The 5.2 ka climate event: Evidence from stable isotope and multi-proxy palaeoecological peatland records in Ireland

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Evidence for a major climate event at 5.2 ka has been reported globally and is associated with considerable societal disruption, but is poorly characterised in northwest Europe. This event forms part of a broader period of re-organisation in the Earth's ocean-atmosphere circulation system between 6 and 5 ka. This study tests the nature and timing of the event in northwest Europe, a region highly sensitive to change in meridional overturning circulation and mid-latitude westerly airflow. Here we report three high-resolution Irish multi-proxy records obtained from ombrotrophic peatlands that have robust chronological frameworks. We identify the 5.2 ka event by a sustained decrease in δ 18 O cellulose at all three sites, with additional and parallel changes in δ 13 C cellulose and palaeoecological (testate amoebae, plant macrofossil and humification) data from two sites in northern Ireland. Data from Sluggan Moss demonstrate a particularly coherent shift towards wetter conditions. These data support the hypothesis that the event was caused by a prolonged period of positive North Atlantic Oscillation conditions, resulting in pervasive cyclonic weather patterns across northwest Europe, increasing precipitation over Ireland.This research was carried out while T.P.R. held UK Natural Environment Research Council studentship at the University of Exeter (NE/G524328/1) and T.J.D held a studentship at the University of Southampton tied to the NERC RAPID Programme (NER/T/S/2002/00460). Radiocarbon support was provided by the NERC 14C Steering Committee (Allocation No.: 1523.0910), the NERC RAPID Programme and the Irish Quaternary Association via the IQUA Bill Watts 14Chrono award

Drivers of Holocene peatland carbon accumulation across a climate gradient in northeastern North America

Peatlands are an important component of the Holocene global carbon (C) cycle and the rate of C sequestration and storage is driven by the balance between net primary productivity and decay. A number of studies now suggest that climate is a key driver of peatland C accumulation at large spatial scales and over long timescales, with warmer conditions associated with higher rates of C accumulation. However, other factors are also likely to play a significant role in determining local carbon accumulation rates and these may modify past, present and future peatland carbon sequestration. Here, we test the importance of climate as a driver of C accumulation, compared with hydrological change, fire, nitrogen content and vegetation type, from records of C accumulation at three sites in northeastern North America, across the N-S climate gradient of raised bog distribution. Radiocarbon age models, bulk density values and %C measurements from each site are used to construct C accumulation histories commencing between 11,200 and 8000cal. years BP. The relationship between C accumulation and environmental variables (past water table depth, fire, peat forming vegetation and nitrogen content) is assessed with linear and multivariate regression analyses. Differences in long-term rates of carbon accumulation between sites support the contention that a warmer climate with longer growing seasons results in faster rates of long-term carbon accumulation. However, mid-late Holocene accumulation rates show divergent trends, decreasing in the north but rising in the south. We hypothesise that sites close to the moisture threshold for raised bog distribution increased their growth rate in response to a cooler climate with lower evapotranspiration in the late Holocene, but net primary productivity declined over the same period in northern areas causing a decrease in C accumulation. There was no clear relationship between C accumulation and hydrological change, vegetation, nitrogen content or fire, but early successional stages of peatland growth had faster rates of C accumulation even though temperatures were probably lower at the time. We conclude that climate is the most important driver of peatland accumulation rates over millennial timescales, but that successional vegetation change is a significant additional influence. Whilst the majority of northern peatlands are likely to increase C accumulation rates under future warmer climates, those at the southern limit of distribution may show reduced rates. However, early succession peatlands that develop under future warming at the northern limits of peatland distribution are likely to have high rates of C accumulation and will compensate for some of the losses elsewhere

Epigenetic memory in induced pluripotent stem cells.

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment

Protocol for: Sheffield Obesity Trial (SHOT): A randomised controlled trial of exercise therapy and mental health outcomes in obese adolescents [ISRCNT83888112]

Background While obesity is known to have many physiological consequences, the psychopathology of this condition has not featured prominently in the literature. Cross-sectional studies have indicated that obese children have increased odds of experiencing poor quality of life and mental health. However, very limited trial evidence has examined the efficacy of exercise therapy for enhancing mental health outcomes in obese children, and the Sheffield Obesity Trial (SHOT) will provide evidence of the efficacy of supervised exercise therapy in obese young people aged 11–16 years versus usual care and an attention-control intervention. Method/design SHOT is a randomised controlled trial where obese young people are randomised to receive; (1) exercise therapy, (2) attention-control intervention (involving body-conditioning exercises and games that do not involve aerobic activity), or (3) usual care. The exercise therapy and attention-control sessions will take place three times per week for eight weeks and a six-week home programme will follow this. Ninety adolescents aged between 11–16 years referred from a children's hospital for evaluation of obesity or via community advertisements will need to complete the study. Participants will be recruited according to the following criteria: (1) clinically obese and aged 11–16 years (Body Mass Index Centile > 98th UK standard) (2) no medical condition that would restrict ability to be active three times per week for eight weeks and (3) not diagnosed with insulin dependent diabetes or receiving oral steroids. Assessments of outcomes will take place at baseline, as well as four (intervention midpoint) and eight weeks (end of intervention) from baseline. Participants will be reassessed on outcome measures five and seven months from baseline. The primary endpoint is physical self-perceptions. Secondary outcomes include physical activity, self-perceptions, depression, affect, aerobic fitness and BMI

Evaluation of a standard provision versus an autonomy promotive exercise referral programme: rationale and study design

Background The National Institute of Clinical Excellence in the UK has recommended that the effectiveness of ongoing exercise referral schemes to promote physical activity should be examined in research trials. Recent empirical evidence in health care and physical activity promotion contexts provides a foundation for testing the utility of a Self Determination Theory (SDT) -based exercise referral consultation. Methods/Design Design: An exploratory cluster randomised controlled trial comparing standard provision exercise on prescription with a Self Determination Theory-based (SDT) exercise on prescription intervention. Participants: 347 people referred to the Birmingham Exercise on Prescription scheme between November 2007 and July 2008. The 13 exercise on prescription sites in Birmingham were randomised to current practice (n=7) or to the SDT-based intervention (n=6). Outcomes measured at 3 and 6-months: Minutes of moderate or vigorous physical activity per week assessed using the 7-day Physical Activity Recall; physical health: blood pressure and weight; health status measured using the Dartmouth CO-OP charts; anxiety and depression measured by the Hospital Anxiety and Depression Scale and vitality measured by the subjective vitality score; motivation and processes of change: perceptions of autonomy support from the advisor, satisfaction of the needs for competence, autonomy, and relatedness via physical activity, and motivational regulations for exercise. Discussion This trial will determine whether an exercise referral programme based on Self Determination Theory increases physical activity and other health outcomes compared to a standard programme and will test the underlying SDT-based process model (perceived autonomy support, need satisfaction, motivation regulations, outcomes) via structural equation modelling. Trial registration The trial is registered as Current Controlled trials ISRCTN07682833

Geckos decouple fore- and hind limb kinematics in response to changes in incline

This work is supported by an NSF grant (NSF IOS-1147043) to TE

Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy

Endometrial apoptosis and neutrophil infiltration during menstruation exhibits spatial and temporal dynamics that are recapitulated in a mouse model.

Abstract Menstruation is characterised by synchronous shedding and restoration of tissue integrity. An in vivo model of menstruation is required to investigate mechanisms responsible for regulation of menstrual physiology and to investigate common pathologies such as heavy menstrual bleeding (HMB). We hypothesised that our mouse model of simulated menstruation would recapitulate the spatial and temporal changes in the inflammatory microenvironment of human menses. Three regulatory events were investigated: cell death (apoptosis), neutrophil influx and cytokine/chemokine expression. Well-characterised endometrial tissues from women were compared with uteri from a mouse model (tissue recovered 0, 4, 8, 24 and 48 h after removal of a progesterone-secreting pellet). Immunohistochemistry for cleaved caspase-3 (CC3) revealed significantly increased staining in human endometrium from late secretory and menstrual phases. In mice, CC3 was significantly increased at 8 and 24 h post-progesterone-withdrawal. Elastase+ human neutrophils were maximal during menstruation; Ly6G+ mouse neutrophils were maximal at 24 h. Human endometrial and mouse uterine cytokine/chemokine mRNA concentrations were significantly increased during menstrual phase and 24 h post-progesterone-withdrawal respectively. Data from dated human samples revealed time-dependent changes in endometrial apoptosis preceding neutrophil influx and cytokine/chemokine induction during active menstruation. These dynamic changes were recapitulated in the mouse model of menstruation, validating its use in menstrual research

Intra-gastric balloon as an adjunct to lifestyle support in severely obese adolescents; Impact on weight, physical activity, cardio-respiratory fitness and psychosocial wellbeing.

BACKGROUND: Severe adolescent obesity (BMI>99.6th centile) is a significant public health challenge. Current non-invasive treatments, including community-based lifestyle interventions, are often of limited effectiveness in this population, with NICE guidelines suggesting the use of bariatric surgery as the last line of treatment (NICE, 2013). Health professionals are understandably reluctant to commission bariatric surgery and as an alternative, the use of an intra-gastric balloon as an adjunct to a lifestyle programme might offer a reversible, potentially safer and less invasive option. OBJECTIVES: Explore the use of an intra-gastric balloon as an adjunct to a lifestyle support programme, to promote weight loss in severely obese adolescents. Outcomes included Weight loss, Waist and Hip measurements, psychosocial outcomes including health related quality of life and physical self-perceptions, physical activity and cardiorespiratory fitness. METHOD: Non-randomised pilot study. Results: 12 severely obese adolescents (5 males, 7 females; mean age 15yrs; BMI >3.5 s.d.; puberty stage 4 or more) and their families were recruited. Mean weight loss at 12 months (n=9) was 3.05 kg±14.69; d=0.002, P=0.550, and a BMI Z-score (n=12) change of 0.2 s.d.; d=0.7, P=0.002 was observed at 6 months with a large effect, but was not sustained at 12 months (mean change 0.1 s.d.; d=0.3, P=0.146 ) At 24 months (n=10) there was a weight gain from baseline of +9.9 kg±1.21 (d=0.4; P=0.433). Adolescent and parent HRQoL scores exceeded the minimal clinical important difference between baseline and 12 months for all domains but showed some decline at 24 months. CONCLUSION: An intra-gastric balloon as an adjunct to a lifestyle support programme represents a safe and well tolerated treatment approach in severely obese adolescents, with short-term effects on weight change. Improvements in psychosocial health, physical activity and cardiorespiratory fitness were maintained at 12 months, with varying results at 24 months