Embryonic stem cells (ESC) are a unique cell population with the ability to self-renew and differentiate into all three germ layers. Human ESC express the telomerase reverse transcriptase (TERT) gene ...and the telomerase RNA (TR) and show telomerase activity, but TERT, TR, and telomerase are all downregulated during the differentiation process. To examine the role of telomerase in human ESC self-renewal and differentiation, we modulated the expression of TERT. Upregulation of TERT and increased telomerase activity enhanced the proliferation and colony-forming ability of human ESC, as well as increasing the S phase of the cell cycle at the expense of a reduced G1 phase. Upregulation of TERT expression was associated with increases in CYCLIN D1 and CDC6 expression, as well as hyperphosphorylation of RB. The differentiated progeny of control ESC showed shortening of telomeric DNA as a result of loss of telomerase activity. In contrast, the differentiated cells from TERT-overexpressing ESC maintained high telomerase activity and accumulated lower concentrations of peroxides than wild-type cells, implying greater resistance to oxidative stress. Although the TERT-overexpressing human ESC are able to form teratoma composed of three germ layers in vivo, their in vitro differentiation to all primitive and embryonic lineages was suppressed. In contrast, downregulation of TERT resulted in reduced ESC proliferation, increased G1, and reduced S phase. Most importantly, downregulation of TERT caused loss of pluripotency and human ESC differentiation to extraembryonic and embryonic lineages. Our results indicate for the first time an important role for TERT in the maintenance of human ESC pluripotency, cell cycle regulation, and in vitro differentiation capacity.
The use of current pulses to move domain walls along nanowires is one of the most exciting developments in spintronics over the past decade. We show that changing the sign of the curvature of a ...nanowire changes the speed of chiral Néel domain walls in perpendicularly magnetized nanowires by up to a factor of 10. The domain walls have an increased or decreased velocity in wires of a given curvature, independent of the domain wall chirality and the sign of the current-induced spin-orbit torques. Thus, adjacent domain walls move at different speeds. For steady motion of domain walls along the curved nanowire, the torque must increase linearly with the radius, which thereby results in a width-dependent tilting of the domain wall. We show that by using synthetic antiferromagnetic nanowires, the influence of the curvature on the domain wall's velocity is eliminated, and all domain walls move together, emphasizing the use of such structures for spintronic applications.
1. Senescence (or 'ageing') is a widespread and important process in wild animal populations, but variation in ageing patterns within and between species is poorly understood. 2. In cooperatively ...breeding species, the costs of reproduction are shared between breeders and one or more helpers. The effects of ageing in breeders may therefore be moderated by the presence of helpers, but there have been very few studies of senescence patterns in natural populations of cooperative breeders. 3. Here, we use 13 years of data from a long-term study population of wild meerkats (Suricata suricatta) to investigate age-related changes in several traits known to be key components of reproductive success in females of this species. 4. Four of the six traits studied exhibited significant declines with age, indicating senescence. Litter size, the number of litters produced per year and the number of pups that survived to emergence from the natal burrow per year all increased with female age up to a peak at c. 4 years, and declined steeply thereafter; the mean pup weight at emergence in a given litter declined steadily from age zero. 5. These results provide the first evidence of reproductive senescence in a wild population of a cooperatively breeding vertebrate. Breeding success declined with age despite the sharing of reproductive costs in this species, but further study is needed to investigate whether helping affects other aspects of senescence, including survival.
Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many ...different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3
T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3
CD8
cytotoxic T cells (CTLs, p = .0079), CD3
CD4
FOXP3
T helper cells (T
, p = .0010), and CD3
CD4
FOXP3
regulatory T cells (Tregs, p = .0089) with no difference in CD68
macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.
•Translating academic science with drug discovery requires high quality assays.•We established a fund and utilised existing infrastructure to address this need.•Engagement with academic networks ...provided a diverse target portfolio.•The scheme provided an excellent training platform for early career researchers.•Successful outputs from the fund leveraged significant follow-on funding.
With industry increasingly sourcing preclinical drug discovery projects from academia it is important that new academic discoveries are enabled through translation with HTS-ready assays. However, many scientifically interesting, novel molecular targets lack associated high-quality, robust assays suitable for hit finding and development. To bridge this gap, the Scottish Universities Life Sciences Alliance (SULSA) established a fund to develop assays to meet quality criteria such as those of the European Lead Factory. A diverse project portfolio was quickly assembled, and a review of the learnings and successful outcomes showed this fund as a new highly cost-effective model for leveraging significant follow-on resources, training early-career scientists and establishing a culture of translational drug discovery in the academic community.
Late recurrence of atrial fibrillation (AF) after radiofrequency ablation remains significant. Asymptomatic recurrence poses a difficult clinical problem as it is associated with an equally increased ...risk of stroke and death compared with symptomatic AF events. Meta-analyses reveal that no single preablation patient characteristic efficiently predicts these AF recurrences. This study aimed to evaluate the prognostic value of premature atrial complex (PAC) occurrence with regard to the risk of late AF recurrence after radiofrequency ablation.
The study cohort consisted of 124 patients with 7-day Holter recordings at 6 months post radiofrequency ablation for AF. No patients had AF recurrence before this time. Patients were followed-up every 6 months. Holter-detected PACs were defined as any supraventricular complexes occurring >30% earlier than expected. During a median follow-up of 4.2 years (first quartile to third quartile Q1-Q3=1.6-4.5), 32 patients (26%) had late recurrences of AF at a median of 462 days (Q1-Q3=319-1026) post radiofrequency ablation. The number of PACs per 24 hours was 248 (Q1-Q3=62-1026) in patients with and 77 (Q1-Q3=24-448) in patients without recurrence of AF (P=0.02). Multivariate analysis of the risk of late AF recurrence found ≥142 PACs per 24 hours to have a hazard ratio 2.84 (confidence interval, 1.26-6.43), P=0.01.
This study showed that occurrence of ≥142 PACs per day at 6 months after PVI was independently associated with a significantly increased risk of late AF recurrence. These results could have important clinical implications for the design of post-PVI follow-up.
URL: http://www.anzctr.org.au. Unique identifier: ACRTN12606000467538.
Novel phtotpolymerisable hole-transport layers based on novel triazatruxenes incorporating six non-conjugated dienes as photo cross-linkable end-groups attached to flexible, aliphatic spacers have ...been synthesised using simple one-step substitution reactions. Hole-only test devices, fabricated using a combination of solution-deposition, spin-coating and initiator-free photochemical cross-linking of these photopolymerisable triazatruxenes, exhibit almost identical current density
voltage profiles before and after cross-linking, and as such, represent a promising new class of hole-transport layer for plastic electronic devices.
Purpose
Severe Combined Immunodeficiency (SCID) is considered to be a paediatric emergency and unless identified promptly can be life-threatening. Frequently, infants are not diagnosed with SCID ...until they have become seriously ill with infection leading to treatment complications and a poorer prognosis. We aimed to test a newly available commercial duplex assay to measure T cell receptor excision circles (TRECs) to establish if this would be suitable for newborn screening for SCID in the UK.
Methods
Over 5000 anonymous retrospective dried blood spots (DBS) were used alongside 18 confirmed SCID positive DBS with a newly available duplex assay to measure TRECs levels and control gene levels. We also included testing of premature babies and babies from neonatal intensive care units (NICU) as these have been shown to have high false positive rates in other TREC screening assays.
Results
All 18 SCID DBS samples were successfully identified as SCID positives in the study. The number of presumptive positives detected was dependent on the TREC cut-off threshold settings. When analysed with five different TRECs cut-off values (20, 25, 30, 35 and 40 TREC copies/μl blood) the presumptive positive rate ranged from 0.04 to 1.00 % of samples tested. Premature infants and neonates from NICU did not show high presumed false positive rates in this assay.
Conclusions
The study demonstrated that this duplex assay kit will identify all newborns with SCID as presumptive positives. The data also shows that with suitable TREC cut-off settings the number of presumptive positives from non-SCID newborns will be manageable in the context of a national screening service.
Describing relationships among weather variables and herbage yield is important for planning livestock grazing, assessing wildlife habitat, and evaluating short- and long-term vegetation dynamics. We ...investigated the effects of weather on herbage yields from 44 Wyoming big sagebrush (Artemisia tridentata subsp. wyomingensis Beetle & Young) steppe sites across eastern Oregon from 2003 to 2012. We used linear and multiple linear regression to relate herbaceous total and functional group yields to monthly and seasonal precipitation, reference evapotranspiration (RET), and temperature. Functional groups were large perennial bunchgrasses, Sandberg bluegrass (Poa secunda J. Presl.), perennial forbs, annual forbs, and annual grasses. Yields and weather variables were normalized prior to regression analysis to account for differences in site characteristics. Normalized variables were obtained by dividing yield and weather variables by their 10-year means. Fall-through-spring (e.g., October-May, September-May) and spring precipitation and RET all contributed to significant predictive models for both functional groups and total herbage. Spring precipitation provided the strongest predictor of perennial bunchgrasses (March-May and June; R.sup.2 = 0.91), perennial forbs (May; R.sup.2 = 0.79), annual grasses (March; R.sup.2 = 0.79), and total herbage (March-May; R.sup.2 = 0.83) yields. Yields of Sandberg bluegrass and annual forbs were most strongly associated with RET for October-May (R.sup.2 = 0.86) and October-April (R.sup.2 = 0.79), respectively. Overall, we found a greater influence of late-winter and spring precipitation than that of models developed several decades ago where crop-year (September-June) precipitation provided more accurate herbage biomass estimates. Describir la relacion de las variables climaticas y las de produccion de forraje es importante para planificar el pastoreo del ganado, evaluar el habitat de la vida silvestre y la dinamica de la vegetacion a corto y largo plazo. Investigamos los efectos del clima en el forraje de 44 sitios esteparios de artemisa grande de Wyoming (Artemisia tridentata subsp. wyomingensis Beetle & Young) en todo el este de Oregon entre 2003 y 2012. Utilizamos regresion lineal y lineal multiple para relacionar la produccion total y los grupos funcionales herbaceos con la precipitacion mensual y estacional, la evapotranspiracion de referencia (RET, por sus siglas en ingles) y la temperatura. Los grupos funcionales fueron: pasto perenne grande, Sandberg bluegrass (Poa secunda J. Presl.), hierba perenne, hierba y pasto anuales. Las variables de produccion y climaticas se normalizaron antes del analisis de regresion con el proposito de controlar las diferencias en las caracteristicas de los sitios. Las variables normalizadas se obtuvieron dividiendo las variables de produccion y climaticas por su promedio de los ultimos 10 anos. Del otono hasta la primavera (es decir, octubre-mayo, septiembre-mayo), la precipitacion de primavera y la RET contribuyeron en la obtencion de modelos predictivos significativos tanto para los grupos funcionales como para el forraje total. La precipitacion de primavera proporciono el mejor indicador de la produccion de pasto perenne (marzo-mayo y junio; R.sup.2 = 0.91), hierba perenne (mayo; R.sup.2 = 0.79), pasto anual (marzo; R.sup.2 = 0.79), y forraje total (marzo-mayo; R.sup.2 = 0.83). La produccion de Sandberg bluegrass y de herbaceas anuales se asociaron mas con la RET en octubre-mayo (R.sup.2 = 0.86) y octubre-abril (R.sup.2 = 0.79), respectivamente. En general, encontramos una mayor influencia de las precipitaciones de finales de invierno y primavera que los modelos presentados hace varias decadas, donde la precipitacion del ano de cosecha (septiembre a junio) proporciono estimaciones mas precisas de la biomasa del forraje.
This paper examines how Estonian and foreign tourists to Saaremaa Island perceive their future experiences in light of a bridge built from mainland Estonia to the island. A logistic regression ...resulted in six predictors (two demographic and four sense of place scales) of perceived future effects of a proposed bridge on future experience, accounting for 18% of the variance. The six predictors of perceived effects of a potential bridge to the mainland on future holiday experience to Saaremaa Island were nationality, education, socio-cultural context, memory, aesthetics, and wellbeing sense of place scales. Estonians were more positive about the bridge, which supports previous discussions of the essence of home and wellbeing. Wellbeing was the strongest and only positive predictor followed by educational level, memory, socio-cultural context, aesthetics, and nationality, which were all negative. Highlights allude to the predictive power of sense of place on perceived environmental change of development (bridge to island) to future experience among tourists.
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