The demographic contributions of connectivity versus local dynamics to population growth of an endangered bird.

Conservation and management increasingly focus on connectivity, because connectivity driven by variation in immigration rates across landscapes is thought to be crucial for maintaining local population and metapopulation persistence. Yet, efforts to quantify the relative role of immigration on population growth across the entire range of species and over time have been lacking. We assessed whether immigration limited local and range-wide population growth of the endangered snail kite Rostrhamus sociabilis in Florida, USA, over 18 years using multi-state, reverse-time modelling that accounts for imperfect detection of individuals and unobservable states. Demographic contributions of immigration varied depending on the dynamics and geographic position of the local populations, were scale-dependent and changed over time. By comparing the relative contributions of immigration versus local demography for periods of significant change in local abundance, we found empirical evidence for a disproportionately large role of immigration in facilitating population growth of a centrally located population-a connectivity 'hub'. The importance of connectivity changed depending of the spatial scale considered, such that immigration was a more important driver of population growth at small versus large spatial scales. Furthermore, the contribution of immigration was much greater during time periods when local population size was small, emphasizing abundance-dependent rescue effects. Our findings suggest that efforts aimed at improving local breeding habitat will likely be most effective at increasing snail kite population growth. More broadly, our results provide much needed information on the role of connectivity for population growth, suggesting that connectivity conservation may have the greatest benefits when efforts focus on centrally located habitat patches and small populations. Furthermore, our results highlight that connectivity is highly dynamic over time and that interpreting the effects of connectivity at local scales may not transfer to region-wide dynamics.

Counteracting effects of a non-native prey on the demography of a native predator culminate in positive population growth.

Identifying impacts of non-native species on native populations is central to conservation and ecology. While effects of non-native predators on native prey populations have recently received much attention, impacts of introduced prey on native predator populations are less understood. Non-native prey can influence predator behavior and demography through direct and indirect pathways, yet quantitative assessments of the relative impacts of multiple, potentially counteracting, effects on native predator population growth remain scarce. Using ≈20 years of range-wide monitoring data, we tested for effects of a recently introduced, rapidly spreading non-native prey species (Pomacea maculata) on the behavior and demography of the endangered Snail Kite (Rostrhamus sociabilis). Previous studies found that food-handling difficulties caused by the large size of P. maculata (relative to the native P. paludosa) can lead to energetic deficiencies in juvenile kites, suggesting the potential for evolutionary traps to occur. However, high densities of P. maculata populations could facilitate kites by providing supplemental food resources. Contrary to prior hypotheses, we found that juvenile apparent survival increased ≈50% in wetlands invaded by non-native snails. Breeding rates and number of young fledged/successful nests were also positively associated with non-native snail presence, suggesting direct trophic benefits to kites. We found no direct effects of the invasive snail on adult survival or daily nest survival rates. Kite movements and breeding distribution closely tracked the spread of non-native snail populations. Since 2005, kites have been heavily concentrated in northern regions where non-native snails have established. This geographic shift has had hidden costs, as use of northern regions is associated with lower adult survival. Despite negative impacts to this key vital rate, matrix population modeling indicated that the multifarious effects of the non-native snail invasion on kites culminated in increased population growth rates, likely lowering short-term extinction risks. Results suggest that considering only particular components of behavior or demography may be inadequate to infer the population-dynamic importance of non-native prey on native predators, including their role in creating potential evolutionary traps. Our findings provide information pertinent to Everglades restoration, highlighting potential management trade-offs for non-native species that may aid imperiled species recovery yet disrupt other native communities.

Consistent scaling of population structure across landscapes despite intraspecific variation in movement and connectivity.

Understanding the spatial scale of population structure is fundamental to long-standing tenets of population biology, landscape ecology and conservation. Nonetheless, identifying such scales has been challenging because a key factor that influences scaling - movement among patches or local populations - is a multicausal process with substantial phenotypic and temporal variation. We resolve this problem via a novel application of network modularity. When applied to movements, modularity provides a formal description of the functional aggregation of populations and identifies potentially critical scales for ecological and evolutionary dynamics. We first test for modularity using several different types of biologically relevant movements across the entire geographic range of an endangered bird, the snail kite (Rostrhamus sociabilis plumbeus). We then ask whether variation in movement based on (i) age, (ii) sex and (iii) time (annual, seasonal and within-season movements) influences spatial population structure (i.e. modularity) in snail kites. We identified significant modularity in annual dispersal of snail kites (all adults, males only, females only, and juveniles only) and in within-breeding season movements of adults, yet no evidence of modularity in seasonal (non-breeding) movements. For those movements with observed modular structure, we found striking similarities in the spatial configuration of population structure, even though movement properties varied considerably among these different types of movements. Our results suggest that the emergence of modularity in population networks can be robust despite movement heterogeneity and differences in patch-based measures of connectivity. Furthermore, our comparison of the population structure and connectivity across multiple movement phases helps to identify wetland patches most critical to population connectivity at multiple spatiotemporal scales. We argue that understanding modularity in populations may provide a robust complement to existing measures of population structure and connectivity and will help to clarify the limiting roles of movement for populations. Such information is increasingly needed for interpreting population persistence and guiding effective conservation strategies with ongoing environmental change.

Affinity for natal environments by dispersers impacts reproduction and explains geographical structure of a highly mobile bird.

Understanding dispersal and habitat selection behaviours is central to many problems in ecology, evolution and conservation. One factor often hypothesized to influence habitat selection by dispersers is the natal environment experienced by juveniles. Nonetheless, evidence for the effect of natal environment on dispersing, wild vertebrates remains limited. Using 18 years of nesting and mark-resight data across an entire North American geographical range of an endangered bird, the snail kite (Rostrhamus sociabilis), we tested for natal effects on breeding-site selection by dispersers and its consequences for reproductive success and population structure. Dispersing snail kites were more likely to nest in wetlands of the same habitat type (lacustrine or palustrine) as their natal wetland, independent of dispersal distance, but this preference declined with age and if individuals were born during droughts. Importantly, dispersing kites that bred in natal-like habitats had lower nest success and productivity than kites that did not. These behaviours help explain recently described population connectivity and spatial structure across their geographical range and reveal that assortative breeding is occurring, where birds are more likely to breed with individuals born in the same wetland type as their natal habitat. Natal environments can thus have long-term and large-scale effects on populations in nature, even in highly mobile animals.

Social network models predict movement and connectivity in ecological landscapes.

Network analysis is on the rise across scientific disciplines because of its ability to reveal complex, and often emergent, patterns and dynamics. Nonetheless, a growing concern in network analysis is the use of limited data for constructing networks. This concern is strikingly relevant to ecology and conservation biology, where network analysis is used to infer connectivity across landscapes. In this context, movement among patches is the crucial parameter for interpreting connectivity but because of the difficulty of collecting reliable movement data, most network analysis proceeds with only indirect information on movement across landscapes rather than using observed movement to construct networks. Statistical models developed for social networks provide promising alternatives for landscape network construction because they can leverage limited movement information to predict linkages. Using two mark-recapture datasets on individual movement and connectivity across landscapes, we test whether commonly used network constructions for interpreting connectivity can predict actual linkages and network structure, and we contrast these approaches to social network models. We find that currently applied network constructions for assessing connectivity consistently, and substantially, overpredict actual connectivity, resulting in considerable overestimation of metapopulation lifetime. Furthermore, social network models provide accurate predictions of network structure, and can do so with remarkably limited data on movement. Social network models offer a flexible and powerful way for not only understanding the factors influencing connectivity but also for providing more reliable estimates of connectivity and metapopulation persistence in the face of limited data.

Racial and socioeconomic disparities in NSCLC molecular diagnostics uptake.

BACKGROUND: Precision therapies, such as targeted and immunotherapies, have substantially changed the landscape of late-stage non-small cell lung cancer (NSCLC). Yet utilization of these therapies is disproportionate across strata defined by race and socioeconomic status (SES), possibly due to disparities in molecular diagnostic testing (or "biomarker testing"), which is a prerequisite to treatment. METHODS: We extracted a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. The primary outcome was receipt of a molecular diagnostic test, based on claims data. The primary predictors were race and SES. Likelihood of receiving a molecular diagnostic test, and overall survival (OS), were investigated using logistic and Cox proportional hazards regression, adjusted for sex, age, residence, histology, marital status, and comorbidity. RESULTS: Of the 28,511 NSCLC patients, 11,209 (39.3%) received molecular diagnostic testing. Compared to White patients, fewer Black patients received a molecular diagnostic test (40.4% vs 27.9%; p < .001). After adjustment, Black patients (ORadj [odds ratio]: 0.64; 95% CI [confidence interval]: 0.58-0.71) and those living in areas with greater poverty (ORadj: 0.85; 95% CI: 0.80-0.89) had statistically significant decreased likelihood of molecular diagnostic testing. Patients who did receive testing had a statistically significant decreased risk of death (HRadj [hazards ratio]: 0.74; 95% CI: 0.72-0.76). These results held in the stratified analysis of stage IV NSCLC patients. CONCLUSION: Disparities exist in comprehensive molecular diagnostics, which is critical for clinical decision making. Addressing barriers to molecular testing could help close gaps in cancer care and improve patient outcomes.

Rapid and Reversible Lithium Insertion in the Wadsley-Roth-Derived Phase NaNb13O33.

The development of new high-performing battery materials is critical for meeting the energy storage requirements of portable electronics and electrified transportation applications. Owing to their exceptionally high rate capabilities, high volumetric capacities, and long cycle lives, Wadsley-Roth compounds are promising anode materials for fast-charging and high-power lithium-ion batteries. Here, we present a study of the Wadsley-Roth-derived NaNb13O33 phase and examine its structure and lithium insertion behavior. Structural insights from combined neutron and synchrotron diffraction as well as solid-state nuclear magnetic resonance (NMR) are presented. Solid-state NMR, in conjunction with neutron diffraction, reveals the presence of sodium ions in perovskite A-site-like block interior sites as well as square-planar block corner sites. Through combined experimental and computational studies, the high rate performance of this anode material is demonstrated and rationalized. A gravimetric capacity of 225 mA h g-1, indicating multielectron redox of Nb, is accessible at slow cycling rates. At a high rate, 100 mA h g-1 of capacity is accessible in 3 min for micrometer-scale particles. Bond-valence mapping suggests that this high-rate performance stems from fast multichannel lithium diffusion involving octahedral block interior sites. Differential capacity analysis is used to identify optimal cycling rates for long-term performance, and an 80% capacity retention is achieved over 600 cycles with 30 min charging and discharging intervals. These initial results place NaNb13O33 within the ranks of promising new high-rate lithium-ion battery anode materials that warrant further research.

Extreme weather and experience influence reproduction in an endangered bird.

Extreme weather events, such as droughts and heat waves, are expected to become more severe and more frequent in the coming years, and understanding their impacts on demographic rates is of increasing interest to both evolutionary ecologists and conservation practitioners. An individual's breeding probability can be a sensitive indicator of the decision to initiate reproductive behavior under varying environmental conditions, has strong fitness consequences, and can be considered the first step in a life history trade-off between allocating resources for breeding activities or self-survival. Using a 14-year time series spanning large variation in climatic conditions and the entirety of a population's breeding range, we estimated the effects of extreme weather conditions (drought) on the state-specific probabilities of breeding and survival of an endangered bird, the Florida Snail Kite (Rostrhamus sociabilis plumbeus). Our analysis accounted for uncertainty in breeding status assignment, a common source of uncertainty that is often ignored when states are based on field observations. Breeding probabilities in adult kites (> 1 year of age) decreased during droughts, whereas the probability of breeding in young kites (1 year of age) tended to increase. Individuals attempting to breed showed no evidence of reduced future survival. Although population viability analyses of this species and other species often implicitly assume that all adults will attempt to breed, we find that breeding probabilities were significantly < 1 for all 13 estimable years considered. Our results suggest that experience is an important factor determining whether or not individuals attempt to breed during harsh environmental conditions and that reproductive effort may be constrained by an individual's quality and/or despotic behavior among individuals attempting to breed.

Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.

The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.

A short-term pharmacodynamic model for monitoring aggrecanase activity: injection of monosodium iodoacetate (MIA) in rats and assessment of aggrecan neoepitope release in synovial fluid using novel ELISAs.

OBJECTIVE: To develop a short-term in vivo model in rats, with an enzyme-linked immunosorbent assay (ELISA) readout for specific aggrecanase-cleaved aggrecan fragments, to facilitate testing of aggrecanase inhibitors. METHODS: Monosodium iodoacetate (MIA), a metabolic inhibitor, was injected into the right knee joint of male Lewis rats and the release of aggrecanase-cleaved fragments of aggrecan containing the NITEGE or ARGN neoepitope was measured in the synovial fluid at 7 days post MIA injection using novel ELISAs. The ELISAs utilize a commercial antibody directed against the hyaluronic-acid binding region (HABR) of aggrecan, in combination with either an alpha-NITEGE antibody (NITEGE ELISA) or an alpha-ARGS/BC3 antibody (ARGS ELISA), to detect aggrecanase-cleavage of aggrecan within the interglobular domain (IGD). Aggrecan fragments present in in vitro digests, in cytokine-treated cartilage explant culture supernatants and in rat synovial fluid lavage samples were detected and quantified using the two ELISAs. Small molecule inhibitors of aggrecanase activity were dosed orally on days 3-7 to determine their ability to inhibit MIA-induced generation of the NITEGE and ARGN neoepitopes measured in the rat synovial fluid. RESULTS: The NITEGE assay was shown to specifically detect the N-terminal fragment of aggrecan comprising the G1 domain and the NITEGE neoepitope sequence. This assay can readily measure aggrecanase-cleaved bovine, human and rat aggrecan without the need for deglycosylation. The ARGS assay specifically detects C-terminal fragments of aggrecan comprising the ARGS/ARGN neoepitope and the G2 domain. Keratan sulfate (KS) residues of aggrecan interfere with this ELISA, and hence this assay works well with native rat articular cartilage aggrecan (that lacks KS residues) and with deglycosylated bovine and human aggrecan. Injection of MIA into the rat knee joints resulted in a time-dependent increase in the release of aggrecanase-cleaved aggrecan fragments into the synovial fluid and treatment with an aggrecanase inhibitor resulted in a dose-dependent inhibition of the generation of these neoepitopes. CONCLUSIONS: We have established a short-term in vivo model in rats that involves measurement of synovial fluid biomarkers that are dependent on aggrecanase activity in the joint. The short duration of the model combined with the mechanistic biomarker readout makes it very useful for the initial in vivo screening of aggrecanase inhibitors prior to testing them in time and resource-intensive disease models of osteoarthritis (OA).

Development of a novel clinical biomarker assay to detect and quantify aggrecanase-generated aggrecan fragments in human synovial fluid, serum and urine.

OBJECTIVE: Proteolytic degradation of aggrecan in articular cartilage is a hallmark feature of osteoarthritis (OA). The present study was aimed at developing a sensitive enzyme linked immunosorbent assay (ELISA) for the detection of aggrecanase-cleaved fragments of aggrecan in human serum and urine to facilitate the clinical development of aggrecanase inhibitors for OA. METHODS: The BC3 monoclonal antibody that detects the ARGS neoepitope sequence in aggrecanase-cleaved aggrecan was engineered and optimized using complementarity determining region (CDR)-saturation mutagenesis to improve its binding affinity to the neoepitope. A sandwich ELISA (BC3-C2 ELISA) was developed using the optimized alpha-ARGS antibody (BC3-C2) as capture antibody and a commercially available antibody directed against the hyaluronic-acid binding region (HABR) of aggrecan as detection antibody. Aggrecanase-cleaved fragments of aggrecan present in in vitro digests, human cartilage explant culture supernatants and in human synovial fluid, serum and urine were detected and quantified using this ELISA. RESULTS: The optimized antibody had a 4-log improvement in affinity for the ARGS containing peptide compared to the parental BC3 antibody, while maintaining the ability to not cross-react with a spanning peptide. The BC3-C2 ELISA demonstrated the ability to detect aggrecanase-cleaved aggrecan fragments in the native state, without the need for deglycosylation. This ELISA was able to measure aggrecanase-generated ARGS containing aggrecan fragments in human articular cartilage (HAC) explant cultures in the basal state (without cytokine stimulation). Treatment with an aggrecanase inhibitor resulted in a dose-dependent inhibition of ARGS neoepitope released into the culture supernatant. The ELISA assay also enabled the detection of ARGS containing fragments in human synovial fluid, serum and urine, suggesting its potential utility as a biomarker of aggrecanase activity. CONCLUSIONS: We have developed a novel ELISA using an optimized ARGS antibody and have demonstrated for the first time, an ELISA-based measurement of aggrecan degradation products in human serum and urine. This assay has the potential to serve as a mechanistic drug activity biomarker in the clinic and is expected to significantly impact/accelerate the clinical development of aggrecanase inhibitors and other disease modifying drugs for OA.

Enhanced protein C activation and inhibition of fibrinogen cleavage by a thrombin modulator.

A modulator of the enzymatic activity of human thrombin, designated LY254603, was identified that enhances the thrombin-catalyzed generation of the anticoagulant factor activated protein C, yet inhibits thrombin-dependent fibrinogen clotting. By means of mutant substrates, it was shown that LY254603 mediates the change in enzymatic substrate specificity through an alteration in thrombin's S3 substrate recognition site, a mechanism that appeared to be independent of allosteric changes induced by either sodium ions or by thrombomodulin. This compound may represent the prototype of a class of agents that specifically modulates the balance between thrombin's procoagulant and anticoagulant functions.

Lobster sniffing: antennule design and hydrodynamic filtering of information in an odor plume.

The first step in processing olfactory information, before neural filtering, is the physical capture of odor molecules from the surrounding fluid. Many animals capture odors from turbulent water currents or wind using antennae that bear chemosensory hairs. We used planar laser-induced fluorescence to reveal how lobster olfactory antennules hydrodynamically alter the spatiotemporal patterns of concentration in turbulent odor plumes. As antennules flick, water penetrates their chemosensory hair array during the fast downstroke, carrying fine-scale patterns of concentration into the receptor area. This spatial pattern, blurred by flow along the antennule during the downstroke, is retained during the slower return stroke and is not shed until the next flick.

Rapid morphological change of a top predator with the invasion of a novel prey.

Invasive exotic species are spreading rapidly throughout the planet. These species can have widespread impacts on biodiversity, yet the ability for native species, particularly long-lived vertebrates, to respond rapidly to invasions remains mostly unknown. Here we provide evidence of rapid morphological change in the endangered snail kite (Rostrhamus sociabilis) across its North American range with the invasion of a novel prey, the island apple snail (Pomacea maculata), a much larger congener of the kite's native prey. In less than one decade since invasion, snail kite bill size and body mass increased substantially. Larger bills should be better suited to extracting meat from the larger snail shells, and we detected strong selection on increased size through juvenile survival. Using pedigree data, we found evidence of both genetic and environmental influences on trait expression and discovered that additive genetic variation in bill size increased with invasion. However, trends in predicted breeding values emphasize that recent morphological changes have been driven primarily by phenotypic plasticity rather than micro-evolutionary change. Our findings suggest that evolutionary change may be imminent and underscore that even long-lived vertebrates can respond quickly to invasive species. Furthermore, these results highlight that phenotypic plasticity may provide a crucial role for predators experiencing rapid environmental change.

Influence of thyroid hormone status on mevalonate metabolism in rats.

Mevalonate, an essential intermediate in cholesterol synthesis, is metabolized either to cholesterol or, by the shunt pathway, to CO2. Previous investigations have demonstrated that the kidneys are the chief site of circulating mevalonate metabolism and that sex hormones as well as insulin markedly influence circulating mevalonate metabolism. The present study examined in rats the influence of thyroid hormone status on mevalonate metabolism in vivo and in vitro. L-thyroxine administration increased renal conversion of circulating mevalonate to cholesterol, 41% in the females and 22% in the males. Conversely, hypothyroidism induced by 6 N propyl-2-thiouracil reduced renal conversion of circulatng mevalonate to cholesterol by 45% in females and 27% in males; thyroid hormone replacement in these animals returned cholesterogenesis in the kidneys to supranormal levels. Neither L-thyroxine nor hypothyroidism altered circulating mevalonate conversion to cholesterol in the liver or carcass. In vitro studies confirmed the in vivo observations. Changes in thyroid hormone produced only minor changes in the shunt pathway of mevalonate metabolism. This study demonstrates that the major effect of the thyroid hormone on the metabolism of circulating mevalonate is to alter the conversion of mevalonate to cholesterol, an effect localized solely to the kidneys.

Sex difference in human mevalonate metabolism.

Two pathways of mevalonate metabolism have been demonstrated: the major (sterol) pathway leads to cholesterol synthesis, whereas the second shunts mevalonate away from sterol production and ultimately results in its oxidation to CO2. Previous studies have demonstrated that the female rat metabolizes circulating mevalonate by the shunt pathway at twice the rate of the male, whereas the male rat converts significantly more circulating mevalonate to cholesterol than the female. The present study extends these observations to humans. Six men and five premenopausal women with normal renal function were injected with R,S-[5-14C]mevalonate, and 14CO2 expired in the breath of the subjects was monitored continuously with an ionization chamber. On an average, the female subjects expired 16.5% and the males 9.8% of the injected R-[5-14C]mevalonate (P less than 0.001). No differences were observed in the plasma and erythrocyte [14C]cholesterol levels. These data demonstrate, in human beings, a sex difference in mevalonate metabolism. The overall impact of the greater mevalonate shunt activity on cholesterol balance in women is unknown.

Abnormality of standing posture improves in patients with bilateral spastic cerebral palsy following lower limb surgery.

OBJECTIVES: The degree of abnormality of the gait pattern of children with bilateral spastic cerebral palsy (BSCP) can be reduced by lower limb orthopaedic surgery. However, little attention is paid to the effects of surgery on standing posture. Here, we investigated the abnormality of standing posture in young people with BSCP as well as the effects of surgery on standing posture. METHODS: We have developed an index of standing posture, the Standing Posture Score (SPS), which is similar in composition to the gait profile score (GPS). We applied SPS retrospectively to 32 typically developing children and 85 children with BSCP before and after surgery to the lower limbs aimed at improving gait. We investigated the relationship between SPS and GPS before surgery and also the relationship between changes in these variables before and after surgery. RESULTS: SPS is significantly higher in young people with BSCP. SPS reduces after surgery and this reduction is correlated with the reduction in GPS. INTERPRETATION: Successful surgery improves the alignment of the lower limbs in BSCP in standing and may have a positive impact on the activities of daily living which depend on a stable and efficient standing posture.

Whole-Genome Sequences of Variants of Bacillus anthracis Sterne and Their Toxin Gene Deletion Mutants.

Here, we report the draft genome sequences of three laboratory variants of Bacillus anthracis Sterne and their double (Δlef Δcya) and triple (Δpag Δlef Δcya) toxin gene deletion derivatives.