Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Cine documental y periodismo : una discusión sobre ética y estética a través de obras estatales

El cinema documental, degut a la seva particular relació amb la realitat, sovint es considera com una eina periodística -i es jutjat com a tal. No obstant això, aquesta relació es complexa y dona lloc a un gran debat sobre la vocació ètica o estètica d'aquestes obres. Aquest treball pretén un apropament al debat a través de l'anàlisi d'una variada selecció de peces d'àmbit estatal. Finalment, es vol arribar a una comprensió més profunda del gènere i el seu potencial informatiu.El cine documental, por su particular relación con la realidad, a menudo es considerado como una herramienta periodística -y es juzgado como tal. Sin embargo, esta relación es compleja y da lugar a un amplio debate sobre la vocación ética o estética de estas obras. Este trabajo pretende un acercamiento a ese debate a través del análisis de una variada selección de piezas de ámbito estatal. La intención es llegar a una comprensión más profunda del género y de su potencial informativo.Due to their specific relationship with reality, documentary films are often regarded as journalistic tools -and are assessed as such. However, this relationship is complex and gives way to a large debate regarding the ethical or aesthetical purposes of these films. This paper aims to get closer to the debate with an analysis of a varied selection of Spanish works. The final intention is to reach a deeper understanding of this genre and its informational potential

The altered gut microbiota in adults with cystic fibrosis

peer-reviewedBackground Cystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed. Results The CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (−0.383, Simpson’s Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity. Conclusions This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.The authors and their work were supported by the Science Foundation of Ireland and funded by the Centre for Science, Engineering and Technology (SFI-CSET) grant 02/CE/B124 and by FP7 funded CFMATTERS (Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified, Grant Agreement no. 603038)

The impact of COVID-19 on the health-related behaviours, mental well-being, and academic engagement of a cohort of undergraduate students in an Irish university setting.

Given the well-established impact of COVID-19 on university students' health and lifestyle parameters, the current study sought to investigate these impacts within an Irish university setting. A cross-sectional design was employed, with a 68-item questionnaire instrument disseminated to all Year 2 undergraduate students in the host institution (N = 2752), yielding a 9.7% response rate ( = 266). This questionnaire elicited students' self-reported changes to health-related behaviours, mental well-being and academic engagement across 4 defined time-points: (T0: prior to COVID-19, T1: initial onset of COVID-19, T2: during COVID-19, and T3: time of data collection). Many items were adapted from previous Irish research and additional validated scales included the Alcohol Use Disorders Identification Test (AUDIT-C) and the World Health Organisation's Well-being scale (WHO-5). Key findings revealed that at T1, substantially more males reported '/' general health than females (76.3% vs. 70.8%), while physical activity patterns followed a similar trend at both T0 (80% vs. 66.1%) and T1 (66.7% vs. 61%). A total of 78.4% of participants reported a body mass gain from T0 to T3, thus reflecting the reduced physical activity levels and compromised nutritional patterns across this period. Worryingly, AUDIT-C scale data revealed hazardous drinking habits were evident in both males and females, while fruit and vegetable intake, physical activity levels, and mental well-being among this cohort remained notably sub-optimal. Ratings of positive academic engagement also decreased substantially between T0 (90.3%) and T3 (30.4%). These findings substantiate the rationale for tailored health promotion interventions in university settings to support students' transition back to traditional programme delivery and, of equal importance, to improve general health and well-being post-COVID-19 within this cohort

Microfabricated inductors for 20 MHz dc-dc converters

This paper presents the design and measured results for micro-fabricated inductors suitable for use in high frequency (> 10 MHz), low power (1 –2 W) dc-dc converters. The design has focused on maximizing inductor efficiency for a given converter specification. Inductors in the range of 100 nH to 300 nH have been fabricated and tested. The small signal measurements show a relatively flat inductance profile, with a 10% drop in inductance at 30 MHz. Inductance vs. dc bias current measurements show less than 15% decrease in inductance at 500 mA current. The performance of the micro-inductors have also been compared to a conventional wire-wound inductor in a 20 MHz dc-dc converter. The converter efficiency is shown to be approximately 4% lower when the micro-inductor is used compared to the when the wirewound inductor is used. The peak efficiency of the micro-inductor in the converter is estimated to be approximately 93%

Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation

The effect of buttermilk or buttermilk powder addition on functionality, textural, sensory and volatile characteristics of Cheddar-style cheese

The influence of buttermilk or buttermilk powder addition to cheese milk or cheese curds respectively on cheese functional properties, free fatty acid profiles and subsequent volatile and sensory characteristics was investigated. Buttermilk addition to cheese milk resulted in a softer cheese compared to other cheeses, with a significantly reduced flowability, while buttermilk powder addition had no influence on cheese firmness but cheese flowability was also reduced compared to the control cheese. Larger pools of free fat, higher levels of free fatty acids, volatile compounds and significant differences in sensory profiles associated with off-flavour were also observed with the addition of buttermilk to cheese milk. Application of light microscopy, using toluidine blue stain, facilitated the visualisation of fat globule structure and distribution within the protein matrix. Addition of 10% buttermilk powder resulted in significant increases in volatile compounds originating from proteolysis pathways associated with roasted, green aromas. Descriptive sensory evaluation indicated few differences between the 10% buttermilk powder and the control cheese, while buttermilk cheeses scored negatively for sweaty, barnyard aromas, oxidized and off flavors, correlating with associated volatile aromas. Addition of 10% buttermilk powder to cheese curds results in cheese comparable to the control Cheddar with some variations in volatile compounds resulting in a cheese with similar structural and sensory characteristics albeit with subtle differences in overall cheese flavor. This could be manipulated to produce cheeses of desirable quality, with potential health benefits due to increased phospholipid levels in chees