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

Explainable AI: The new 42?

Explainable AI is not a new field. Since at least the early exploitation of C.S. Pierce’s abductive reasoning in expert systems of the 1980s, there were reasoning architectures to support an explanation function for complex AI systems, including applications in medical diagnosis, complex multi-component design, and reasoning about the real world. So explainability is at least as old as early AI, and a natural consequence of the design of AI systems. While early expert systems consisted of handcrafted knowledge bases that enabled reasoning over narrowly well-defined domains (e.g., INTERNIST, MYCIN), such systems had no learning capabilities and had only primitive uncertainty handling. But the evolution of formal reasoning architectures to incorporate principled probabilistic reasoning helped address the capture and use of uncertain knowledge. There has been recent and relatively rapid success of AI/machine learning solutions arises from neural network architectures. A new generation of neural methods now scale to exploit the practical applicability of statistical and algebraic learning approaches in arbitrarily high dimensional spaces. But despite their huge successes, largely in problems which can be cast as classification problems, their effectiveness is still limited by their un-debuggability, and their inability to “explain” their decisions in a human understandable and reconstructable way. So while AlphaGo or DeepStack can crush the best humans at Go or Poker, neither program has any internal model of its task; its representations defy interpretation by humans, there is no mechanism to explain their actions and behaviour, and furthermore, there is no obvious instructional value.. the high performance systems can not help humans improve. Even when we understand the underlying mathematical scaffolding of current machine learning architectures, it is often impossible to get insight into the internal working of the models; we need explicit modeling and reasoning tools to explain how and why a result was achieved. We also know that a significant challenge for future AI is contextual adaptation, i.e., systems that incrementally help to construct explanatory models for solving real-world problems. Here it would be beneficial not to exclude human expertise, but to augment human intelligence with artificial intelligence

Improved accelerated breath-hold radial cine image reconstruction by acquiring additional free-breathing data between breath-holds

Engineering and Applied Science

The first IRAM/PdBI polarimetric millimeter survey of active galactic nuclei. II. Activity and properties of individual sources

We present an analysis of the linear polarization of six active galactic nuclei - 0415+379 (3C~111), 0507+179, 0528+134 (OG+134), 0954+658, 1418+546 (OQ+530), and 1637+574 (OS+562). Our targets were monitored from 2007 to 2011 in the observatory-frame frequency range 80-253 GHz, corresponding to a rest-frame frequency range 88-705 GHz. We find average degrees of polarization m_L ~ 2-7%; this indicates that the polarization signals are effectively averaged out by the emitter geometries. We see indication for fairly strong shocks and/or complex, variable emission region geometries in our sources, with compression factors 10 deg. An analysis of correlations between source fluxes and polarization parameter points out special cases: the presence of (at least) two distinct emission regions with different levels of polarization (for 0415+379) as well as emission from a single, predominant component (for 0507+179 and 1418+546). Regarding the evolution of flux and polarization, we find good agreement between observations and the signal predicted by "oblique shock in jet" scenarios in one source (1418+546). We attempt to derive rotation measures for all sources, leading to actual measurements for two AGN and upper limits for three sources. We derive values of RM = -39,000 +/- 1,000 (stat) +/- 13,000 (sys) rad/m^2 and RM = 420,000 +/- 10,000 (stat) +/- 110,000 (sys) rad/m^2 for 1418+546 and 1637+574, respectively; these are the highest values reported to date for AGN. These values indicate magnetic field strengths of the order ~0.0001 G. For 0415+379, 0507+179, and 0954+658 we derive upper limits |RM| < 17,000 rad/m^2. From the relation |RM| ~ nu^a we find a = 1.9 +/- 0.3 for 1418+546, in good agreement with a = 2 as expected for a spherical or conical outflow.Comment: 23 pages, 8 figures, 4 tables. Accepted by Astronomy and Astrophysics. Minor language editing, one missing reference (Macquart et al. 2006) adde

A VLBA survey of the core shift effect in AGN jets I. Evidence for dominating synchrotron opacity

The effect of a frequency dependent shift of the VLBI core position (known as the "core shift") was predicted more than three decades ago and has since been observed in a few sources, but often within a narrow frequency range. This effect has important astrophysical and astrometric applications. To achieve a broader understanding of the core shift effect and the physics behind it, we conducted a dedicated survey with NRAO's Very Long Baseline Array (VLBA). We used the VLBA to image 20 pre-selected sources simultaneously at nine frequencies in the 1.4-15.4 GHz range. The core position at each frequency was measured by referencing it to a bright, optically thin feature in the jet. A significant core shift has been successfully measured in each of the twenty sources observed. The median value of the core shift is found to be 1.21 mas if measured between 1.4 and 15.4 GHz, and 0.24 mas between 5.0 and 15.4 GHz. The core position, r, as a function of frequency, n, is found to be consistent with an r n^-1 law. This behavior is predicted by the Blandford & Koenigl model of a purely synchrotron self-absorbed conical jet in equipartition. No systematic deviation from unity of the power law index in the r(n) relation has been convincingly detected. We conclude that neither free-free absorption nor gradients in pressure and/or density in the jet itself and in the ambient medium surrounding the jet play a significant role in the sources observed within the 1.4-15.4 GHz frequency range. These results support the interpretation of the parsec-scale core as a continuous Blandford-Koenigl type jet with smooth gradients of physical properties along it.Comment: 31 pages, 6 figures, 5 tables; accepted to Astronomy & Astrophysic

The development and evaluation of the Writing Assessment Measure (WAM) to assess children's narrative writing.

The study evaluated the reliability and validity of the Writing Assessment Measure (WAM), developed to reflect the skills which children of different abilities are expected to achieve in written expression, as part of the National Curriculum guidelines in England and Wales. The focus was on its potential use in investigations of children's written narrative in order to inform and target related interventions. The study involved 97 children aged 7–11 from one urban primary school in England. Prompt 1 was administered to all the children in their classrooms together with a standardised written expression test. After three weeks, the same procedure was followed and Prompt 2 was administered. Statistical analyses of the reliability and validity of the instrument showed that it is consistent over time and can be scored reliably by different raters. Content validity of the instrument was demonstrated through inspection of item total correlations which were all significant. Analyses for concurrent validity showed that the instrument correlates significantly with the Wechsler Written Expressive Language sub-test. Significant differences between children of different age and writing skill were also found. The findings indicate that the instrument has potential utility to professionals assessing children's writing

Height dependent molecular trapping in stacked cyclic porphyrin nanorings

Stacked layers of cyclic porphyrin nanorings constitute nanoscale receptacles with variable height and diameter which preferentially adsorb sublimed molecules. Using scanning tunnelling microscopy we determine the filling capacity of these nanoring traps, and the dependence of adsorbate capture on stack height and diameter

Yoga and pilates in the management of low back pain

Many interventions for the management of low back pain exist, however most have modest efficacy at best, and there are few with clearly demonstrated benefits once pain becomes chronic. Therapeutic exercise, on the other hand, does appear to have significant benefits for managing patients with chronic low back pain (CLBP) in terms of decreasing pain and improving function. In addition, because chronic pain is complex and does not fit a simple model, there have also been numerous trials investigating and demonstrating the efficacy of multidisciplinary pain programs for CLBP. It follows that interventions that treat more than one aspect of LBP would have significant benefits for this patient population. Yoga and Pilates which have, both been gaining in popularity over the last decade are two mind–body exercise interventions that address both the physical and mental aspects of pain with core strengthening, flexibility, and relaxation. There has been a slow evolution of these nontraditional exercise regimens into treatment paradigms for LBP, although few studies examining their effects have been published. The following article will focus on the scientific and theoretical basis of using yoga and Pilates in the management of CLBP