous orbit and leads to a local peak inside of geosynchronous orbit. The flux response of protons and non-relativistic electrons could result from a phase density that increases toward increasing radial distance, but this cannot be determined for sure due to the particle energization associated with pressure enhancements. Our results for relativistic electrons are consistent with previous results obtained using magnetic field models, thus providing additional confirmation that these results are correct and indicating that they are not the result of errors in their selected magnetic field model