Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications

Complex circular subsidence structures in tephra deposited on large blocks of ice: Varða tuff cone, Öræfajökull, Iceland

Several broadly circular structures up to 16 m in diameter, into which higher strata have sagged and locally collapsed, are present in a tephra outcrop on southwest Öræfajökull, southern Iceland. The tephra was sourced in a nearby basaltic tuff cone at Varða. The structures have not previously been described in tuff cones, and they probably formed by the melting out of large buried blocks of ice emplaced during a preceding jökulhlaup that may have been triggered by a subglacial eruption within the Öræfajökull ice cap. They are named ice-melt subsidence structures, and they are analogous to kettle holes that are commonly found in proglacial sandurs and some lahars sourced in ice-clad volcanoes. The internal structure is better exposed in the Varða examples because of an absence of fluvial infilling and reworking, and erosion of the outcrop to reveal the deeper geometry. The ice-melt subsidence structures at Varða are a proxy for buried ice. They are the only known evidence for a subglacial eruption and associated jökulhlaup that created the ice blocks. The recognition of such structures elsewhere will be useful in reconstructing more complete regional volcanic histories as well as for identifying ice-proximal settings during palaeoenvironmental investigations

Pasture Management in the US Midwest – An Assessment of Current Practices and Future Opportunities

Managed grazing offers significant potential to improve the sustainability of livestock farms in the US Midwest, however the benefits of managed grazing are largely influenced by the management practices employed on farm. The objective of this study was to gain an understanding of current grazing practices on Midwest farms and to identify the knowledge and support needs of graziers. A total of 185 responses were received from a range of different enterprises including dairy, beef, and sheep production. Results show a substantial degree of variation in grazing management practices between respondents and highlights significant scope for improvement on farms particularly in the areas of pasture measurement and budgeting, and grazing infrastructure. Reported benefits of managed grazing included lower environmental impact, better pasture and animal performance, better animal health and welfare, and lower costs. Challenges with managed grazing included time and labor input, maintaining pasture quantity and quality during the grazing season, adverse weather conditions such as excessive rain and drought, and animal health challenges such as heat stress, parasites and in some cases coyotes. The study highlighted opportunities for research and extension providers to better support farmers with information and advice and identified knowledge gaps in areas such as pasture species selection, soil fertility, grazing infrastructure, pasture budgeting, legumes, and pasture measurement. The study successfully gained an insight into graziers in the Midwest, the outputs of which, will be valuable to a number of key stakeholders going forward, including researchers, extension agents, farmers and policy makers

'HepCheck Dublin': An Intensified Hepatitis C Screening Programme in a Homeless Population Demonstrates the Need for Alternative Models of Care

Background: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9% to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. Methods: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. Results: 597 individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were ‘new positives’ and 44% were ‘known positives’. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. 46 subjects were referred to specialised services and two subjects completed HCV treatment. Conclusions: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV

Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS

The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin

Geomechanical modelling of sinkhole development using distinct elements: model verification for a single void space and application to the Dead Sea area

Mechanical and/or chemical removal of material from the subsurface may generate large subsurface cavities, the destabilisation of which can lead to ground collapse and the formation of sinkholes. Numerical simulation of the interaction of cavity growth, host material deformation and overburden collapse is desirable to better understand the sinkhole hazard but is a challenging task due to the involved high strains and material discontinuities. Here, we present 2-D distinct element method numerical simulations of cavity growth and sinkhole development. Firstly, we simulate cavity formation by quasi-static, stepwise removal of material in a single growing zone of an arbitrary geometry and depth. We benchmark this approach against analytical and boundary element method models of a deep void space in a linear elastic material. Secondly, we explore the effects of properties of different uniform materials on cavity stability and sinkhole development. We perform simulated biaxial tests to calibrate macroscopic geotechnical parameters of three model materials representative of those in which sinkholes develop at the Dead Sea shoreline: mud, alluvium and salt. We show that weak materials do not support large cavities, leading to gradual sagging or suffusion-style subsidence. Strong materials support quasi-stable to stable cavities, the overburdens of which may fail suddenly in a caprock or bedrock collapse style. Thirdly, we examine the consequences of layered arrangements of weak and strong materials. We find that these are more susceptible to sinkhole collapse than uniform materials not only due to a lower integrated strength of the overburden but also due to an inhibition of stabilising stress arching. Finally, we compare our model sinkhole geometries to observations at the Ghor Al-Haditha sinkhole site in Jordan. Sinkhole depth ∕ diameter ratios of 0.15 in mud, 0.37 in alluvium and 0.33 in salt are reproduced successfully in the calibrated model materials. The model results suggest that the observed distribution of sinkhole depth ∕ diameter values in each material type may partly reflect sinkhole growth trends

Distinct element modeling of geophysical signatures during sinkhole collapse

PosterDjamil Al-Halbouni, Eoghan P. Holohan, Abbas Taheri, and Torsten Dah

Adaptive Evolution and the Birth of CTCF Binding Sites in the Drosophila Genome

Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ~2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes

Shear wave reflection seismic yields subsurface dissolution and subrosion patterns: application to the Ghor Al-Haditha sinkhole site, Dead Sea, Jordan

Near-surface geophysical imaging of alluvial fan settings is a challenging task but crucial for understating geological processes in such settings. The alluvial fan of Ghor Al-Haditha at the southeast shore of the Dead Sea is strongly affected by localized subsidence and destructive sinkhole collapses, with a significantly increasing sinkhole formation rate since ca. 1983. A similar increase is observed also on the western shore of the Dead Sea, in correlation with an ongoing decline in the Dead Sea level. Since different structural models of the upper 50 m of the alluvial fan and varying hypothetical sinkhole processes have been suggested for the Ghor Al-Haditha area in the past, this study aimed to clarify the subsurface characteristics responsible for sinkhole development. For this purpose, high-frequency shear wave reflection vibratory seismic surveys were carried out in the Ghor Al-Haditha area along several crossing and parallel profiles with a total length of 1.8 and 2.1 km in 2013 and 2014, respectively. The sedimentary architecture of the alluvial fan at Ghor Al-Haditha is resolved down to a depth of nearly 200 m at a high resolution and is calibrated with the stratigraphic profiles of two boreholes located inside the survey area. The most surprising result of the survey is the absence of evidence of a thick (> 2–10 m) compacted salt layer formerly suggested to lie at ca. 35–40 m depth. Instead, seismic reflection amplitudes and velocities image with good continuity a complex interlocking of alluvial fan deposits and lacustrine sediments of the Dead Sea between 0 and 200 m depth. Furthermore, the underground section of areas affected by sinkholes is characterized by highly scattering wave fields and reduced seismic interval velocities. We propose that the Dead Sea mud layers, which comprise distributed inclusions or lenses of evaporitic chloride, sulfate, and carbonate minerals as well as clay silicates, become increasingly exposed to unsaturated water as the sea level declines and are consequently destabilized and mobilized by both dissolution and physical erosion in the subsurface. This new interpretation of the underlying cause of sinkhole development is supported by surface observations in nearby channel systems. Overall, this study shows that shear wave seismic reflection technique is a promising method for enhanced near-surface imaging in such challenging alluvial fan settings

Right Ventricle Has Normal Myofilament Function But Shows Perturbations in the Expression of Extracellular Matrix Genes in Patients With Tetralogy of Fallot Undergoing Pulmonary Valve Replacement

BACKGROUND: Patients with repair of tetralogy of Fallot (rToF) who are approaching adulthood often exhibit pulmonary valve regurgitation, leading to right ventricle (RV) dilatation and dysfunction. The regurgitation can be corrected by pulmonary valve replacement (PVR), but the optimal surgical timing remains under debate, mainly because of the poorly understood nature of RV remodeling in patients with rToF. The goal of this study was to probe for pathologic molecular, cellular, and tissue changes in the myocardium of patients with rToF at the time of PVR. METHODS AND RESULTS: We measured contractile function of permeabilized myocytes, collagen content of tissue samples, and the expression of mRNA and selected proteins in RV tissue samples from patients with rToF undergoing PVR for severe pulmonary valve regurgitation. The data were compared with nondiseased RV tissue from unused donor hearts. Contractile performance and passive stiffness of the myofilaments in permeabilized myocytes were similar in rToF‐PVR and RV donor samples, as was collagen content and cross‐linking. The patients with rToF undergoing PVR had enhanced mRNA expression of genes associated with connective tissue diseases and tissue remodeling, including the small leucine‐rich proteoglycans ASPN (asporin), LUM (lumican), and OGN (osteoglycin), although their protein levels were not significantly increased. CONCLUSIONS: RV myofilaments from patients with rToF undergoing PVR showed no functional impairment, but the changes in extracellular matrix gene expression may indicate the early stages of remodeling. Our study found no evidence of major damage at the cellular and tissue levels in the RV of patients with rToF who underwent PVR according to current clinical criteria