HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

O2 deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O2. However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to “fine tune” adaptive responses to hypoxic environments

Derivation and Improvements of the Quantum Canonical Ensemble from a Regularized Microcanonical Ensemble

We develop a regularization of the quantum microcanonical ensemble, called a Gaussian ensemble, which can be used for derivation of the canonical ensemble from microcanonical principles. The derivation differs from the usual methods by giving an explanation for the, at the first sight unreasonable, effectiveness of the canonical ensemble when applied to certain small, isolated, systems. This method also allows a direct identification between the parameters of the microcanonical and the canonical ensemble and it yields simple indicators and rigorous bounds for the effectiveness of the approximation. Finally, we derive an asymptotic expansion of the microcanonical corrections to the canonical ensemble for those systems, which are near, but not quite, at the thermodynamical limit and show how and why the canonical ensemble can be applied also for systems with exponentially increasing density of states. The aim throughout the paper is to keep mathematical rigour intact while attempting to produce results both physically and practically interesting.Comment: 17 pages, latex2e with iopar

Yawning as a new potential diagnostic marker for neurological diseases.

Yawning apparatus and exact location of the yawn reflex remains controversial. Yet yawning is a significant behavioural response and potentially a new diagnostic marker of neurological disease. Association between cortisol, electromyography (EMG) and yawning was found in humans supporting Thompson Cortisol Hypothesis (TCH) which complements thermoregulation hypotheses indicating brain cooling occurs when yawning. 28 male, 54 female volunteers, 18-69 years, randomly allocated to experimentally controlled conditions of provoked yawning. Saliva samples were collected at start and after yawning, or after stimuli presentation, in absence of yawning. EMG data was collected from jaw muscles at rest and after yawning. Specially designed yawning susceptibility scale, Hospital Anxiety and Depression Scale, General Health Questionnaire, demographic, health details were collected. Between- and within-subjects comparisons of yawners and non-yawners was conducted. Exclusion criteria: chronic fatigue, diabetes, fibromyalgia, heart condition, high blood pressure, hormone replacement therapy, multiples sclerosis, stroke. Yawning group: significant difference between saliva cortisol samples, rest and yawning t (37)=2.842, p=0.007, compared with non-yawners, rest and post-stimuli, which was non-significant. Yawners, rest EMG: -100 to 200 millionth of a volt (mean=182.2) and -60 000 to 18 000 (mean=3 897.4) after yawning. Non-yawners, rest EMG: -80 to 120 (mean=37.2) and -400 to 800 (mean=57.5) after stimuli presentation. Yawners showed larger peak following yawn compared with post-stimuli for non-yawners. Significant supporting evidence for TCH suggests cortisol levels are elevated during yawning. Changes in cortisol levels may become a new diagnostic tool in early diagnosis of neurological symptoms. Bournemouth University Research & Ethics BU-KAPP06-09/13

The use of repeated blood pressure measures for cardiovascular risk prediction: a comparison of statistical models in the ARIC study.

Many prediction models have been developed for the risk assessment and the prevention of cardiovascular disease in primary care. Recent efforts have focused on improving the accuracy of these prediction models by adding novel biomarkers to a common set of baseline risk predictors. Few have considered incorporating repeated measures of the common risk predictors. Through application to the Atherosclerosis Risk in Communities study and simulations, we compare models that use simple summary measures of the repeat information on systolic blood pressure, such as (i) baseline only; (ii) last observation carried forward; and (iii) cumulative mean, against more complex methods that model the repeat information using (iv) ordinary regression calibration; (v) risk-set regression calibration; and (vi) joint longitudinal and survival models. In comparison with the baseline-only model, we observed modest improvements in discrimination and calibration using the cumulative mean of systolic blood pressure, but little further improvement from any of the complex methods. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.J.K.B. was supported by the Medical Research Council grant numbers G0902100 and MR/K014811/1. This work was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The ARIC study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C).This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/sim.714

Uptake and transport of novel amphiphilic polyelectrolyte-insulin nanocomplexes by caco-2 cells - towards oral insulin

“The original publication is available at www.springerlink.com”. Copyright SpringerPurpose: The influence of polymer architecture on cellular uptake and transport across Caco-2 cells of novel amphiphilic polyelectrolyte-insulin nanocomplexes was investigated. Method: Polyallylamine (PAA) (15 kDa) was grafted with palmitoyl chains (Pa) and subsequently modified with quaternary ammonium moieties (QPa). These two amphiphilic polyelectrolytes (APs) were tagged with rhodamine and their uptake by Caco-2 cells or their polyelectrolyte complexes (PECs) with fluorescein isothiocyanate-insulin (FITC-insulin) uptake were investigated using fluorescence microscopy. The integrity of the monolayer was determined by measurement of transepithelial electrical resistance (TEER). Insulin transport through Caco-2 monolayers was determined during TEER experiments. Result: Pa and insulin were co-localised in the cell membranes while QPa complexes were found within the cytoplasm. QPa complex uptake was not affected by calcium, cytochalasin D or nocodazole. Uptake was reduced by co-incubation with sodium azide, an active transport inhibitor. Both polymers opened tight junctions reversibly where the TEER values fell by up to 35 % within 30 minutes incubation with Caco-2 cells. Insulin transport through monolayers increased when QPa was used (0.27 ngmL-1 of insulin in basal compartment) compared to Pa (0.14 ngmL-1 of insulin in basal compartment) after 2 hours. Conclusion: These APs have been shown to be taken up by Caco-2 cells and reversibly open tight cell junctions. Further work is required to optimise these formulations with a view to maximising their potential to facilitate oral delivery of insulin.Peer reviewe

Photon Propagation Around Compact Objects and the Inferred Properties of Thermally Emitting Neutron Stars

Anomalous X-ray pulsars, compact non-pulsing X-ray sources in supernova remnants, and X-ray bursters are three distinct types of sources for which there are viable models that attribute their X-ray emission to thermal emission from the surface of a neutron star. Inferring the surface area of the emitting regions in such systems is crucial in assessing the viability of different models and in providing bounds on the radii of neutron stars. We show that the inferred areas of the emitting regions may be over- or under-estimated by a factor of <=2, because of the geometry of the system and general relativistic light deflection, combined with the effects of phase averaging. Such effects make the determination of neutron-star radii uncertain, especially when compared to the ~5% level required for constraining the equation of state of neutron-star matter. We also note that, for a given spectral shape, the inferred source luminosities and pulse fractions are anticorrelated because they depend on the same properties of the emitting regions, namely their sizes and orientations, i.e., brighter sources have on average weaker pulsation amplitudes than fainter sources. We argue that this property can be used as a diagnostic tool in distinguishing between different spectral models. As an example, we show that the high inferred pulse fraction and brightness of the pulsar RXS J1708-40 are inconsistent with isotropic thermal emission from a neutron-star surface. Finally, we discuss the implication of our results for surveys in the soft X-rays for young, cooling neutron stars in supernova remnants and show that the absence of detectable pulsations from the compact source at the center of Cas A (at a level of >=30%) is not a strong argument againts its identification with a spinning neutron star.Comment: 6 pages, 6 figures, to appear in the Astrophysical Journal; minor change

Bias modelling in evidence synthesis

Policy decisions often require synthesis of evidence from multiple sources, and the source studies typically vary in rigour and in relevance to the target question. We present simple methods of allowing for differences in rigour (or lack of internal bias) and relevance (or lack of external bias) in evidence synthesis. The methods are developed in the context of reanalysing a UK National Institute for Clinical Excellence technology appraisal in antenatal care, which includes eight comparative studies. Many were historically controlled, only one was a randomized trial and doses, populations and outcomes varied between studies and differed from the target UK setting. Using elicited opinion, we construct prior distributions to represent the biases in each study and perform a bias-adjusted meta-analysis. Adjustment had the effect of shifting the combined estimate away from the null by approximately 10%, and the variance of the combined estimate was almost tripled. Our generic bias modelling approach allows decisions to be based on all available evidence, with less rigorous or less relevant studies downweighted by using computationally simple methods

Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways.

BACKGROUND: Mendelian randomization uses genetic variants, assumed to be instrumental variables for a particular exposure, to estimate the causal effect of that exposure on an outcome. If the instrumental variable criteria are satisfied, the resulting estimator is consistent even in the presence of unmeasured confounding and reverse causation. METHODS: We extend the Mendelian randomization paradigm to investigate more complex networks of relationships between variables, in particular where some of the effect of an exposure on the outcome may operate through an intermediate variable (a mediator). If instrumental variables for the exposure and mediator are available, direct and indirect effects of the exposure on the outcome can be estimated, for example using either a regression-based method or structural equation models. The direction of effect between the exposure and a possible mediator can also be assessed. Methods are illustrated in an applied example considering causal relationships between body mass index, C-reactive protein and uric acid. RESULTS: These estimators are consistent in the presence of unmeasured confounding if, in addition to the instrumental variable assumptions, the effects of both the exposure on the mediator and the mediator on the outcome are homogeneous across individuals and linear without interactions. Nevertheless, a simulation study demonstrates that even considerable heterogeneity in these effects does not lead to bias in the estimates. CONCLUSIONS: These methods can be used to estimate direct and indirect causal effects in a mediation setting, and have potential for the investigation of more complex networks between multiple interrelated exposures and disease outcomes

General Relativistic Constraints on Emission Models of Anomalous X-ray Pulsars

Most models of anomalous X-ray pulsars (AXPs) account for the observed X-ray spectra and pulsations by means of radiation processes that occur on the surfaces of neutron stars. For any such model, general relativistic deflection of light severely suppresses the amplitude of the observed pulsations. We calculate the expected pulsation amplitudes of AXPs according to various models and compare the results with observations. We show that the high (<= 70%) pulse amplitudes observed in some AXPs can be accounted for only if the surface emission is localized (spot radius <40 degrees) and strongly beamed (cos^n[theta'] with n>2, where theta' is the angle to the normal). These constraints are incompatible with those cooling and magnetar models in which the observed X-rays originate as thermal emission from the neutron-star surface. Accretion models, on the other hand, are compatible with observations for a wide range of parameters. Finally, definitive conclusions cannot be reached on magnetospheric models, since their localization and beaming properties are not well understood.Comment: 7 pages, 9 figures, submitted to The Astrophysical Journa