Search

Objective: This study investigated differences in stress, anxiety, and social support between collegiate student-athletes and nonathletes during the COVID-19 pandemic. Participants: College students enrolled at a NCAA Division III private liberal arts college in the Midwest. Methods: Participants (n = 58) completed a series of surveys each month for 4 months that included the Generalized Anxiety Disorder Questionnaire, Perceived Stress Scale Questionnaire, and Multidimensional Scale of Perceived Social Support Questionnaire. Results: There were significant main effects of time for stress and social support across the 4 months (p < 0.05), but not for anxiety. There was a significant difference in anxiety levels between athletes and nonathletes (p < 0.01), but not for social support or stress (p > 0.05). Conclusions: Nonathletes maintained support networks, or found alternate outlets of support, in addition to coping with anxiety and stress levels when compared to athletes.

Abstract Introduction KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. Methods We contrasted tumor development between Kras G12C and Kras G12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of Kras G12C and Kras G12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRAS G12C or KRAS G12D -mutant NSCLC. Results KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Conclusions Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

Abstract The capacity to perceive tactile input at the fingertips, referred to as tactile sensitivity, is known to diminish with age due to regressive changes to mechanoreceptor density and morphology. Sensitivity is measured as perceptual responses to stimuli of varying intensity. Contrary to traditional sensitivity monitoring instruments, smartphones are uniquely suited for remote assessment and have shown to deliver highly calibrated stimuli along a broad spectrum of intensity, which may improve test reliability. The aim of this study was to evaluate a vibration-emitting smartphone application, the Vibratus App, as a mode of estimating tactile sensory thresholds in the aging adult. The peripheral nerve function of 40 neurologically healthy volunteers (ages 18–71) was measured using monofilaments, a 128-Hz tuning fork, the Vibratus App, and nerve conduction studies (NCS). Between group differences were analyzed to determine each measurement’s sensitivity to age. Spearman correlation coefficients depicted the associative strength between hand-held measurements and sensory nerve action potential (SNAP) amplitude. Inter-rater reliability of traditional instruments and the software-operated smartphone were assessed by intraclass correlation coefficient (ICC2,k ). Measurements taken with Vibratus App were significantly different between age groups (p

We analyzed body lice collected from persons experiencing homelessness in Winnipeg, Manitoba, Canada, during 2020–2021 to confirm vector species and ecotype and to identify louseborne pathogens. Of 556 lice analyzed from 7 persons, 17 louse pools (218 lice) from 1 person were positive for the louseborne bacterium Bartonella quintana.

Summary: Background: Simlukafusp alfa (FAP-IL2v) is an immune cytokine engineered to selectively promote immune responses in the tumour microenvironment. We evaluated the antitumour activity and safety of FAP-IL2v plus atezolizumab in recurrent and/or metastatic cervical squamous cell carcinoma (SCC) in a phase 2 basket study (NCT03386721). Methods: Patients with confirmed metastatic, persistent or recurrent cervical SCC who had progressed on ≥1 anti-cancer therapy and had measurable disease were enrolled. FAP-IL2v 10 mg was administered once every 3 weeks (Q3W) or once weekly (QW) for 4 weeks then once every 2 weeks (Q2W) with the corresponding Q3W or Q2W atezolizumab regimens. The primary endpoint was objective response rate by investigator assessment. Findings: Forty-eight patients were enrolled (Q3W: n = 47; QW/Q2W: n = 1). Among 45 response evaluable patients, objective responses occurred in 12 patients (27%; CI 16.0–41.0), including 3 complete and 9 partial responses. Responses occurred in 6/19 PD-L1 positive patients (32%; 95% CI 15.4–54.0) and 5/24 PD-L1 negative patients (21%; 95% CI 9.2–35.6). Median duration of response was 13.3 months (95% CI 7.6–NE). Median progression-free survival was 3.7 months (95% CI 3.3–9.0). Adverse events (AEs) were consistent with the known safety profile of each drug. AEs leading to withdrawal of either agent occurred in 6 patients (13%). Pronounced expansion and activation of natural killer and CD8 T cells in peripheral blood and increased tumour infiltration and inflammation were observed. Interpretation: FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC. Funding: F. Hoffmann-La Roche Ltd.

Background:Bartonella quintana is a body-louse-borne bacterium. Canadian B. quintana disease has been reported primarily in populations experiencing homelessness and in Indigenous communities with limited access to water. We sought to understand the epidemiology of B. quintana in Canada. Methods: This study combined an analysis of laboratory data from Canada’s National Microbiology Laboratory (NML) with a systematic review of the literature. Laboratory data included quantitative polymerase chain reaction (qPCR) cycle threshold values and indirect immunofluorescent antibody titers with the year and province of the sample acquisition. For the systematic review, we searched PubMed, Scopus, Embase, and Web of Science for articles published before 15 July 2024, with terms related to B. quintana in Canada. Results: Thirty-three individuals with qPCR-positive B. quintana were documented in seven provinces and one territory. The number of cases increased over time (p-value = 0.005), with the greatest number of cases being reported in 2022 and 2023. The percent positivity for the B. quintana qPCR performed at the NML increased over time (p-value = 0.036). The median immunoglobulin G titer demonstrated a sustained increase starting in 2017. The systematic review identified fourteen individuals with qPCR-positive B. quintana (none had a qPCR performed at the NML) and seven probable cases of B. quintana disease. Four of these twenty-one individuals from the systematic review died (19%). All fatalities were attributed to endocarditis. Conclusions: The detection of B. quintana disease in seven provinces and one territory suggests that B. quintana has a national distribution. B. quintana disease is increasingly diagnosed in Canada, indicating ongoing transmission across geographic settings.

Neutrinoless double beta decay is one of the most sensitive probes for new physics beyond the Standard Model of particle physics. One of the isotopes under investigation is ^{136}Xe, which would double beta decay into ^{136}Ba. Detecting the single ^{136}Ba daughter provides a sort of ultimate tool in the discrimination against backgrounds. Previous work demonstrated the ability to perform single atom imaging of Ba atoms in a single-vacancy site of a solid xenon matrix. In this paper, the effort to identify signal from individual barium atoms is extended to Ba atoms in a hexa-vacancy site in the matrix and is achieved despite increased photobleaching in this site. Abrupt fluorescence turn-off of a single Ba atom is also observed. Significant recovery of fluorescence signal lost through photobleaching is demonstrated upon annealing of Ba deposits in the Xe ice. Following annealing, it is observed that Ba atoms in the hexa-vacancy site exhibit antibleaching while Ba atoms in the tetra-vacancy site exhibit bleaching. This may be evidence for a matrix site transfer upon laser excitation. Our findings offer a path of continued research toward tagging of Ba daughters in all significant sites in solid xenon.

Abstract Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0 $$\nu \beta \beta $$ ν β β ), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0 $$\nu \beta \beta $$ ν β β of $$^{136}$$ 136 Xe with projected half-life sensitivity of $$1.35\times 10^{28}$$ 1.35 × 10 28 yr. To reach this sensitivity, the design goal for nEXO is $$\le $$ ≤ 1% energy resolution at the decay Q-value ( $$2458.07\pm 0.31$$ 2458.07 ± 0.31 keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163 K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay Q-value for the nEXO design.

Abstract The development and expansion of wind energy is considered a key threat to bat populations in North America and globally. Several approaches to mitigating the impacts of wind energy development on bat populations have been developed, including curtailing wind turbine operation at night during lower wind speeds when bats are thought to be more active. Blanket curtailment approaches have shown substantial promise in reducing bat fatalities at wind energy facilities, but they also reduce the amount of energy extracted from the wind by turbines. A related approach, referred to as smart curtailment, uses bat activity and other variables to predict when bats will be at the greatest risk at a given wind facility. In some contexts, a smart curtailment approach might reduce bat fatalities while also reducing energy loss relative to blanket curtailment. However, it has not been clear how to compare blanket curtailment and smart curtailment approaches in terms of annual energy production at wind facilities. Here, we describe a new approach to simulating the influence of blanket and smart curtailment approaches on energy production at wind energy facilities, and demonstrate the approach using 6 wind energy development areas in the Canadian province of Alberta. We show how stakeholders involved can explore the potential influences of various kinds of bat activity on energy production. We present the results of our Alberta analysis and conclude with some caveats and recommendations for future work on simulating the influences of bat curtailment on energy production at wind energy facilities.

Childhood obesity remains chronic and high in the U.S., driven by factors including poor dietary habits and lack of physical activity. Interventions that address multiple causal factors may be the most appropriate strategy to address rising childhood obesity rates. The Cooperative Extension Service offers programs across the country to address causal factors of childhood obesity, but few coordinated or concerted efforts have been made to determine overlap, reduce duplication, or identify best practices in programming. To fill this gap, the National Institute of Food and Agriculture Multistate Project W3005 Extension Workgroup sought to develop a novel tool to compare programs with components related to childhood obesity prevention. This manuscript details the iterative process used to develop the Childhood Obesity Prevention Program in Extension Rubric (COPPER), provides findings from the pilot process, and reveals the broad application and potential of this tool within Extension and nutrition education. The newly developed COPPER tool is multi-functional and may be beneficial in program development, implementation, adoption, and/or adaptation of programs in new settings. This tool will be useful for Extension, public health, and other community organizations focused on issues central to childhood obesity targeting children, parents, and/or caregivers.

Abstract Introduction Zambia has made tremendous progress towards HIV epidemic control; however, gaps remain among key populations (KPs), such as female sex workers (FSWs), men who have sex with men (MSM), people who inject drugs (PWID) and people in prisons and enclosed settings due to cultural, social and legal barriers. The University of Maryland, Baltimore Zambia Community HIV Epidemic Control for Key Populations (Z‐CHECK) project aimed to improve HIV case‐finding, linkage and treatment adherence at the community level for KPs in Zambia. We describe Z‐CHECK strategies and examine HIV positivity yield and antiretroviral therapy (ART) linkage among KPs to inform ongoing programme improvement. Methods Z‐CHECK recruited, trained and deployed peer community health workers (CHWs) for KP groups, with ongoing mentorship in community engagement. CHWs offered HIV testing in safe spaces and escorted newly HIV‐diagnosed clients for same‐day ART initiation. Z‐CHECK also reached out to KP community leaders and gatekeepers for KP mobilization and trained healthcare workers (HCWs) on KP services and sensitivity. We conducted a retrospective observational review of routinely collected aggregate data for KPs aged ≥15 years at high risk for HIV transmission across five districts in Zambia from January 2019 to December 2020. Results Z‐CHECK provided HIV testing for 9211 KPs, of whom 2227 were HIV positive (positivity yield, 24%). Among these, 1901 (85%) were linked to ART; linkage for MSM, FSW, PWID and people in prisons and enclosed settings was 95%, 89%, 86% and 65%, respectively. Programme strategies that contributed to high positivity yield and linkage included the use of peer KP CHWs, social network testing strategies and opportunities for same‐day ART initiation. Challenges to programme implementation included stigma and discrimination among HCWs, as well as KP CHW attrition, which may be explained by high mobility. Conclusions Peer CHWs were highly effective at reaching KP communities, identifying persons living with HIV and linking them to care. Engaging KP community gatekeepers resulted in high diffusion of health messages and increased access to health resources. The mobility of CHWs and HCWs is a challenge for programme implementation. Innovative interventions are needed to support PWID and people in prisons and enclosed settings.

Abstract Understanding how risk factors affect populations across their annual cycle is a major challenge for conserving migratory birds. For example, disease outbreaks may happen on the breeding grounds, the wintering grounds, or during migration and are expected to accelerate under climate change. The ability to identify the geographic origins of impacted individuals, especially outside of breeding areas, might make it possible to predict demographic trends and inform conservation decision‐making. However, such an effort is made more challenging by the degraded state of carcasses and resulting low quality of DNA available. Here, we describe a rapid and low‐cost approach for identifying the origins of birds sampled across their annual cycle that is robust even when DNA quality is poor. We illustrate the approach in the common loon (Gavia immer), an iconic migratory aquatic bird that is under increasing threat on both its breeding and wintering areas. Using 300 samples collected from across the breeding range, we develop a panel of 158 single‐nucleotide polymorphisms (SNP) loci with divergent allele frequencies across six genetic subpopulations. We use this SNP panel to identify the breeding grounds for 142 live nonbreeding individuals and carcasses. For example, genetic assignment of loons sampled during botulism outbreaks in parts of the Great Lakes provides evidence for the significant role the lakes play as migratory stopover areas for loons that breed across wide swaths of Canada, and highlights the vulnerability of a large segment of the breeding population to botulism outbreaks that are occurring in the Great Lakes with increasing frequency. Our results illustrate that the use of SNP panels to identify breeding origins of carcasses collected during the nonbreeding season can improve our understanding of the population‐specific impacts of mortality from disease and anthropogenic stressors, ultimately allowing more effective management.

Here, authors report on acoustic cavities in 2D materials operating in the 50–600 GHz range and show that quality factors approach the limit set by lattice anharmonicity. Functionality expanded by heterogeneities (steps and interfaces) is demonstrated through coupled cavities and frequency comb generation.

Intense red colours in birds are often owing to ketocarotenoids (KCs). In many land birds, KCs are oxidized from dietary yellow precursors, presumably by the avian carotenoid ketolase CYP2J19, the regulation and constraints of which have important implications for condition-dependence and honest signalling of carotenoid colour displays. We investigated hepatic CYP2J19 gene expression in the seasonally and sexually dichromatic southern red bishop (Euplectes orix) in relation to season, sex, progression of the prenuptial moult, testis size, body condition, redness and circulating sex steroids. A coloration function of CYP2J19 is supported by a seasonal upregulation prior to and during the carotenoid-depositing stage of the male prenuptial moult. However, CYP2J19 expression was similarly high in females (which do not moult prenuptially), and remained high in males after moult, suggesting additional or alternative roles of hepatic CYP2J19 or its products, such as detoxification or antioxidant functions. In males, the CYP2J19 upregulation preceded and was unrelated to the rise in plasma testosterone, but was correlated with androstenedione, probably of adrenal origin and compatible with luteinizing hormone-induced and (in females) oestrogen-suppressed moult. Finally, contrary to ideas that carotenoid ketolation rate mediates honest signalling of male quality, CYP2J19 expression was not related to plumage redness or male body condition.

Abstract Objective Our objective was to apply next-generation sequence-based DNA barcoding to identify the remnant larval bloodmeals in wild-caught host-seeking (unengorged) Ixodes scapularis nymphs (n = 216). To infer host species identification, vertebrate DNA was amplified using universal primers for cytochrome c oxidase subunit I (COI) and sequenced using next-generation sequencing (NGS) for comparison against known barcode references. Results Bloodmeal identification was unsuccessful in most samples (99% of 216 specimens) demonstrating a very low detection rate of this assay. Sequences that surpassed quality thresholds were obtained for 41.7% of nymphs (n = 90) and of those, confident species identification was obtained for 15.6% of nymphs (n = 14). Wild host identifications were only obtained from 2 specimens, where DNA from the eastern grey squirrel (Sciurus carolinensis) was identified. Human and bovine DNA was identified in remaining nymphs and considered to be contaminants. Further optimization of the technique is required to improve detection of remnant bloodmeals in host-seeking nymphs.

As far as is currently known, patterned fens of the Great Sandy Region (GSR; Australia) are globally unique in that they arise from the particular hydrological characteristics of a sub-tropical coastal dune system. This article outlines their extent, distribution, characteristics, values and threats. Seven distinct clusters of fens, containing 700 ha of obvious ‘patterning’ resembling that in temperate mires, cover a total area of around 7,000 ha within largely acidic (pH < 5) wet heath ecosystems. Unlike patterned mires in the Northern Hemisphere dominated by Sphagnum (moss) species, these examples are dominated by the restiad species Empodisma minus. Habitat is provided for many endangered fauna including frogs and fish adapted to the unusually acidic conditions. All of the GSR fens fall within the proposed Great Sandy World Heritage Area. The carbon sequestration process that characterises peaty environments makes these fens a fertile source of information on many aspects of environmental history. They are intrinsically sensitive to fluctuations in rainfall, evaporation and sea level, and thus to climate change. A more direct key threat is extraction of resources including, notably, groundwater. However, the fens have remained largely free from human disturbance since the early Holocene and, with their identification and recognition, the challenge now is to maintain these systems in their natural state and continue benefiting from the ecosystem services provided as a result of their excellent condition.

Abstract Background Lyme disease is emerging in Canada due to expansion of the range of the tick vector Ixodes scapularis from the United States. National surveillance for human Lyme disease cases began in Canada in 2009. Reported numbers of cases increased from 144 cases in 2009 to 2025 in 2017. It has been claimed that few (

We used a high-resolution magnetic spectrograph to study neutron pair-correlated 0+ states in 136Ba, produced via the Ba138(p,t) reaction. In conjunction with state-of-the-art shell model calculations, these data benchmark part of the dominant Gamow-Teller component of the nuclear matrix element (NME) for 136Xe neutrinoless double beta (0νββ) decay. We demonstrate for the first time an evaluation of part of a 0νββ decay NME by use of an experimental observable, presenting a new avenue of approach for more accurate calculations of 0νββ decay matrix elements.

KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).

Blanket bogs are rare types of peatland that are recognised internationally for important habitat provision, and nationally and locally as important carbon stores and sinks. These ecosystems enjoy particular attention and protection within the European Union, but gaps highlighted in the Spanish national peatland inventory leave many areas of Spain’s blanket bog habitat unprotected and exposed to anthropogenic pressures such as livestock or wind farm development. This research identifies and offers classification of four currently unmapped areas of blanket bog located in the Cordillera Cantábrica (north Spain) on the administrative boundaries between the regions of Cantabria and Castilla y León. Peat depth was surveyed on a 15 m spaced grid at all sites and mesotope units were defined from topography and hydrological flow patterns. Two sloping and two mound blanket bogs were identified containing a range of bog and fen mesotope units. Maximum peat depth at the five sites ranges from 1.78 to 2.82 m covering an area of 43 ha of blanket bog (> 30 cm peat depth). The survey also estimates that more than 300,000 m³ of peat has accumulated across all sites. This study adds significantly to the known global distribution of blanket mire and suggests that an urgent update of national peatland inventories is needed more widely, not least in Spain, to identify currently unmapped areas of blanket bog. The approach used here can be employed wherever blanket mires occur in the world to promote their designation and the preservation of peatland diversity and carbon storage.

Chemosynthetic microbial communities in hydrothermal environments receiving meteoric and geothermal fluids are understudied. Here, Colman et al. use metagenomics to study one such community from a hot spring at Yellowstone National Park, revealing exceptional biodiversity and unique functional potential.

Peatlands are a globally significant store of carbon. During the second half of the 20th century new planting techniques combined with tax incentives encouraged commercial forestry across large areas of peat bog in the UK, particularly in the Flow Country of northern Scotland. Such planting was controversial and was ultimately halted by removal of the tax incentives, and policies to prevent new planting. Here we review the literature on UK peatland afforestation in relation to carbon and climate implications, and identify key issues for future research. The effects of conifer planting on peat bog carbon storage in the UK are poorly understood. A large body of research on peatland forestry exists, particularly from naturally forested fen peatlands in Fennoscandia and Russia, but the different conditions in the UK mean that results are not directly transferable. Data on the responses of UK peat bogs to afforestation are required to address this shortfall. Studies are required that quantify the loss of carbon from the peat and evaluate it against the accumulation of carbon above and below ground in trees, considering the likely residence time of carbon in wood products.

Abstract Background The common loon (Gavia immer) is one of five species that comprise the avian order Gaviiformes. Loons are specialized divers, reaching depths up to 60 m while staying submerged for intervals up to three minutes. In this study we used comparative genomics to investigate the genetic basis of the common loon adaptations to its ecological niche. We used Illumina short read DNA sequence data from a female bird to produce a draft assembly of the common loon (Gavia immer) genome. Results We identified 14,169 common loon genes, which based on well-resolved avian genomes, represent approximately 80.7% of common loon genes. Evolutionary analyses between common loon and Adelie penguin (Pygoscelis adeliae), red-throated loon (Gavia stellata), chicken (Gallus gallus), northern fulmar (Fulmarus glacialis), and rock pigeon (Columba livia) show 164 positively selected genes in common and red-throated loons. These genes were enriched for a number of protein classes, including those involved in muscle tissue development, immunoglobulin function, hemoglobin iron binding, G-protein coupled receptors, and ATP metabolism. Conclusions Signatures of positive selection in these areas suggest the genus Gavia may have adapted for underwater diving by modulating their oxidative and metabolic pathways. While more research is required, these adaptations likely result in (1) compensations in oxygen respiration and energetic metabolism, (2) low-light visual acuity, and (3) elevated solute exchange. This work represents the first effort to understand the genomic adaptations of the common loon as well as other Gavia and may have implications for subsequent studies that target particular genes for loon population genetic, ecological or conservation studies.

Protodolomite was detected in sediments from Great Salt Lake (GSL), Utah, United States, that have no history of elevated temperature or pressure, conditions that are thought to promote dolomitization of sedimentary carbonates. Protodolomite was abundant in a non-oolitic sediment core from the South Arm (SA) of GSL at < 17% salinity but was rare in an oolitic sediment core collected from the North Arm (NA) of GSL at > 26% salinity. Protodolomite was also abundant in a non-oolitic NA sediment hand sample yet was absent in a nearby oolitic sediment hand sample in locations that likely receive allochthonous nutrients. Protodolomite was not detected in benthic photosynthetic mats from the SA. However, the mats comprised aragonite with halite and minimal calcite; benthic photosynthetic mats do not form in the NA. To begin to identify potential controls on the formation of protodolomite in the SA and NA of GSL, the composition and abundance of 16S rRNA gene transcripts, carbon cycling activities, and porewater geochemistry of the sediment cores were characterized. Transcripts affiliated with a dominant halophilic, heterotrophic sulfate-reducing bacterium were detected in the uppermost sections of the SA core and their abundance was positively correlated with rates of acetate oxidation/assimilation and concentrations of sulfide. Differences in the quality of organic matter between the SA and NA cores, as indicated by carbon to nitrogen ratios, indicate fresh deposition of photosynthetic biomass at the SA sediment core site but not in the NA sediment core site. Sediment grains from the SA core exhibit micrometer-sized euhedral protodolomite crystals that were not detected in the NA core. Collectively, these observations suggest that deposition of photosynthetic biomass drives the development of a sharp, anoxic lens of heterotrophic sulfate reduction. Sulfide, in turn, may promote dehydration of Mg2+-water complexes and primary protodolomite nucleation and growth. The scarcity of dolomite in the NA sediment core may result from constraints imposed by a combination of extreme hypersalinity and depositional environment on phototrophs and sulfate reducers, their activities, and the thermodynamics of protodolomite formation.

In recent years, the field of sexual selection has exploded, with advances in theoretical and empirical research complementing each other in exciting ways. This perspective piece is the product of a “stock-taking” workshop on sexual selection and sexual conflict. Our aim is to identify and deliberate on outstanding questions and to stimulate discussion rather than provide a comprehensive overview of the entire field. These questions are organized into four thematic sections we deem essential to the field. First we focus on the evolution of mate choice and mating systems. Variation in mate quality can generate both competition and choice in the opposite sex, with implications for the evolution of mating systems. Limitations on mate choice may dictate the importance of direct vs. indirect benefits in mating decisions and consequently, mating systems, especially with regard to polyandry. Second, we focus on how sender and receiver mechanisms shape signal design. Mediation of honest signal content likely depends on integration of temporally variable social and physiological costs that are challenging to measure. We view the neuroethology of sensory and cognitive receiver biases as the main key to signal form and the ‘aesthetic sense’ proposed by Darwin. Since a receiver bias is sufficient to both initiate and drive ornament or armament exaggeration, without a genetically correlated or even coevolving receiver, this may be the appropriate ‘null model’ of sexual selection. Thirdly, we focus on the genetic architecture of sexually selected traits. Despite advances in modern molecular techniques, the number and identity of genes underlying performance, display and secondary sexual traits remains largely unknown. In-depth investigations into the genetic basis of sexual dimorphism in the context of long-term field studies will reveal constraints and trajectories of sexually selected trait evolution. Finally, we focus on sexual selection and conflict as drivers of speciation. Population divergence and speciation are often influenced by an interplay between sexual and natural selection. The extent to which sexual selection promotes or counteracts population divergence may vary depending on the genetic architecture of traits as well as the covariance between mating competition and local adaptation. Additionally, post-copulatory processes, such as selection against heterospecific sperm, may influence the importance of sexual selection in speciation. We propose that efforts to resolve these four themes can catalyze conceptual progress in the field of sexual selection, and we offer potential avenues of research to advance this progress.

This article explores Karl Barth’s exegesis of the ‘sepultus est…’ from the Apostles’ Creed, as articulated in his 1935 Credo lectures. I argue that Barth accords the sepultus a degree of theological significance that is against the grain, not only of the majority of western interpretations of Jesus’s burial, but also of his own later interpretation of it within his Kirchliche Dogmatik. Specifically, this article argues that in his 1935 lectures, Barth exegetes the sepultus in terms of a divine self-surrender to the ‘pure pastness’ that is the ‘state and fate’ of all humanity. As a consequence, the sepultus can then be used as the pivot to a different, and more hopeful, future.

Background There is limited empirical information on service-level outcome domains and indicators for the large number of people with intellectual disabilities being treated in forensic psychiatric hospitals. Aims This study identified and developed the domains that should be used to measure treatment outcomes for this population. Method A systematic review of the literature highlighted 60 studies which met eligibility criteria; they were synthesised using content analysis. The findings were refined within a consultation and consensus exercises with carers, patients and experts. Results The final framework encompassed three a priori superordinate domains: (a) effectiveness, (b) patient safety and (c) patient and carer experience. Within each of these, further sub-domains emerged from our systematic review and consultation exercises. These included severity of clinical symptoms, offending behaviours, reactive and restrictive interventions, quality of life and patient satisfaction. Conclusions To index recovery, services need to measure treatment outcomes using this framework.

Twelve evolutionarily unrelated oxidoreductases form enzyme complexes that catalyze the simultaneous coupling of exergonic and endergonic oxidation–reduction reactions to circumvent thermodynamic barriers and minimize free energy loss in a process known as flavin-based electron bifurcation. Common to these 12 bifurcating (Bf) enzymes are protein-bound flavin, the proposed site of bifurcation, and the electron carrier ferredoxin. Despite the documented role of Bf enzymes in balancing the redox state of intracellular electron carriers and in improving the efficiency of cellular metabolism, a comprehensive description of the diversity and evolutionary history of Bf enzymes is lacking. Here, we report the taxonomic distribution, functional diversity, and evolutionary history of Bf enzyme homologs in 4,588 archaeal, bacterial, and eukaryal genomes and 3,136 community metagenomes. Bf homologs were primarily detected in the genomes of anaerobes, including those of sulfate-reducers, acetogens, fermenters, and methanogens. Phylogenetic analyses of Bf enzyme catalytic subunits (oxidoreductases) suggest they were not a property of the Last Universal Common Ancestor of Archaea and Bacteria, which is consistent with the limited and unique taxonomic distributions of enzyme homologs among genomes. Further, phylogenetic analyses of oxidoreductase subunits reveal that non-Bf homologs predate Bf homologs. These observations indicate that multiple independent recruitments of flavoproteins to existing oxidoreductases enabled coupling of numerous new electron Bf reactions. Consistent with the role of these enzymes in the energy metabolism of anaerobes, homologs of Bf enzymes were enriched in metagenomes from subsurface environments relative to those from surface environments. Phylogenetic analyses of homologs from metagenomes reveal that the earliest evolving homologs of most Bf enzymes are from subsurface environments, including fluids from subsurface rock fractures and hydrothermal systems. Collectively, these data suggest strong selective pressures drove the emergence of Bf enzyme complexes via recruitment of flavoproteins that allowed for an increase in the efficiency of cellular metabolism and improvement in energy capture in anaerobes inhabiting a variety of subsurface anoxic habitats where the energy yield of oxidation-reduction reactions is generally low.

Genome-wide analysis of thymic lymphomas from Tp53−/− mice with wild-type or C-terminally truncated Rag2 revealed numerous off-target, RAG-mediated DNA rearrangements. A significantly higher fraction of these errors mutated known and suspected oncogenes/tumor suppressor genes than did sporadic rearrangements (p < 0.0001). This tractable mouse model recapitulates recent findings in human pre-B ALL and allows comparison of wild-type and mutant RAG2. Recurrent, RAG-mediated deletions affected Notch1, Pten, Ikzf1, Jak1, Phlda1, Trat1, and Agpat9. Rag2 truncation substantially increased the frequency of off-target V(D)J recombination. The data suggest that interactions between Rag2 and a specific chromatin modification, H3K4me3, support V(D)J recombination fidelity. Oncogenic effects of off-target rearrangements created by this highly regulated recombinase may need to be considered in design of site-specific nucleases engineered for genome modification.

Sea ice thickness is a fundamental climate state variable that provides an integrated measure of changes in the high-latitude energy balance. However, observations of mean ice thickness have been sparse in time and space, making the construction of observation-based time series difficult. Moreover, different groups use a variety of methods and processing procedures to measure ice thickness, and each observational source likely has different and poorly characterized measurement and sampling errors. Observational sources used in this study include upward-looking sonars mounted on submarines or moorings, electromagnetic sensors on helicopters or aircraft, and lidar or radar altimeters on airplanes or satellites. Here we use a curve-fitting approach to determine the large-scale spatial and temporal variability of the ice thickness as well as the mean differences between the observation systems, using over 3000 estimates of the ice thickness. The thickness estimates are measured over spatial scales of approximately 50 km or time scales of 1 month, and the primary time period analyzed is 2000–2012 when the modern mix of observations is available. Good agreement is found between five of the systems, within 0.15 m, while systematic differences of up to 0.5 m are found for three others compared to the five. The trend in annual mean ice thickness over the Arctic Basin is −0.58 ± 0.07 m decade−1 over the period 2000–2012. Applying our method to the period 1975–2012 for the central Arctic Basin where we have sufficient data (the SCICEX box), we find that the annual mean ice thickness has decreased from 3.59 m in 1975 to 1.25 m in 2012, a 65% reduction. This is nearly double the 36% decline reported by an earlier study. These results provide additional direct observational evidence of substantial sea ice losses found in model analyses.

V(D)J recombination-associated DNA double-strand breaks (DSBs) are normally repaired by the high-fidelity classical nonhomologous end-joining (cNHEJ) machinery. Previous studies implicated the recombination-activating gene (RAG)/DNA postcleavage complex (PCC) in regulating pathway choice by preventing access to inappropriate repair mechanisms such as homologous recombination (HR) and alternative NHEJ (aNHEJ). Here, we report that RAG2’s “acidic hinge,” previously of unknown function, is critical for several key steps. Mutations that reduce the hinge’s negative charge destabilize the PCC, disrupt pathway choice, permit repair of RAG-mediated DSBs by the translocation-prone aNHEJ machinery, and reduce genomic stability in developing lymphocytes. Structural predictions and experimental results support our hypothesis that reduced flexibility of the hinge underlies these outcomes. Furthermore, sequence variants present in the human population reduce the hinge’s negative charge, permit aNHEJ, and diminish genomic integrity.

The study of sea ice using airborne remote sensing platforms provides unique capabilities to measure a wide variety of sea ice properties. These measurements are useful for a variety of topics including model evaluation and improvement, assessment of satellite retrievals, and incorporation into climate data records for analysis of interannual variability and long-term trends in sea ice properties. In this paper we describe methods for the retrieval of sea ice thickness, freeboard, and snow depth using data from a multi-sensor suite of instruments on NASA's Operation IceBridge airborne campaign. We assess the consistency of the results through comparison with independent data sets that demonstrate that the IceBridge products are capable of providing a reliable record of snow depth and sea ice thickness. We explore the impact of inter-campaign instrument changes and associated algorithm adaptations as well as the applicability of the adapted algorithms to the ongoing IceBridge mission. The uncertainties associated with the retrieval methods are determined and placed in the context of their impact on the retrieved sea ice thickness. Lastly, we present results for the 2009 and 2010 IceBridge campaigns, which are currently available in product form via the National Snow and Ice Data Center.

In the United States, monk parakeets (Myiopsitta monachus) are expanding their geographical distribution, and their overall population size is growing exponentially. Monk parakeets are causing widespread economic damage in the United States by nesting on utility structures, which leads to electrical fires and power outages. Although few life history data are available for the species from North America, extensive data are available from the species’ native range in South America. Incorporating data from South America into the population viability analysis program VORTEX, we simulated population growth in United States monk parakeets to determine whether it is likely that the United States population shows life history patterns similar to those in the native range. The answer was, no. The intrinsic rate of growth (r) of monk parakeets in the United States (r = 0.119 during the period 1976–2003) was almost double the rate of population growth (r = 0.064) for the simulated population. Modifying the South American data to allow for reduced mortality, higher fecundity, or a greater proportion of breeding females resulted in population growth rates similar to those in the United States. We extended the simulations to examine the effectiveness of alternative control measures on the monk parakeet population by using the modified life history data. Simulations revealed that it would be necessary to remove 20% of the adult population or to destroy 50% of the nests each year to reduce the population size of monk parakeets. In practical terms, such massive management efforts are unlikely to be sustainable. Instead, control of monk parakeets will likely require an integrated approach including removal of local problem nests on a case-by-case basis and long-term population reduction through trapping or chemical sterilization.

Iain RJ Macpherson, Colin R Lindsay, Nicholas S ReedBeatson West of Scotland Cancer Centre, Glasgow, United KingdomAbstract: Anemia is a common complication of systemic anti-cancer treatment. In this context epoetin beta, like other erythropoiesis-stimulating agents (ESAs), has demonstrable efficacy in raising Hb concentration and reducing the requirement for red cell transfusion. Consequently ESA therapy has gained increasing prominence in the management of chemotherapy-related anemia. However, recent trial data have suggested a higher rate of thromboembolic events, enhanced tumor progression and reduced survival in some patients with cancer who receive ESA therapy. In response, regulatory authorities have mandated increasingly restrictive label changes. In light of these new developments we consider the current role of epoetin beta in the management of chemotherapy-related anemia.Keywords: anemia, cancer, erythropoietin, epoetin, chemotherapy

Colin R. Lindsay1, T R Jeffry Evans1,21Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; 2University of Glasgow, CR-UK Beatson Laboratories, Garscube Estate, Glasgow, United KingdomAbstract: The current generation of novel anticancer therapies that are in preclinical and clinical development are based on exploiting our increasing understanding of the molecular and cellular basis of cancer development and progression. Accelerated rates of cell division and proliferation have been postulated to predispose to the development of malignant disease. The insulin-like growth factor (IGF) signaling system has an important physiological role in regulating cellular proliferation and apoptosis. This function has led to considerable interest in its relevance to neoplasia over the last decade. In this review, we give an overview of the IGF system physiology, discuss the epidemiological significance of IGF signaling and neoplasia, and review the preclinical and clinical studies in targeting IGF receptors as cancer therapies.Keywords: insulin, growth factor, IGF-1, clinical trials

Tumours metastasizing to the pituitary gland are uncommon. Symptomatic patients with pituitary metastases can present with diabetes insipidus, headache, visual field defects and/or anterior pituitary hormonal dysfunction. Treatment options for pituitary metastases include, surgical resection, cranial or parasellar irradiation and/or chemotherapy, and hormonal replacement if indicated. The overall prognosis of pituitary metastases is poor. We present a case of hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.

Until recently, treatment for metastatic melanoma was characterised by a limited availability of treatment options that offer objective survival benefit. Cytotoxic agents fundamentally lack the ability to achieve disease control and cytokine therapy with interleukin-2 has an unacceptably high – for the use across all patient cohorts – rate of toxicities. The validation of braf as an oncogene driving melanoma tumorigenesis, as well as the discovery of the role of CTLA-4 receptor in the evasion of anticancer immune response by melanoma, has revolutionised our treatment options against a disease with dismal prognosis. Quick implementation of translational discoveries brought about BRAF/MEK inhibition in clinic, while at the same time, wider experience with CTLA-4 blockade enabled clinicians to manage previously fatal immune-related toxicities with greater confidence. The suitability for clinical use of other oncogenic drivers such as NRAS and c-kit is currently being tested whilst the PD-1/PD-L1/PD-L2 axis has emerged as a new immunotherapy target with exciting early phase results. The recent exponential progress in treatment of melanoma has set an example of translational medicine and the current review aims to explain why, as well as suggesting new goals for the future.

Defining the architecture of a specific cancer genome, including its structural variants, is essential for understanding tumor biology, mechanisms of oncogenesis, and for designing effective personalized therapies. Short read paired-end sequencing is currently the most sensitive method for detecting somatic mutations that arise during tumor development. However, mapping structural variants using this method leads to a large number of false positive calls, mostly due to the repetitive nature of the genome and the difficulty of assigning correct mapping positions to short reads. This study describes a method to efficiently identify large tumor-specific deletions, inversions, duplications and translocations from low coverage data using SVDetect or BreakDancer software and a set of novel filtering procedures designed to reduce false positive calls. Applying our method to a spontaneous T cell lymphoma arising in a core RAG2/p53-deficient mouse, we identified 40 validated tumor-specific structural rearrangements supported by as few as 2 independent read pairs.

BACKGROUND: Sexual signals, such as bright plumage coloration in passerine birds, reflect individual quality, and testosterone (T) may play a critical role in maintaining signal honesty. Manipulations of T during molt have yielded mixed effects on passerine plumage color, in most cases delaying molt or leading to production of drab plumage. However, the majority of these studies have been conducted on species that undergo a post-nuptial molt when T is low; the role of T in species that acquire breeding plumage during a pre-nuptial molt remains largely unexplored. METHODOLOGY/PRINCIPAL FINDINGS: We experimentally tested the effects of increased T on plumage color in second-year male red-backed fairy-wrens (Malurus melanocephalus), a species in which after-second-year males undergo a pre-nuptial molt into red/black (carotenoid and melanin-based) plumage and second-year males either assume red/black or brown breeding plumage. T treatment stimulated a rapid and early onset pre-nuptial molt and resulted in red/black plumage acquisition, bill darkening, and growth of the sperm storage organ, but had no effect on body condition or corticosterone concentrations. Control males molted later and assumed brown plumage. T treated males produced feathers with similar but not identical reflectance parameters to those of unmanipulated after-second-year red/black males; while reflectance spectra of red back and black crown feathers were similar, black breast feathers differed in UV chroma, hue and brightness, indicating a potentially age and plumage patch-dependent response to T for melanin- vs. carotenoid-pigmentation. CONCLUSIONS/SIGNIFICANCE: We show that testosterone is the primary mechanism functioning during the pre-nuptial molt to regulate intrasexually variable plumage color and breeding phenotype in male red-backed fairy-wrens. Our results suggest that the effects of T on plumage coloration may vary with timing of molt (pre- vs. post-nuptial), and that the role of T in mediating plumage signal production may differ across age classes, plumage patches, and between pigment-types.

We report a case of autoimmune polyglandular syndrome type 1 (APS1) complicated by severe vascular insufficiency due to diffuse vascular calcification. APS1 is characterised clinically by multiple autoimmune conditions and development of at least two components of the triad of mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. We highlight the problems in current serum calcium monitoring methods and suggest that fluctuations in serum calcium concentrations due to difficulties treating hypoparathyroidism may have contributed to the vascular calcification seen in this case.