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We studied the floral reproductive biology and nectar chemistry of Jaltomata grandiflora (Solanaceae), an apparently rare perennial of Michoacán, Mexico. During day 1, flowers are pistillate (stigma receptive, anthers not yet presenting pollen); flowers close for the night. Early in the morning of day 2, the corolla re-opens, stamens elongate to five times their earlier length, and anthers dehisce; the dehisced anthers remain about 2 mm from the stigma for much of day 2. In the afternoon of day 2, the corolla again closes, the corolla–androecium abscises, and only then can pollen be seen on the stigma. Protogyny and herkogamy likely promote outcrossing during days 1 and 2, respectively. Autonomous self-pollination takes place at the end of the corolla's life and allows fruit and seed production in the absence of pollinators but results in fruits that are lighter and contain fewer seeds than fruits resulting from manual self-pollinations. Carbohydrates from floral nectar samples were separated and quantified using hydrophilic interaction liquid chromatography coupled with corona charged aerosol detection. In nectar, mean sucrose concentration (0.482 mg/mg nectar), is about 10 and five times higher than glucose (0.043 mg/mg nectar) and fructose (0.095 mg/mg nectar) concentrations.

Background: Translational gaps exist in implementing health innovations rapidly in clinical practice. Pragmatic effectiveness and implementation studies, therefore, play a pivotal role in understanding how high-value health innovations could be deployed and delivered in healthcare systems to reduce barriers to adoption and provide more rapid patient benefit. Victorion-spirit is an ongoing pragmatic, 9-month, phase IIIb, open-label, multicentre, randomised controlled study evaluating the implementation, patient experience, and delivery of the subcutaneous lipid-lowering therapy, inclisiran sodium 300 mg, in participants with elevated low-density lipoprotein cholesterol (LDL-C) who are on established lipid-lowering medication, or have been recommended lipid-lowering therapy, but are unable to tolerate treatment. Methods: Victorion-spirit utilises a type 1 hybrid effectiveness-implementation design, where the primary objective is to demonstrate superiority of inclisiran with or without (±) behavioural support versus standard of care (SOC; e.g., statin and/or other lipid-lowering therapies) + behavioural support in terms of percentage reduction in LDL-C from baseline to Day 270 in a primary care setting. Secondary objectives will evaluate implementation of inclisiran ± behavioural support versus SOC + behavioural support through assessment of patient satisfaction and patient activation/empowerment after treatment at Day 90; adherence to cardiovascular disease self-management; and serious adverse event profile. Additionally, a process evaluation ascertaining the views of patients, providers and national health service (NHS) commissioners will explore barriers and enablers to integrating inclisiran within primary care. Conclusions: The results of Victorion-spirit have potential to change our approach to lipid management and inform further implementation efforts in healthcare systems, such as the NHS. Trial registration: ClinicalTrials.gov NCT04087400.

Combining existing knowledge of museum exhibition visitor experience with concepts of User Experience (UX), a model for Museum Exhibition User Experience (MEUX) is presented. The model was developed from research interviews and surveys with UK museum professionals and presents the museum exhibition experience from both museum and visitor perspectives. Its use as an evaluation tool for visitor experience is explored at Oxford University Museum of Natural History (OUMNH). In comparing results with those from staff, a disconnect emerged between museum and visitor preferences on motivations for visiting and what outcomes emerge from visits. The incorporation of the theoretical MEUX model into museum practice enables holistic conceptualization of the visitor experience through the pragmatic and hedonic qualities of an exhibition. With the development of further evaluation tools, this framework and methodology accurately captures institutional and visitor preferences and can evaluate how the development decisions of museums influence and impact the visitor experience.

International audience; Earth's climate cooled markedly during the late Miocene from 12 to 5 million years ago, with far-reaching consequences for global ecosystems. However, the driving forces of these changes remain controversial. A major obstacle to progress is the uncertainty over the role played by greenhouse gas radiative forcing. Here we present boron isotope compositions for planktic foraminifera, which record carbon dioxide change for the interval of most rapid cooling, the late Miocene cooling event between 7 and 5 Ma. Our record suggests that CO2 declined by some 100 ppm over this two-million-year-long interval to a minimum at approximately 5.9 Ma. Having accounted for non-CO2 greenhouse gasses and slow climate feedbacks, we estimate global mean surface temperature change for a doubling of CO2—equilibrium climate sensitivity—to be 3.9 °C (1.8-6.7 °C at 95% confidence) on the basis of comparison of our record of radiative forcing from CO2 with a record of global mean surface temperature change. We conclude that changes in CO2 and climate were closely coupled during the latest Miocene and that equilibrium climate sensitivity was within range of estimates for the late Pleistocene, other intervals of the Cenozoic and the twenty-first century as presented by the Intergovernmental Panel on Climate Change.

Introduction: Missions beyond low Earth orbit (LEO) will expose astronauts to ionizing radiation (IR) in the form of solar energetic particles (SEP) and galactic cosmic rays (GCR) including high atomic number and energy (HZE) nuclei. The gastrointestinal (GI) system is documented to be highly radiosensitive with even relatively low dose IR exposures capable of inducing mucosal lesions and disrupting epithelial barrier function. IR is also an established risk factor for colorectal cancer (CRC) with several studies examining long-term GI effects of SEP/GCR exposure using tumor-prone APC mouse models. Studies of acute short-term effects of modeled space radiation exposures in wildtype mouse models are more limited and necessary to better define charged particle- induced GI pathologies and test novel medical countermeasures (MCMs) to promote astronaut safety.Methods: In this study, we performed ground-based studies where male and female C57BL/6J mice were exposed to γ-rays, 50 MeV protons, or 1 GeV/n Fe-56 ions at the NASA Space Radiation Laboratory (NSRL) with histology and immunohistochemistry endpoints measured in the first 24 h post-irradiation to define immediate SEP/GCR-induced GI alterations.Results: Our data show that unlike matched γ-ray controls, acute exposures to protons and iron ions disrupts intestinal function and induces mucosal lesions, vascular congestion, epithelial barrier breakdown, and marked enlargement of mucosa-associated lymphoid tissue. We also measured kinetics of DNA double-strand break (DSB) repair using gamma-H2AX- specific antibodies and apoptosis via TUNEL labeling, noting the induction and disappearance of extranuclear cytoplasmic DNA marked by gamma-H2AX only in the charged particle-irradiated samples. We show that 18 h pre-treatment with curcumin-loaded nanolipoprotein particles (cNLPs) delivered via IV injection reduces DSB-associated foci levels and apoptosis and restore crypt villi lengths.Discussion: These data improve our understanding of physiological alterations in the GI tract immediately following exposures to modeled space radiations and demonstrates effectiveness of a promising space radiation MCM.

The mid-Pliocene (3.3–3.0 Ma) is the most recent period in Earth’s history of sustained, global warmth analogous to predicted near-future climates. Despite considerable efforts to characterize and understand the climate dynamics of the mid-Pliocene, the deep ocean and its response to this warming remains poorly understood. Here we present new mid-Pliocene Mg/Ca and Δ47 (“clumped isotope”) temperatures from the deep Pacific and North Atlantic oceans. These records cover the transition from Marine Isotope Stage (MIS) M2 — considered the most pronounced “glacial” stage of the mid-Pliocene — to the warm KM5 interglacial. We find that a large (>4 °C) temperature gradient existed between these two basins throughout that interval, with the deep North Atlantic considerably warmer and likely saltier than at present. We interpret our results to indicate that the deep Pacific and North Atlantic oceans were bathed by water masses with very different physical properties during the mid-Pliocene, and that only limited deep oceanic exchange occurred between the two basins. Our results point to a fundamentally different mode of ocean circulation or mixing compared to the present, where heat and salt is distributed from the North Atlantic into the Pacific. The amplitude of cooling observed at both sites during MIS M2 suggests that changes in benthic δ18O associated with this cold stage were mostly driven by temperature change in the deep ocean rather than ice volume.

Purpose: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.Experimental Design: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.Results: rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10−37). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).Conclusion: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors. Clin Cancer Res; 21(2); 365–72. ©2014 AACR.

AimsTo explore barriers to, and facilitators of, adherence to compression therapy, from the perspective of people with venous leg ulcers.DesignAn interpretive, qualitative, descriptive study involving interviews with patients.MethodsParticipants were purposively sampled from respondents to a survey exploring attitudes to compression therapy in people with venous leg ulcers. Sampling continued until data saturation: 25 interviews between December 2019 and July 2020. Inductive thematic analysis of interview transcripts was undertaken to create a framework for the data, followed by deductive analysis informed by the Common-Sense Model of Self-Regulation.ResultsA range of knowledge and understanding about the cause of venous leg ulcers and the mechanisms of compression therapy was demonstrated, which was not particularly related to adherence. Participants talked about their experience with different compression methods and their concerns about the length of time healing could take. They also spoke about aspects of the organization of services which affected their care.ConclusionIdentifying specific, individual barriers/facilitators to compression therapy is not simple, rather factors combine to make adherence more or less likely or possible. There was no clear relationship between an understanding of the cause of VLUs or the mechanism of compression therapy and adherence; different compression therapies presented different challenges for patients; unintentional non-adherence was frequently mentioned; and the organization of services could impact on adherence. Ways in which people could be supported to adhere to compression therapy are indicated. Implications for practice include issues relating to communication with patients; taking into account patients' lifestyles and ensuring that they know about useful ‘aids’; providing services that are accessible and provide continuity of appropriately trained staff; minimizing unintentional non-adherence; and acknowledging that healthcare professionals will always need to support/advise those who cannot tolerate compression.ImpactCompression therapy is a cost-effective, evidence-based treatment for venous leg ulcers. However, there is evidence that patients do not always adhere to this therapy and there is limited research investigating reasons why patients do not wear compression. The study found no clear relationship between an understanding of the cause of VLUs or the mechanism of compression therapy and adherence; that different compression therapies presented different challenges for patients; that unintentional non-adherence was frequently mentioned and that the organization of services could impact on adherence. Attending to these findings offers the opportunity to increase the proportion of people undergoing appropriate compression therapy and achieving complete wound healing, the main outcome desired by this group.Patient/Public ContributionA patient representative sits on the Study Steering Group, contributing to the work from developing the study protocol and interview schedule to interpretation and discussion of findings. Members of a Wounds Research Patient and Public Involvement Forum were consulted about interview questions.

Boron isotopes in planktonic foraminifera are a widely used proxy to determine ancient surface seawater pH, and by extension atmospheric CO2 concentration and climate forcing on geological time scales. Yet, to reconstruct absolute values for pH and CO2, we require a δ11Bforam-borate to pH calibration and independent determinations of ocean temperature, salinity, a second carbonate parameter, and the boron isotope composition of seawater. Although δ11B-derived records of atmospheric CO2 have been shown to perform well against ice core-based CO2 reconstructions, these tests have been performed at only a few locations and with limited temporal resolution. Here we present two highly resolved CO2 records for the late Pleistocene from ODP Sites 999 and 871. Our δ11B-derived CO2 record shows a very good agreement with the ice core CO2 record with an average offset of 4.6 ± 49 (2σ) ppm, and a RMSE of 25 ppm, with minor short-lived overestimations of CO2 (of up to ~50 ppm) occurring during some glacial onsets. We explore potential drivers of this disagreement and conclude that partial dissolution of foraminifera has a minimal effect on the CO2 offset. We also observe that the general agreement between δ11B -derived and ice core CO2 is improved by optimising the δ11Bforam-borate calibration. Despite these minor issues a strong linear relationship between relative change in climate forcing from CO2 (from ice core data) and pH change (from δ11B) exists over the late Pleistocene, confirming that pH change is a robust proxy of climate forcing over relatively short (2 beyond the reach of the ice cores and can help improve determinations of climate sensitivity for ancient time intervals.

Nonparametric methods are widely used for assessing the performance of firms and other organizations in the private and public sectors. Typically, FDH or DEA estimators that estimate the attainable sets and its efficient boundary by enveloping the cloud of observed units in the appropriate input-output space are used. The statistical properties of these estimators have been established and inference is available using appropriate nonparametric techniques. In particular, hypotheses on model structure and the production process can be tested using using recent theoretical results including Central Limit Theorems on limiting distribution of means of efficiency scores. This chapter shows how these results can be used for testing the equality of means of efficiency, convexity of production sets and separability with respect to environmental factors are considered, and in addition for analyzing the dynamics of the production process over time. An empirical illustration is provided by using the various results and tests to examine the performance of municipal governments in the U.S. in providing local public goods.

Woodland caribou ( Rangifer tarandus caribou) are threatened in Canada because of the drastic decline in population size caused primarily by human-induced landscape changes that decrease habitat and increase predation risk. Conservation efforts have largely focused on reducing predators and protecting critical habitat, whereas research on dietary niches and the role of potential food constraints in lichen-poor environments is limited. To improve our understanding of dietary niche variability, we used a next-generation sequencing approach with metabarcoding of DNA extracted from faecal pellets of woodland caribou located on Lake Superior in lichen-rich (mainland) and lichen-poor (island) environments. Amplicon sequencing of fungal ITS2 region revealed lichen-associated fungi as predominant in samples from both populations, but amplification at the chloroplast trnL region, which was only successful on island samples, revealed primary consumption of yew ( Taxus spp.) based on relative read abundance (83.68%) with dogwood ( Cornus spp.; 9.67%) and maple ( Acer spp.; 4.10%) also prevalent. These results suggest that conservation efforts for caribou need to consider the availability of food resources beyond lichen to ensure successful outcomes. More broadly, we provide a reliable methodology for assessing ungulate diet from archived faecal pellets that could reveal important dietary shifts over time in response to climate change.

This paper estimates the shadow price of equity for U.S. commercial banks over 2001–2018 using nonparametric local-linear estimators of the underlying cost frontier and tests the existence of “Too-Big-to-Fail” (TBTF) banks. Evidence for the existence of TBTF banks is found. We find that a negative correlation exists between the shadow price of equity and the size of banks in each year, suggesting that big banks pay less for equity than small banks. In addition, in each year there are more banks with a negative shadow price of equity in the fourth quartile based on total assets than in the other three quartiles. The data also reveal that for each year, the estimated mean shadow price of equity for the 50 largest banks is smaller than the mean price of deposits, even though equity is commonly viewed as a riskier asset than deposits. Finally, we find that the top 10 largest banks are willing to pay much more at the start of the global financial crisis and after the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010 than the other periods. These results imply that these regulations are effective in reducing the implicit subsidy, at least for the top 10 largest banks. However, it is also evident that the recapitalization has imposed significant equity funding costs for the top 10 largest banks.

Intra-specific diversification in the northern hemisphere is a recent phenomenon, particularly for vertebrates, due to climatic oscillations during the Quaternary. Caribou (Rangifer tarandus) are a recently diversified, keystone species in North America with a continental-wide distribution and a large amount of phenotypic variation. We assess patterns of intra-specific genetic variation and adaptive divergence, which are of critical interest to the fields of evolutionary biology and conservation. We characterized the relationship among caribou ecotypes and rapidly evolving genes among intra-specific lineages using phylogenomic analyses and a newly assembled chromosome-scale reference genome and 66 high-coverage genomes. Nine phylogenomic lineages showed different levels of introgression, with some lineages highly introgressed. Despite this, dN/dS ratios of all genes in the caribou genome (>30,000) identified 700-800 genes with significant signatures of positive selection in each lineage. These genes function in diverse pathways ranging from immune responses to circulatory systems, with the most enriched molecular pathways found in lineages with high levels of introgression. Glacial cycles and repeated introgression events between caribou lineages likely inflated both neutral and adaptive genetic variation: findings that are particularly timely given the importance of intra-specific diversity and adaptive variation in wild species for resilience to global change.

Density is an important demographic parameter that is commonly overlooked in studies of wild populations. Here, we examined the effects of variable spatially explicit density on a range of demographic parameters in a wild population of a cryptic ungulate, boreal woodland caribou (Rangifer tarandus caribou). Using non-invasive genetic sampling, we applied spatial capture–recapture methods with landscape covariates to estimate the density of boreal woodland caribou across a 108,806 km2 study area. We then created a familial network from the reconstructed parent–offspring relationships to determine whether spatial density influenced sex-specific individual reproductive success, female pregnancy status, and dispersal distance. We found that animal density varied greatly in response to land cover types and disturbance; animal density was most influenced by landscape composition and distance to roads varying from 0 in areas with >20% deciduous cover to 270 caribou per 1,000 km2 in areas presenting contiguous older coniferous cover. We found that both male and female reproductive success varied with density, with males showing a higher probability of having offspring in higher-density areas, and the opposite for females. No differences were found in female pregnancy rates occurring in high- and low-density areas. Dispersal distances varied with density, with offspring moving shorter distances when parents were found in higher-density areas. Familial networks showed lower-closeness centrality and lower-degree centrality for females in higher-density areas, indicating that females found in higher-density areas tend to be less broadly associated with animals across the range. Although high-density areas do reflect good-quality caribou habitat, the observed decreased closeness and degree centrality measures, dispersal rates, and lower female recruitment rates suggest that remnant habitat patches across the landscape may create population sinks.

Conservation genomics is an important tool to manage threatened species under current biodiversity loss. Recent advances in sequencing technology mean that we can now use whole genomes to investigate demographic history, local adaptation, inbreeding, and more in unprecedented detail. However, for many rare and elusive species only non-invasive samples such as faeces can be obtained, making it difficult to take advantage of whole genome data. We present a method to extract DNA from the mucosal layer of faecal samples to re-sequence high coverage whole genomes using standard laboratory techniques. We use wild collected faecal pellets collected from caribou (Rangifer tarandus), a species undergoing declines in many parts of its range in Canada and subject to comprehensive conservation and population monitoring measures. We compare four faecal genomes to two tissue genomes sequenced in the same run. Quality metrics were similar between faecal and tissue samples with the main difference being the alignment success of raw reads to the reference genome due to differences in low quality and endogenous DNA content, affecting overall coverage. One of our faecal genomes was only re-sequenced at low coverage (1.6 ×), however the other three obtained between 7 and 15 ×, compared to 19 and 25 × for the tissue samples. We successfully re-sequenced high-quality whole genomes from faecal DNA and are one of the first to obtain genome-wide data from wildlife faecal DNA in a non-primate species. Our work represents an important advancement for non-invasive conservation genomics.

Pleistocene glacial cycles influenced the diversification of high-latitude wildlife species through recurrent periods of range contraction, isolation, divergence, and expansion from refugia and subsequent admixture of refugial populations. We investigate population size changes and the introgressive history of caribou (Rangifer tarandus) in western Canada using 33 whole genome sequences coupled with larger-scale mitochondrial data. We found that a major population expansion of caribou occurred starting around 110,000 years ago (kya), the start of the last glacial period. Additionally, we found effective population sizes of some caribou reaching ~700,000 to 1,000,000 individuals, one of the highest recorded historical effective population sizes for any mammal species thus far. Mitochondrial analyses dated introgression events prior to the LGM dating to 20-30 kya and even more ancient at 60 kya, coinciding with colder periods with extensive ice coverage, further demonstrating the importance of glacial cycles and events prior to the LGM in shaping demographic history. Reconstructing the origins and differential introgressive history has implications for predictions on species responses under climate change. Our results have implications for other whole genome analyses using pairwise sequentially Markovian coalescent (PSMC) analyses, as well as highlighting the need to investigate pre-LGM demographic patterns to fully reconstruct the origin of species diversity, especially for high-latitude species.

The evolutionary origins and hybridization patterns of Canis species in North America have been hotly debated for the past 30 years. Disentangling ancestry and timing of hybridization in Great Lakes wolves, eastern Canadian wolves, red wolves, and eastern coyotes are most often partitioned into a 2‐species model that assigns all ancestry to gray wolves and/or coyotes, and a 3‐species model that includes a third, North American evolved eastern wolf genome. The proposed models address recent or sometimes late Holocene hybridization events but have largely ignored potential Pleistocene era progenitors and opportunities for hybridization that may have impacted the current mixed genomes in eastern Canada and the United States. Here, we re‐analyze contemporary and ancient mitochondrial DNA genomes with Bayesian phylogenetic analyses to more accurately estimate divergence dates among lineages. We combine that with a review of the literature on Late Pleistocene Canis distributions to: (a) identify potential Pleistocene progenitors to southern North American gray wolves and eastern wolves; and (b) illuminate opportunities for ancient hybridization events. Specifically, we propose that Beringian gray wolves (C. lupus) and extinct large wolf‐like coyotes (C. latrans orcutti) are likely progenitors to Mexican and Plains gray wolves and eastern wolves, respectively, and may represent a potentially unrecognized source of introgressed genomic variation within contemporary Canis genomes. These events speak to the potential origins of contemporary genomes and provide a new perspective on Canis ancestry, but do not negate current conservation priorities of dwindling wolf populations with unique genomic signatures and key ecologically critical roles.

The Sahara is the largest hot desert on Earth. Yet the timing of its inception and its response to climatic forcing is debated, leading to uncertainty over the causes and consequences of regional aridity. Here we present detailed records of terrestrial inputs from Africa to North Atlantic deep-sea sediments, documenting a long and sustained history of astronomically paced oscillations between a humid and arid Sahara from over 11 million years ago. We show that intervals of strong dust emissions from the heart of the continent predate both the intensification of Northern Hemisphere glaciation and the oldest land-based evidence for a Saharan desert by millions of years. We find no simple long-term gradational transition towards an increasingly arid climate state in northern Africa, suggesting that aridity was not the primary driver of gradual Neogene expansion of African savannah C4 grasslands. Instead, insolation-driven wet–dry shifts in Saharan climate were common over the past 11 Myr, and we identify three distinct stages in the sensitivity of this relationship. Our data provide context for evolutionary outcomes on Africa; for example, we find that astronomically paced arid intervals predate the oldest fossil evidence of hominid bipedalism by at least 4 Myr.

Past hydroclimate change in Africa and the Arabian Peninsula plays a vital role in early human evolution and dispersal. Although arid today, North Africa and the Arabian Peninsula experienced periodic humid intervals, during which strengthened rainfall driven by astronomical forcing (chiefly eccentricity-modulated precessional cycles) transformed the Saharo-Arabian desert into a vegetated landscape cross-cut by rivers and lakes. The relationship between hydroclimate variability and hominid evolution is strongly debated and continuous palaeoclimate reconstructions are required to provide a context for understanding evolutionary outcomes on land. However, there are major discrepancies between different types of proxy data and between these reconstructions and those generated by numerical models as to the spatial and temporal occurrence of humid events and to the seasonality of the rainfall responsible. Two major contributing problems concern (i) the incontinuous nature of palaeo records from terrestrial archives (palaeolake sediments and stalagmites) and (ii) the challenges of attribution associated with records from marine sediment cores. Here, we report geochemical and stable isotope data from the Arabian Sea to reconstruct past environmental changes in a multi-proxy approach, which will help us to understand the relationship between palaeoclimate change and hominid evolution, reveal how the West Asian monsoon responded to a period of increased global warmth and furthermore, provide a reliable data set for model simulations in the future.

Highlights • We present LGC record of the Pb isotope composition Labrador Sea seawater. • These data can be used to track Laurentide Ice Sheet extent over Hudson Bay. • LIS retreat during the PGM was relatively fast compared to the LGM • The LIS first advanced significantly over Hudson Bay during MIS 4. • Our record does not support significant LIS retreat during MIS 3. Understanding the history of continental ice-sheet growth on North America, and in particular that of the Laurentide Ice Sheet (LIS), is important for palaeoclimate and sea-level reconstructions. Information on ice-sheet extent pre-dating the Last Glacial Maximum (LGM) is heavily reliant, though, on the outputs of numerical models underpinned by scant geological data. Important aspects of LIS history that remain unresolved include the timing of its collapse during Termination 2, the first time that it expanded significantly during the Last Glacial Cycle, and whether its volume was significantly reduced during marine isotope stage (MIS) 3. To address these issues and more, we present authigenic iron-manganese (Fe–Mn) oxyhydroxide-derived high-resolution records of Pb isotope data and associated rare earth element profiles for samples spanning the past ∼130 kyr from northwest North Atlantic Labrador Sea, IODP Site U1302/3. We use these new data to track chemical weathering intensity and solute flux to the Labrador Sea associated with LIS extent on the adjacent highly radiogenic (high Pb isotope composition) North American Superior Province (SP) craton since the Penultimate Glacial Maximum (PGM). Our new records show that relatively high (radiogenic) values characterise warm marine isotope stages (MIS) 5, 3 and 1 and the lowest (most unradiogenic) values occurred during cold stages MIS 6, 4 and 2. The radiogenic Pb isotope excursion associated with Termination 2 is short-lived relative to the one documented for Termination 1, suggesting that LIS retreat during the PGM was relatively fast compared to the LGM and that its collapse during the last interglacial occurred ∼125 ka. Highly radiogenic inputs to the Labrador Sea during MIS 5d-a, ∼116–71 ka, most likely reflect a spin-up in Labrador Current vigour, incipient glaciation and renewed glacial erosion of high grounds of the eastern SP craton by localised wet-based ice-caps. A large decrease in Pb isotope values towards unradiogenic LGM-like compositions between ∼75–65 ka across the MIS 5/4 transition likely reflects a slow-down in Labrador Current vigour, an increase in subaerial deposition of aeolian dust and a significant advance of the LIS across Hudson Bay caused a strong reduction or even abandonment of Pb sourcing from the SP. The relatively radiogenic Pb isotope composition of bottom-waters bathing our study site during MIS 3, 57–29 ka, is unlikely to support a recently proposed major reduction in LIS extent for this time. Instead, we argue these values are better explained by southern Greenland Ice Sheet retreat, increased chemical weathering of the Ketelidian Mobile Belt and subsequent Pb runoff from Greenland.

In social species, reproductive success and rates of dispersal vary among individuals resulting in spatially structured populations. Network analyses of familial relationships may provide insights on how these parameters influence population‐level demographic patterns. These methods, however, have rarely been applied to genetically derived pedigree data from wild populations.Here, we use parent–offspring relationships to construct familial networks from polygamous boreal woodland caribou (Rangifer tarandus caribou) in Saskatchewan, Canada, to inform recovery efforts. We collected samples from 933 individuals at 15 variable microsatellite loci along with caribou‐specific primers for sex identification. Using network measures, we assess the contribution of individual caribou to the population with several centrality measures and then determine which measures are best suited to inform on the population demographic structure. We investigate the centrality of individuals from eighteen different local areas, along with the entire population.We found substantial differences in centrality of individuals in different local areas, that in turn contributed differently to the full network, highlighting the importance of analyzing networks at different scales. The full network revealed that boreal caribou in Saskatchewan form a complex, interconnected familial network, as the removal of edges with high betweenness did not result in distinct subgroups. Alpha, betweenness, and eccentricity centrality were the most informative measures to characterize the population demographic structure and for spatially identifying areas of highest fitness levels and family cohesion across the range. We found varied levels of dispersal, fitness, and cohesion in family groups. Synthesis and applications: Our results demonstrate the value of different network measures in assessing genetically derived familial networks. The spatial application of the familial networks identified individuals presenting different fitness levels, short‐ and long‐distance dispersing ability across the range in support of population monitoring and recovery efforts., Network analyses of familial relationships may provide insights on how fitness influences population‐level demographic patterns in socially structured populations. Here, we use networks to reconstruct parent‐offspring relationships and create a familial network from polygamous boreal woodland caribou (Rangifer tarandus caribou), assessing the contribution of individual caribou to the population with several centrality metrics and determine which metrics are best suited to inform on population demographic structure. The familial network revealed that boreal caribou in Saskatchewan form a complex, interconnected social network, and identified areas of higher fitness levels and social cohesion across the range in support of population monitoring and recovery efforts.

Kalman filter-based retrodiction plays an indispensable role in modern multitarget tracking and retrodiction (MTTR) algorithms. To this end, the Rauch–Tung–Striebel (RTS) smoother is a widely used Kalman filter-based target state smoother. With a large number of targets, MTTR algorithms, particularly with large window sizes, become very computationally intensive. If not addressed, these algorithms will not meet the requirements for tracking a large number of targets in real time. A natural approach is to parallelize these algorithms to render them useful, particularly in the context of emerging multicore platforms. However, this is nontrivial, as the governing mathematical framework of the RTS smoother, namely the dependencies between complex computations, prevents any form of parallelization. Although the MTTR component can naively be parallelized ignoring the smoothing component, the overall benefit, as we demonstrate in this article, is a fraction of the best possible benefits. In this article, by carefully reformulating the underlying mathematical framework that is necessary for retrodiction, we propose a novel, easily parallelizable RTS smoother. The proposed parallelized RTS smoother we outline in this article has best data reuse and enables the overall MTTR problem to be parallelized more efficiently. We demonstrate this on a state-of-the-art multicore processor platform using the shared-memory parallelism. Our results show that the parallel MTTR solution, which includes gating, assignment, tracking, and retrodiction, can offer nearly 150 times speed up against a fully sequential version. With excellent computational performance, our proposed RTS smoother enables very large window sizes with little or no impact on the overall performance.

Clock genes exhibit substantial control over gene expression and ultimately life-histories using external cues such as photoperiod, and are thus likely to be critical for adaptation to shifting seasonal conditions and novel environments as species redistribute their ranges under climate change. Coding trinucleotide repeats (cTNRs) are found within several clock genes, and may be interesting targets of selection due to their containment within exonic regions and elevated mutation rates. Here, we conduct inter-specific characterization of the NR1D1 cTNR between Canada lynx and bobcat, and intra-specific spatial and environmental association analyses of neutral microsatellites and our functional cTNR marker, to investigate the role of selection on this locus in Canada lynx. We report signatures of divergent selection between lynx and bobcat, with the potential for hybrid-mediated gene flow in the area of range overlap. We also provide evidence that this locus is under selection across Canada lynx in eastern Canada, with both spatial and environmental variables significantly contributing to the explained variation, after controlling for neutral population structure. These results suggest that cTNRs may play an important role in the generation of functional diversity within some mammal species, and allow for contemporary rates of adaptation in wild populations in response to environmental change. We encourage continued investment into the study of cTNR markers to better understand their broader relevance to the evolution and adaptation of mammals.

Accurately estimating abundance is a critical component of monitoring and recovery of rare and elusive species. Spatial capture–recapture (SCR) models are an increasingly popular method for robust estimation of ecological parameters. We provide an analytical framework to assess results from empirical studies to inform SCR sampling design, using both simulated and empirical data from noninvasive genetic sampling of seven boreal caribou populations (Rangifer tarandus caribou), which varied in range size and estimated population density. We use simulated population data with varying levels of clustered distributions to quantify the impact of nonindependence of detections on density estimates, and empirical datasets to explore the influence of varied sampling intensity on the relative bias and precision of density estimates. Simulations revealed that clustered distributions of detections did not significantly impact relative bias or precision of density estimates. The genotyping success rate of our empirical dataset (n = 7,210 samples) was 95.1%, and 1,755 unique individuals were identified. Analysis of the empirical data indicated that reduced sampling intensity had a greater impact on density estimates in smaller ranges. The number of captures and spatial recaptures was strongly correlated with precision, but not absolute relative bias. The best sampling designs did not differ with estimated population density but differed between large and small ranges. We provide an efficient framework implemented in R to estimate the detection parameters required when designing SCR studies. The framework can be used when designing a monitoring program to minimize effort and cost while maximizing effectiveness, which is critical for informing wildlife management and conservation., We provide an analytical framework to assess results from empirical studies to inform spatial capture–recapture sampling design, using both simulated and empirical data from noninvasive genetic sampling of seven boreal caribou populations (Rangifer tarandus caribou). Simulations revealed that clustered distributions of detections did not significantly impact relative bias or precision of density estimates, and analysis of the empirical data indicated that reduced sampling intensity had a greater impact on density estimates in smaller ranges. The framework can be used when designing a monitoring program to minimize effort and cost while maximizing effectiveness, which is critical for informing wildlife management and conservation.

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

(131)I-metaiodobenzylguanidine ((131)I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early (131)I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with (131)I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after (131)I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after (131)I-mIBG exposure, with mean log(2) fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after (131)I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after (131)I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after (131)I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal (131)I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal (131)I.