Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

Range-wide sources of variation in reproductive rates of northern spotted owls

We conducted a range-wide investigation of the dynamics of site-level reproductive rate of northern spotted owls using survey data from 11 study areas across the subspecies geographic range collected during 1993–2018. Our analytical approach accounted for imperfect detection of owl pairs and misclassification of successful reproduction (i.e., at least one young fledged) and contributed further insights into northern spotted owl population ecology and dynamics. Both nondetection and state misclassification were important, especially because factors affecting these sources of error also affected focal ecological parameters. Annual probabilities of site occupancy were greatest at sites with successful reproduction in the previous year and lowest for sites not occupied by a pair in the previous year. Site-specific occupancy transition probabilities declined over time and were negatively affected by barred owl presence. Overall, the site-specific probability of successful reproduction showed substantial year-to-year fluctuations and was similar for occupied sites that did or did not experience successful reproduction the previous year. Site-specific probabilities for successful reproduction were very small for sites that were unoccupied the previous year. Barred owl presence negatively affected the probability of successful reproduction by northern spotted owls in Washington and California, as predicted, but the effect in Oregon was mixed. The proportions of sites occupied by northern spotted owl pairs showed steep, near-monotonic declines over the study period, with all study areas showing the lowest observed levels of occupancy to date. If trends continue it is likely that northern spotted owls will become extirpated throughout large portions of their range in the coming decades

Species-specific variation in nesting and postfledging resource selection for two forest breeding migrant songbirds

<div><p>Habitat selection is a fundamental component of community ecology, population ecology, and evolutionary biology and can be especially important to species with complex annual habitat requirements, such as migratory birds. Resource preferences on the breeding grounds may change during the postfledging period for migrant songbirds, however, the degree to which selection changes, timing of change, and whether all or only a few species alter their resource use is unclear. We compared resource selection for nest sites and resource selection by postfledging juvenile ovenbirds (<i>Seiurus aurocapilla</i>) and Acadian flycatchers (<i>Empidonax virescens</i>) followed with radio telemetry in Missouri mature forest fragments from 2012−2015. We used Bayesian discrete choice modeling to evaluate support for local vegetation characteristics on the probability of selection for nest sites and locations utilized by different ages of postfledging juveniles. Patterns of resource selection variation were species-specific. Resource selection models indicated that Acadian flycatcher habitat selection criteria were similar for nesting and dependent postfledging juveniles and selection criteria diverged when juveniles became independent from adults. After independence, flycatcher resource selection was more associated with understory foliage density. Ovenbirds differed in selection criteria between the nesting and postfledging periods. Fledgling ovenbirds selected areas with higher densities of understory structure compared to nest sites, and the effect of foliage density on selection increased as juveniles aged and gained independence. The differences observed between two sympatric forest nesting species, in both the timing and degree of change in resource selection criteria over the course of the breeding season, illustrates the importance of considering species-specific traits and postfledging requirements when developing conservation efforts, especially when foraging guilds or prey bases differ. We recommend that postfledging habitat selection be considered in future conservation efforts dealing with Neotropical migrants and other forest breeding songbirds.</p></div

Understory foliage density affected location utility differently across Acadian flycatcher life-stages.

<p>The estimated relative probability of use (± 95% credible intervals) for Acadian flycatchers as a function of understory foliage density for nest sites (A), late dependent fledglings near (dotted lines) and far (solid lines) from nonforest edge (B), and for independent fledglings (C) in Missouri, 2013−2015. Probability curves were created for each stage by holding non-focal covariates at their means; when edge interaction effects were present, curves were created using the 10^th percentile (near edge = 20 m) and 90^th percentiles (far from edge = 300 m).</p

Parameter coefficients from Acadian flycatcher discrete choice models.

<p>Mean population-level parameter coefficients and 95% credible intervals from Acadian flycatcher discrete choice models for nests, dependent fledglings in the first week out of the nest (early dependent), dependent fledglings after the first week out of the nest (late dependent), and independent fledglings (> 19 days post-fledge) in Missouri from 2013−2015.</p

Understory foliage density affected location utility for postfledging ovenbirds.

<p>Estimated relative probability of use (±95% credible intervals) as a function of understory foliage density for ovenbirds in the first 7 days postfledging (A) and after 7 days postfledging (B) for birds near (dotted lines) and far (solid lines) from forest edge in Missouri, 2012−2015. Probability curves were created by holding non-focal covariates at their means and distance to edge at the 10^th percentile (near edge = 10 m) and 90^th percentile (far from edge = 300 m).</p

Parameter coefficients from ovenbird discrete choice models.

<p>Mean population-level parameter coefficients and 95% credible intervals (bars) from ovenbird discrete choice models for nest sites, dependent fledglings in the first week out of the nest (early dependent), and fledglings after the first week out of the nest (late dependent and independent) in Missouri from 2012−2015.</p