The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors

In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.     

Perceived wintering latitude determines timing of song output in a migratory bird

Migratory bird populations frequently consist of individuals that overwinter variable distances from the breeding site. Seasonal changes in photoperiod, which varies with latitude, underlie seasonal changes in singing frequency in birds. Therefore, migratory populations that consist of individuals that overwinter at different latitudes with large overwintering ranges could experience within‐population variation in seasonal production of song. To test the influence of overwintering latitude on intrapopulation variance in song production in the spring, we subjected two groups of Eastern Song Sparrows (Melospiza melodia melodia) from the same partially migratory breeding population to different photoperiodic schedules associated with a 1,300‐km difference in overwintering location. One group remained on the natural photoperiodic schedule of the breeding site (resident group) while the other group experienced a nonbreeding photoperiod that mimicked a southern migration in the fall followed by a northern migration back to the breeding site in the spring (migratory group). We compared song output between the two groups in three different stages (nonbreeding, prebreeding, and breeding). Little singing occurred during nonbreeding stage sample dates (20 November, 6 December) for the resident group, and no singing occurred for the migrant group. During the prebreeding stage (27 January, 7 February), significantly more singing occurred in the resident group than in the migrant group. During the breeding stage (21 March, 4 April), after a simulated migration for the migrants, song output was similar in both groups. These results suggest that within‐population variation in wintering latitude may contribute to variation in seasonal changes in singing behavior, which may covary with readiness to breed. Studies utilizing confirmed migrants and residents, rather than merely simulated migrants and residents, are also needed to better understand these processes.     

Predicting Pasture and Forest Landowner Intention to Create Early Successional Habitat

As human land uses expand across the landscape, the management practices of private landowners are an essential part of effective conservation. Early successional habitats (ESH) and the species that depend on them are a priority in the eastern United States, and efforts to create ESH on private lands has primarily focused on forest landowners and timber harvests. Private pasture lands in a forested landscape present an additional opportunity to create and maintain ESH, yet our understanding of landowner values and attitudes about management strategies in pastures is lacking. To address this, we surveyed private landowners in 5 Virginia counties who own ≥10.1 ha at >610 m elevation (n = 503). Our primary objective was to understand how a variety of factors such as landowner values, past experience with habitat management, and perceived barriers to carrying out habitat management are associated with private landowner intention to carry out 7 ESH management strategies (i.e., reduced mowing, reduced grazing, timber harvests within forest, timber harvests at a field-forest border, prescribed fire, use of machinery, and use of herbicides to control invasive species) for the benefit of wildlife in the next 5 years. We used boosted regression trees to determine which factors best predicted the intention to carry out each management strategy. We were able to predict accuracy >75% of the time for landowner intention to engage in open pasture and timber management strategies. Landowner values were not consistent across the different management strategies; landowners likely to reduce mowing or grazing valued ecological aspects of their land (e.g., pollinator habitat, water quality), whereas landowners likely to harvest timber valued hunting and revenue. Past experience with wildlife management was the strongest predictor of likelihood to reduce mowing and grazing. Our results suggest that expanding outreach efforts to include pasture management options would engage a broader set of landowners in creating ESH, especially if such efforts highlighted the benefits to pollinator species, water quality, and enhanced opportunities for hunting and other types of recreation. © 2021 The Wildlife Society.     

mTOR Inhibition Elicits a Dramatic Response in PI3K-Dependent Colon Cancers

The phosphatidylinositide-3-kinase (PI3K) signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca*). The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca* mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6), indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.     

INTERSPECIFIC COMPETITION ALTERS NONLINEAR SELECTION ON OFFSPRING SIZE IN THE FIELD

Offspring size is one of the most important life‐history traits with consequences for both the ecology and evolution of most organisms. Surprisingly, formal estimates of selection on offspring size are rare, and the degree to which selection (particularly nonlinear selection) varies among environments remains poorly explored. We estimate linear and nonlinear selection on offspring size, module size, and senescence rate for a sessile marine invertebrate in the field under three different intensities of interspecific competition. The intensity of competition strongly modified the strength and form of selection acting on offspring size. We found evidence for differences in nonlinear selection across the three environments. Our results suggest that the fitness returns of a given offspring size depend simultaneously on their environmental context, and on the context of other offspring traits. Offspring size effects can be more pervasive with regards to their influence on the fitness returns of other traits than previously recognized, and we suggest that the evolution of offspring size cannot be understood in isolation from other traits. Overall, variability in the form and strength of selection on offspring size in nature may reduce the efficacy of selection on offspring size and maintain variation in this trait.     

Physiological costs and carry-over effects of avian interspecific brood parasitism influence reproductive tradeoffs

Although models of co-evolution between brood parasites and their hosts primarily focus upon the cost to hosts in the current reproductive bout, the impact of brood parasitism may carry over to future reproductive attempts by altering resource allocation. Glucocorticoid stress hormones help mediate resource allocation to reproduction, yet they have rarely been examined in brood parasitic systems. Here we determined if shifts in parental care and corticosterone had carry-over effects on future reproductive effort in the rufous-and-white wren (Thryophilus rufalbus), a host of the Central American striped cuckoo (Tapera naevia). We found that parasitized parents had significantly higher stress-induced, but not baseline, corticosterone than natural parents during the fledgling stage, which was associated with changes in parental care. The high investment in current reproduction while parasitized may be due to the value of fledged chicks in tropical systems. This maladaptive response by parasitized parents was associated with delayed re-nesting and a reduced likelihood of nesting in the subsequent breeding season. Although a reduction in future reproductive effort can result from a combination of factors, this work suggests that fitness costs of brood parasitism are mediated by changes in corticosterone and parental care behavior that carry over into subsequent breeding seasons.     

Habitat selection by adult walleye during spawning season in irrigation reservoirs: a patch occupancy modeling approach

Recruitment of walleye (Sander vitreus Mitchill) is limited in irrigation reservoirs of the Republican River basin in southwestern Nebraska. The causal mechanism for this limited recruitment is unknown, but may be related to a lack of suitable spawning habitat. Patch occupancy models were developed to describe variation in detection probability and habitat selection during spawning season using shoreline electrofishing data. Detection of adult walleye was negatively affected by water temperature, silt substrate, and woody cover. Adult walleye selected sites with cooler water temperatures and greater fetch at Enders Reservoir, and large rock substrate and no cover at Hugh Butler Lake; these characteristics are limited to areas on or near the riprap dams in both reservoirs. Walleye eggs were also only found in these areas. We conclude that patch occupancy modeling provided valuable information when considering habitat improvement projects and propose a management approach for the addition of walleye spawning habitat in irrigation reservoirs.