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Management decisions often focus on the habitat selection of marked individuals without considering the contribution to demographic performance in selected habitats. Because habitat selection is not always adaptive, understanding the spatial relationship between habitat selection and demographic performance is critical to management decisions. Mapping both habitat selection and demographic performance for species of conservation concern can help guide population‐scale conservation efforts. We demonstrate a quantitative approach to differentiate areas supporting selection and survival at large spatial extents. As a case study, we applied this approach to greater sage‐grouse (Centrocercus urophasianus; hereafter, sage‐grouse), an indicator species for sagebrush ecosystems. We evaluated both habitat selection and survival across multiple reproductive life stages (nesting, brood‐rearing) in the Bi‐State Distinct Population Segment, a genetically distinct and geographically isolated population of sage‐grouse on the southwestern edge of the species' range. Our approach allowed us to identify both mismatches between selection and survival and trade‐offs between reproductive life stages. These findings suggest resource demands vary across time, with predation risk being a dominant driver of habitat selection during nesting and early brood‐rearing periods when chicks are smaller and flightless, whereas access to forage resources becomes more important during late brood rearing when resources become increasingly limited. Moving beyond identifying and managing habitat solely based on species occupancy or use by incorporating demographic measures allows managers to tailor actions to their specific goals; for example, protections of areas that support high selection and high survival and restoration actions focused on increasing survival in areas of high selection and low survival. Habitat selection is not always adaptive, so understanding the link between habitat selection and demographic performance is critical to management decisions. We evaluated both selection and survival across multiple reproductive life stages in a genetically distinct and geographically isolated population of greater sage‐grouse, an indicator species for sagebrush ecosystems. Our approach allowed us to identify both mismatches between selection and survival and trade‐offs between life stages.

Greater sage-grouse (Centrocercus urophasianus) have experienced considerable range contraction and reduced abundance in response to habitat loss and degradation. Translocation is a conservation action that is often used to reintroduce extirpated populations or augment existing small populations. Translocations have had limited success in restoring viable populations of sage-grouse; a lack of success is attributed to long-distance post-release movements away from release sites, reduced survival, and lack of reproductive success of translocated individuals. Translocating female sage-grouse with their chicks (brood translocation) is a technique aimed at promoting breeding area fidelity and reproduction and may be beneficial to population restoration efforts. Furthermore, the ability to capture, relocate, and release individuals while minimizing translocation-induced loss increases the overall probability of restoration success. Accordingly, we developed a protocol to translocate female sage-grouse and their broods simultaneously, using a delayed-release system that included a custom release box and acclimation pen. We tested our protocol across 2 separate restoration projects in North Dakota and California during 2017–2019 with a total of 38 translocated females and 196 chicks. We successfully released 174/196 chicks (88.8%) from 32/38 (84.2%) broods. Our protocol builds on existing translocation methods used to translocate sage-grouse and will likely prove to be a critical technique in restoring sage-grouse populations.

Expansion of human enterprise across western North America has resulted in an increase in availability of anthropogenic resource subsidies for generalist species. This has led to increases in generalists’ population numbers across landscapes that were previously less suitable for their current demographic rates. Of particular concern are growing populations of common ravens (Corvus corax; ravens), because predation by ravens is linked to population declines of sensitive species. Ecosystem managers seek management options for mitigating the adverse effects of raven predation where unsustainable predator–prey conflicts exist. We present 3 case studies examining how manipulating reproductive success of ravens influences demographic rates of 2 sensitive prey species. Two case studies examine impacts of removing raven nests or oiling raven eggs on nest survival of greater sage-grouse (Centrocercus urophasianus; sage-grouse) within Wyoming and the Great Basin of California and Nevada, USA, respectively. The third case study uses Mojave desert tortoise (Gopherus agassizii; tortoise) decoys to examine effects of oiling raven eggs on depredation rates of juvenile tortoises in the Mojave Desert in California. Initial trial years from all 3 case studies were consistent in finding improved vital rates associated with the application of strategies for reducing reproductive success of ravens. Specifically, removal of raven nests resulted in increased nest survival of sage-grouse within treatment areas where predation by ravens was the primary cause of nest failure. In addition, nest survival of sage-grouse and survival of juvenile tortoise decoys was higher following a treatment of oiling the eggs of ravens in their nests at 2 sites within the Great Basin and 4 tortoise conservation areas in the Mojave Desert in California. Along with specialized technologies that can make techniques such as egg-oiling more feasible, these findings support these management practices as important tools for managing ravens, especially in areas where breeding ravens have negative impacts on sensitive prey species.

Vitiligo is a T-cell mediated skin disorder characterized by progressive loss of skin color. In individuals genetically predisposed to the disease, various triggers contribute to the initiation of vitiligo. Precipitating factors can stress the skin, leading to T-cell activation and recruitment. Though hereditary factors are implicated in the pathogenesis of vitiligo, it is unknown whether precipitating, stressful events play a role in vitiligo. To understand this, we utilized a validated perceived stress scale (PSS) to measure this parameter in vitiligo patients compared to persons without vitiligo. Additionally, we probed a clinical database, using a knowledge linking software called ROCKET, to gauge stress-related conditions in the vitiligo patient population. From a pool of patients in an existing database, a hundred individuals with vitiligo and twenty-five age- and sex-matched comparison group of individuals without vitiligo completed an online survey to quantify their levels of perceived stress. In parallel, patients described specifics of their disease condition, including the affected body sites, the extent, duration and activity of their vitiligo. Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo. ROCKET analyses suggested signs of metabolic-related disease (i.e., 'stress') preceding vitiligo development. No correlation was found between perceived stress and the stage or the extent of disease, suggesting that elevated stress may not be a consequence of pigment loss alone. The data provide further support for stress as a precipitating factor in vitiligo development.

Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.

Dated molecular phylogenies are the basis for understanding species diversity and for linking changes in rates of diversification with historical events such as restructuring in developmental pathways, genome doubling, or dispersal onto a new continent. Valid fossil calibration points are essential to the accurate estimation of divergence dates, but for many groups of flowering plants fossil evidence is unavailable or limited. Arabidopsis thaliana, the primary genetic model in plant biology and the first plant to have its entire genome sequenced, belongs to one such group, the plant family Brassicaceae. Thus, the timing of A. thaliana evolution and the history of its genome have been controversial. We bring previously overlooked fossil evidence to bear on these questions and find the split between A. thaliana and Arabidopsis lyrata occurred about 13 Mya, and that the split between Arabidopsis and the Brassica complex (broccoli, cabbage, canola) occurred about 43 Mya. These estimates, which are two- to threefold older than previous estimates, indicate that gene, genomic, and developmental evolution occurred much more slowly than previously hypothesized and that Arabidopsis evolved during a period of warming rather than of cooling. We detected a 2- to 10-fold shift in species diversification rates on the branch uniting Brassicaceae with its sister families. The timing of this shift suggests a possible impact of the Cretaceous–Paleogene mass extinction on their radiation and that Brassicales codiversified with pierid butterflies that specialize on mustard-oil–producing plants.

Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.

Depression affects 20-30% of HIV-infected patients and is associated with worse HIV outcomes. Although effective depression treatment is available, depression is largely untreated or undertreated in this population. We quantified gaps in antidepressant treatment, treatment adjustments, and outcomes among US patients in routine HIV care in the nationally distributed CNICS observational clinical cohort. This cohort combines detailed clinical data with regular, self-reported depressive severity assessments (Patient Health Questionnaire-9, PHQ-9). We considered whether participants with likely depression received antidepressants, whether participants on antidepressants with persistently high depressive symptoms received timely dose adjustments, and whether participants achieved depression remission. We considered a cross-sectional analysis (6,219 participants in care in 2011-2012) and a prospective analysis (2,936 participants newly initiating CNICS care when PHQ-9 screening was active). The cross-sectional sample was 87% male, 53% Caucasian, 25% African American, and 18% Hispanic; the prospective sample was similar. In both samples, 39-44% had likely depression, with 44-60% of those receiving antidepressants. Of participants receiving antidepressants, 20-26% experienced persistently high depressive symptoms; only a small minority of those received antidepressant dose adjustments. Overall, 35-40% of participants on antidepressants achieved full depression remission. Remission among participants with persistently high depressive symptoms was rare regardless of dose adjustments. In this large, diverse cohort of US patients engaged in routine HIV care, we observed large gaps in antidepressant treatment, timely dose adjustment to address persistently high depressive symptoms, and antidepressant treatment outcomes. These results highlight the importance of more effective pharmacologic depression treatment models for HIV-infected patients.

Muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations 1 , 2 . The FCMD gene, fukutin , shares some homology with fringe -like glycosyltransferases, and the MEB gene, POMGnT1 , seems to be a new glycosyltransferase 3 , 4 . Here we show, in both MEB and FCMD patients, that α-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of α-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy ( myd ) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan–ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure 1 . However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments 2 . In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration–time profiles in humans 3 . Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study 4 using dynamic [ 11 C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [ 11 C]rifampin PET–CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET–CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET–CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration–time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development. Distinct patterns of exposure to a first-line tuberculosis drug in separate lung lesions within patients are revealed by PET–CT imaging. Use of the technique might help optimize the duration and dosing of antimicrobial drugs.