Natural killer cells in placentation and cancer: Implications for hypertension during pregnancy

Hypertension during pregnancy is the most common medical condition encountered during gestation. Despite this, knowledge of the mechanisms that underlie the disease and the development of new therapies are limited. Hypertension during pregnancy and some forms of cancer confer an increased risk to the development of cardiovascular disease later in life; one mechanism which may link these conditions is the involvement of natural killer (NK) cells. Whilst immunology and immunotherapy are well-developed areas in oncology; the complex mechanisms of the immune system in health and disease at the maternal-fetal interface are less well-defined. Natural killer (NK) cells have emerged as key immune cells involved in physiology and pathology of pregnancy. These small lymphocytes are present in the decidua (the uterine-specific uNK cells) and are distinct from peripheral NK cells. The uNK cell population plays a vital role in mediating trophoblast invasion and affecting decidual vascular remodelling whereas the role of the peripheral NK cell population during pregnancy is less well-defined. This review will give an overview of NK cell biology followed by a discussion of the current evidence for the role of uterine and peripheral NK cells at the maternal-fetal interface in health and disease. Furthermore, examples of NK cell research from cancer biology will be employed to inform future directions of research. By combining this knowledge from oncology where the field of immunotherapy has now matured into clinical trials; it is hopeful that new mechanisms can be elucidated to generate targets for similar therapeutic strategies for women with hypertensive pregnancies where interventions are needed

Complex metaprobe production and characterisation for metabolic studies in relation to bowel health

Introduction - Colorectal cancer is the third most common cancer in the UK and the second most common cause of cancer mortality. There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. The Glasgow Prognostic Score includes a measure of systemic inflammatory response and has been used successfully as a predictor of survival rate in cancer patients. Butyric acid is one of the short chain fatty acids (SCFA) produced by colonic bacteria through fermentation of dietary non-digestible carbohydrate (NDC). This simple organic acid is known to have anti-inflammatory and possibly direct anti-neoplastic effects. The inaccessibility of the human colon means that little is known of the in vivo rate of butyrate production, its metabolic fate or the foodstuffs that may maximise its production. Butyrate may be produced in greater quantities from other SCFA such as acetate and lactate rather than by direct production by saccharolytic bacteria. Specialist organisms may be responsible for producing butyrate through conversion of other SCFA which are produced by fermentation in the colon. The distal site of butyrate production may be a very important feature and the implication that slowly fermentable NDC, such as resistant starch, may be significant. Previous Work - The European Union project EUROSTARCH (www.eurostarch.org) investigated the way in which different starchy foods are digested and metabolised within the body. The results of this project have informed the development of low GI foods. Results have also increased our knowledge of NDC fermentation and promise to lead to improvements in human bowel health. We pioneered the measurement of starch digestion and fermentation during this project. What are Metaprobes? The term metaprobe is used to describe stable isotope labelled tracers. Complex metaprobes are produced by biological synthesis e.g. the introduction of 13C enriched CO2 gas during the production of crops. Simple metaprobes are produced by chemical synthesis e.g. urea. We can produce complex metaprobes by labelling staple foods such as cereals using the stable isotope 13C incorporated from enriched 13CO2 during anthesis of the crops. Complex metaprobes are unique tools with which to study human metabolism in health and disease and they can be used in several ways. The labelled cereals allow in vivo measurement of butyrate production from dietary NDC and to permit its production to be monitored. Hypothesis - 30% of cancer deaths in the UK are bowel related. Butyric acid produced naturally through fermentation of dietary carbohydrates, is a potent and natural anti-inflammatory agent which can protect against cancer. We urgently need to develop methods to quantify butyrate production in vivo. Aims - Three aims are recognised: optimising the preparation of complex metaprobes of barley and wheat grain; optimising yield and 13C-enrichment of whole grain and its starch and protein fractions; using complex metaprobes to compare SCFA production in vivo. Plan of Work - This project will include a review of complex metaprobe production for human nutrition and health studies in relation to bowel health. The practical work will include production and characterisation of complex metaprobes (13C-labelled cereals) and their application to study butyrate production in a pilot study on volunteer human subjects. I have successfully grown cereal crops with different varieties of barley and wheat in glasshouse conditions. During the anthesis phase, the plants were placed in growth cabinets at 18oC with 18 hours of light in every 24 hours. The plants were labelled using 13C enriched CO2 gas and are incubated for a further 24 hours and returned to the glasshouse. Examples of the harvest are Wheat var Paragon produced 1.7 Kg labelled grain at 0.278 ape 13C enrichment and Barley var Cellar produced 3.4 Kg labelled grain at 0.198 ape 13C enrichment. Some of the 13C labelled grain has already been used for human nutrition studies. The 13C-enrichment of starch glucose has been measured by liquid chromatography isotope ratio mass spectrometry (LC-IRMS) analysis. These cereal grains can be incorporated into common foodstuffs for in vivo studies of the production of butyrate and other SCFA. Volunteers were fed two meals made from 13C-enriched barley grain: porridge and whole grain barley. Whole grains being rich in resistant starch. Samples of urine will be used to measure butyrate production. Breath samples will be used to measure oxidation of the 13C-enriched barley, which is a global measure of digestion and fermentation. Laboratory procedures such as ultrafiltration and solid phase extraction will be applied to urine samples. These sample preparation procedures will be followed by SCFA analysis by GC-IRMS. Future Direction - Future clinical trials will be considered with Prof Donald C McMillan, University Dept of Surgery, Glasgow Royal Infirmary as a means of identifying the role of butyrate in colonic cancer. The current screening process recognises three phases: early stage diagnosis; polyp development; diagnosis and treatment of advance stage colonic cancer. We wish to study the role of butyrate and its production using our newly developed complex metaprobe tools

Detecting periodicity in experimental data using linear modeling techniques

Fourier spectral estimates and, to a lesser extent, the autocorrelation function are the primary tools to detect periodicities in experimental data in the physical and biological sciences. We propose a new method which is more reliable than traditional techniques, and is able to make clear identification of periodic behavior when traditional techniques do not. This technique is based on an information theoretic reduction of linear (autoregressive) models so that only the essential features of an autoregressive model are retained. These models we call reduced autoregressive models (RARM). The essential features of reduced autoregressive models include any periodicity present in the data. We provide theoretical and numerical evidence from both experimental and artificial data, to demonstrate that this technique will reliably detect periodicities if and only if they are present in the data. There are strong information theoretic arguments to support the statement that RARM detects periodicities if they are present. Surrogate data techniques are used to ensure the converse. Furthermore, our calculations demonstrate that RARM is more robust, more accurate, and more sensitive, than traditional spectral techniques.Comment: 10 pages (revtex) and 6 figures. To appear in Phys Rev E. Modified styl

GEMPAK: An arbitrary aircraft geometry generator

A computer program, GEMPAK, has been developed to aid in the generation of detailed configuration geometry. The program was written to allow the user as much flexibility as possible in his choices of configurations and the detail of description desired and at the same time keep input requirements and program turnaround and cost to a minimum. The program consists of routines that generate fuselage and planar-surface (winglike) geometry and a routine that will determine the true intersection of all components with the fuselage. This paper describes the methods by which the various geometries are generated and provides input description with sample input and output. Also included are descriptions of the primary program variables and functions performed by the various routines. The FORTRAN program GEMPAK has been used extensively in conjunction with interfaces to several aerodynamic and plotting computer programs and has proven to be an effective aid in the preliminary design phase of aircraft configurations

Multi-Player Diffusion Games on Graph Classes

We study competitive diffusion games on graphs introduced by Alon et al. [1] to model the spread of influence in social networks. Extending results of Roshanbin [8] for two players, we investigate the existence of pure Nash equilibria for at least three players on different classes of graphs including paths, cycles, grid graphs and hypercubes; as a main contribution, we answer an open question proving that there is no Nash equilibrium for three players on (m x n) grids with min(m, n) >= 5. Further, extending results of Etesami and Basar [3] for two players, we prove the existence of pure Nash equilibria for four players on every d-dimensional hypercube.Comment: Extended version of the TAMC 2015 conference version now discussing hypercube results (added details for the proof of Proposition 1

Estimating the distribution of dynamic invariants: illustrated with an application to human photo-plethysmographic time series

Dynamic invariants are often estimated from experimental time series with the aim of differentiating between different physical states in the underlying system. The most popular schemes for estimating dynamic invariants are capable of estimating confidence intervals, however, such confidence intervals do not reflect variability in the underlying dynamics. We propose a surrogate based method to estimate the expected distribution of values under the null hypothesis that the underlying deterministic dynamics are stationary. We demonstrate the application of this method by considering four recordings of human pulse waveforms in differing physiological states and show that correlation dimension and entropy are insufficient to differentiate between these states. In contrast, algorithmic complexity can clearly differentiate between all four rhythms

Time transfer between the Goddard Optical Research Facility and the U.S. Naval Observatory using 100 picosecond laser pulses

A horizontal two-way time comparison link in air between the University of Maryland laser ranging and time transfer equipment at the Goddard Optical Research Facility (GORF) 1.2 m telescope and the Time Services Division of the U.S. Naval Observatory (USNO) was established. Flat mirrors of 25 cm and 30 cm diameter respectively were placed on top of the Washington Cathedral and on a water tower at the Beltsville Agricultural Research Center. Two optical corner reflectors at the USNO reflect the laser pulses back to the GORF. Light pulses of 100 ps duration and an energy of several hundred microjoules are sent at the rate of 10 pulses per second. The detection at the USNO is by means of an RCA C30902E avalanche photodiode and the timing is accomplished by an HP 5370A computing counter and an HP 1000 computer with respect to a 10 pps pulse train from the Master Clock

A Dose Relationship Between Brain Functional Connectivity and Cumulative Head Impact Exposure in Collegiate Water Polo Players.

A growing body of evidence suggests that chronic, sport-related head impact exposure can impair brain functional integration and brain structure and function. Evidence of a robust inverse relationship between the frequency and magnitude of repeated head impacts and disturbed brain network function is needed to strengthen an argument for causality. In pursuing such a relationship, we used cap-worn inertial sensors to measure the frequency and magnitude of head impacts sustained by eighteen intercollegiate water polo athletes monitored over a single season of play. Participants were evaluated before and after the season using computerized cognitive tests of inhibitory control and resting electroencephalography. Greater head impact exposure was associated with increased phase synchrony [r (16) > 0.626, p < 0.03 corrected], global efficiency [r (16) > 0.601, p < 0.04 corrected], and mean clustering coefficient [r (16) > 0.625, p < 0.03 corrected] in the functional networks formed by slow-wave (delta, theta) oscillations. Head impact exposure was not associated with changes in performance on the inhibitory control tasks. However, those with the greatest impact exposure showed an association between changes in resting-state connectivity and a dissociation between performance on the tasks after the season [r (16) = 0.481, p = 0.043] that could also be attributed to increased slow-wave synchrony [F (4, 135) = 113.546, p < 0.001]. Collectively, our results suggest that athletes sustaining the greatest head impact exposure exhibited changes in whole-brain functional connectivity that were associated with altered information processing and inhibitory control

Medical recipients of the Victoria cross during the Anglo-Boer war, 1899 -1902

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