A Genome Assembly-Integrated Dog 1 Mb BAC Microarray: A Cytogenetic Resource for Canine Cancer Studies and Comparative Genomic Analysis

Molecular cytogenetic studies have been instrumental in defining the nature of numerical and structural chromosome changes in human cancers, but their significance remains to be fully understood. The emergence of high quality genome assemblies for several model organisms provides exciting opportunities to develop novel genome-integrated molecular cytogenetic resources that now permit a comparative approach to evaluating the relevance of tumor-associated chromosome aberrations, both within and between species. We have used the dog genome sequence assembly to identify a framework panel of 2,097 bacterial artificial chromosome (BAC) clones, selected at intervals of approximately one megabase. Each clone has been evaluated by multicolor fluorescence in situ hybridization (FISH) to confirm its unique cytogenetic location in concordance with its reported position in the genome assembly, providing new information on the organization of the dog genome. This panel of BAC clones also represents a powerful cytogenetic resource with numerous potential applications. We have used the clone set to develop a genome-wide microarray for comparative genomic hybridization (aCGH) analysis, and demonstrate its application in detection of tumor-associated DNA copy number aberrations (CNAs) including single copy deletions and amplifications, regional aneuploidy and whole chromosome aneuploidy. We also show how individual clones selected from the BAC panel can be used as FISH probes in direct evaluation of tumor karyotypes, to verify and explore CNAs detected using aCGH analysis. This cytogenetically validated, genome integrated BAC clone panel has enormous potential for aiding gene discovery through a comparative approach to molecular oncology.Organismic and Evolutionary Biolog

Identification of influential probe types in epigenetic predictions of human traits: implications for microarray design

BACKGROUND: CpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying probe subsets based on their biological and statistical properties can maximise predictions whilst minimising array content. Variance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of probes considered, (ii) mean probe variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test samples comprised ≤ 4450 and ≤ 2578 unrelated individuals from Generation Scotland, respectively. RESULTS: As the number of probes under consideration decreased, so too did the estimates from variance components and prediction analyses. Methylation QTL status and mean probe variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on probes with known or reported methylation QTLs compared to probes without reported methylation QTLs. Relative effect sizes were 45% larger for predictors based on probes with mean Beta-values between 10 and 90% compared to those based on hypo- or hypermethylated probes (Beta-value ≤ 10% or ≥ 90%). CONCLUSIONS: Arrays with fewer probes could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpG probes in array content selection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01320-9

Improving Nursing Facility Care Through an Innovative Payment Demonstration Project: Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care Phase 2

Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) is a 2‐phase Center for Medicare and Medicaid Innovations demonstration project now testing a novel Medicare Part B payment model for nursing facilities and practitioners in 40 Indiana nursing facilities. The new payment codes are intended to promote high‐quality care in place for acutely ill long‐stay residents. The focus of the initiative is to reduce hospitalizations through the diagnosis and on‐site management of 6 common acute clinical conditions (linked to a majority of potentially avoidable hospitalizations of nursing facility residents1): pneumonia, urinary tract infection, skin infection, heart failure, chronic obstructive pulmonary disease or asthma, and dehydration. This article describes the OPTIMISTIC Phase 2 model design, nursing facility and practitioner recruitment and training, and early experiences implementing new Medicare payment codes for nursing facilities and practitioners. Lessons learned from the OPTIMISTIC experience may be useful to others engaged in multicomponent quality improvement initiatives

Greening of grey infrastructure should not be used as a Trojan horse to facilitate coastal development

Climate change and coastal urbanization are driving the replacement of natural habitats with artificial structures and reclaimed land globally. These novel habitats are often poor surrogates for natural habitats. The application of integrated greening of grey infrastructure (IGGI) to artificial shorelines demonstrates how multifunctional structures can provide biodiversity benefits whilst simultaneously serving their primary engineering function. IGGI is being embraced globally, despite many knowledge gaps and limitations. It is a management tool to compensate anthropogenic impacts as part of the Mitigation Hierarchy. There is considerable scope for misuse and ‘greenwashing’ however, by making new developments appear more acceptable, thus facilitating the regulatory process. We encourage researchers to exercise caution when reporting on small-scale experimental trials. We advocate that greater attention is paid to when experiments ‘fail’ or yield unintended outcomes. We advise revisiting, repeating and expanding on experiments to test responses over broader spatio-temporal scales to improve the evidence base. Synthesis and applications. Where societal and economic demand makes development inevitable, particular attention should be paid to avoiding, minimizing and rehabilitating environmental impacts. Integrated greening of grey infrastructure (IGGI) should be implemented as partial compensation for environmental damage. Mutual benefits for both humans and nature can be achieved when IGGI is implemented retrospectively in previously developed or degraded environments. We caution, however, that any promise of net biodiversity gain from new developments should be scrutinized and any local ecological benefits set in the context of the wider environmental impacts. A ‘greened’ development will always impinge on natural systems, a reality that is much less recognized in the sea than on land.</p

The accretion origin of the Milky Way's stellar halo

We have used data from the Sloan Digital Sky Survey (SDSS) Data Release 5 to explore the overall structure and substructure of the stellar halo of the Milky Way using about 4 million color-selected main sequence turn-off stars. We fit oblate and triaxial broken power-law models to the data, and found a `best-fit' oblateness of the stellar halo 0.5<c/a<0.8, and halo stellar masses between Galactocentric radii of 1 and 40kpc of (3.7+/-1.2)x10^8 M_sun. The density profile of the stellar halo is approximately r^{-3}; it is possible that the power law slope is shallower inside 20kpc and steeper outside that radius. Yet, we found that all smooth and symmetric models were very poor fits to the distribution of stellar halo stars because the data exhibit a great deal of spatial substructure. We quantified deviations from a smooth oblate/triaxial model using the RMS of the data around the model profile on scales >~100pc, after accounting for the (known) contribution of Poisson uncertainties. The fractional RMS deviation of the actual stellar distribution from any smooth, parameterized halo model is >~40%: hence, the stellar halo is highly structured. We compared the observations with simulations of galactic stellar halos formed entirely from the accretion of satellites in a cosmological context by analysing the simulations in the same way as the data. While the masses, overall profiles, and degree of substructure in the simulated stellar halos show considerable scatter, the properties and degree of substructure in the Milky Way's halo match well the properties of a `typical' stellar halo built exclusively out of the debris from disrupted satellite galaxies. Our results therefore point towards a picture in which an important fraction of the Milky Way's stellar halo has been accreted from satellite galaxies.Comment: Submitted to the Astrophysical Journal. 14 pages; 11 figure

Positron Emission Tomography-Computed Tomography Compared with Invasive Mediastinal Staging in Non-small Cell Lung Cancer: Results of Mediastinal Staging in the Early Lung Positron Emission Tomography Trial

IntroductionPatients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. 18Fluorodeoxyglucose positron emission tomography combined with computed tomography (18FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment.MethodsIn this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy.ResultsAll 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48–85%), and specificity was 94% (95% CI, 88–97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43–80%) and 95% (95% CI, 90–98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure.ConclusionsPET-CT assessment of the mediastinum is associated with a clinically relevant false-positive result. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT

Birth weight associations with DNA methylation differences in an adult population

The Developmental Origins of Health and Disease (DOHaD) theory predicts that prenatal and early life events shape adult health outcomes. Birth weight is a useful indicator of the foetal experience and has been associated with multiple adult health outcomes. DNA methylation (DNAm) is one plausible mechanism behind the relationship of birth weight to adult health. Through data linkage between Generation Scotland and historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division, a sample of 1,757 individuals with available birth weight and DNAm data was derived. Epigenome-wide association studies (EWAS) were performed in two independently generated DNAm subgroups (n(Set1) = 1,395, n(Set2) = 362), relating adult DNAm from whole blood to birth weight. Meta-analysis yielded one genome-wide significant CpG site (p = 5.97x10(−9)), cg00966482. There was minimal evidence for attenuation of the effect sizes for the lead loci upon adjustment for numerous potential confounder variables (body mass index, educational attainment, and socioeconomic status). Associations between birth weight and epigenetic measures of biological age were also assessed. Associations between lower birth weight and higher Grim Age acceleration (p((FDR)) = 3.6x10(−3)) and shorter DNAm-derived telomere length (p((FDR)) = 1.7x10(−3)) are described, although results for three other epigenetic clocks were null. Our results provide support for an association between birth weight and DNAm both locally at one CpG site, and globally via biological ageing estimates

Design catalogue for eco-engineering of coastal artificial structures:a multifunctional approach for stakeholders and end-users

Coastal urbanisation, energy extraction, food production, shipping and transportation have led to the global proliferation of artificial structures within the coastal and marine environments (sensu “ocean sprawl”), with subsequent loss of natural habitats and biodiversity. To mitigate and compensate impacts of ocean sprawl, the practice of ecoengineering of artificial structures has been developed over the past decade. Eco-engineering aims to create sustainable ecosystems that integrate human society with the natural environment for the benefit of both. The science of eco-engineering has grown markedly, yet synthesis of research into a user-friendly and practitioner-focused format is lacking. Feedback from stakeholders has repeatedly stated that a “photo user guide” or “manual” covering the range of eco-engineering options available for artificial structures would be beneficial. However, a detailed and structured “user guide” for eco-engineering in coastal and marine environments is not yet possible; therefore we present an accessible review and catalogue of trialled eco-engineering options and a summary of guidance for a range of different structures tailored for stakeholders and end-users as the first step towards a structured manual. This work can thus serve as a potential template for future eco-engineering guides. Here we provide suggestions for potential eco-engineering designs to enhance biodiversity and ecosystem functioning and services of coastal artificial structures with the following structures covered: (1) rock revetment, breakwaters and groynes composed of armour stones or concrete units; (2) vertical and sloping seawalls; (3) over-water structures (i.e., piers) and associated support structures; and (4) tidal river walls

Borderline personality traits, rumination and self-injurious behavior: An empirical test of the emotional cascades model in adult male offenders

The aim of the study was to examine whether the emotional cascade model, which suggests that the relationship between emotional and behavioural dysregulation in Borderline Personality Disorder (BPD) is mediated by rumination, applies to a sample of adult male offenders. The study focused on individuals with “BPD traits” and two dysregulated behaviors that are particularly relevant to the prison population: non-suicidal self-injury (NSSI) and suicidality. Participants were 179 adult male offenders detained in a medium-secure prison, all of whom completed a battery of measures and self-reported their actual prison behaviour. The results support the application of the emotional cascade model to adult male offenders, suggesting that emotional cascades may play an important role in NSSI and suicidality in this population, although this relationship needs further exploration. These findings highlight the benefits of targeting rumination to manage risk of NSSI and suicidality within custodial settings

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

BACKGROUND: Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)-a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. METHODS: We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults (n = 889) and a large, cross-sectional cohort (n = 7028). RESULTS: We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = - 0.08 and - 0.05); however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = - 0.15 and - 0.08). CONCLUSIONS: An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of individuals, and thus clearer inference of associations with incident health outcomes