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The enteroendocrine system is located in the gastrointestinal (GI) tract, and makes up the largest endocrine system in the human body. Despite that, its roles and functions remain incompletely understood. Gut regulatory peptides are the main products of enteroendocrine cells, and play an integral role in the digestion and absorption of nutrients through their effect on intestinal secretions and gut motility. Several peptides, such as cholecystokinin, polypeptide YY and glucagon-like peptide-1, have traditionally been reported to suppress appetite following food intake, so-called satiety hormones. In this review, we propose that, in the healthy individual, this system to regulate appetite does not play a dominant role in normal food intake regulation, and that there is insufficient evidence to wholly link postprandial endogenous gut peptides with appetite-related behaviours. Instead, or additionally, top-down, hedonic drive and neurocognitive factors may have more of an impact on food intake. In GI disease however, supraphysiological levels of these hormones may have more of an impact on appetite regulation as well as contributing to other unpleasant abdominal symptoms, potentially as part of an innate response to injury. Further work is required to better understand the mechanisms involved in appetite control and unlock the therapeutic potential offered by the enteroendocrine system in GI disease and obesity.
The deep subsurface of other planetary bodies is of special interest for robotic and human exploration. The subsurface provides access to planetary interior processes, thus yielding insights into planetary formation and evolution. On Mars, the subsurface might harbour the most habitable conditions. In the context of human exploration, the subsurface can provide refugia for habitation from extreme surface conditions. We describe the fifth Mine Analogue Research (MINAR 5) programme at 1 km depth in the Boulby Mine, UK in collaboration with Spaceward Bound NASA and the Kalam Centre, India, to test instruments and methods for the robotic and human exploration of deep environments on the Moon and Mars. The geological context in Permian evaporites provides an analogue to evaporitic materials on other planetary bodies such as Mars. A wide range of sample acquisition instruments (NASA drills, Small Planetary Impulse Tool (SPLIT) robotic hammer, universal sampling bags), analytical instruments (Raman spectroscopy, Close-Up Imager, Minion DNA sequencing technology, methane stable isotope analysis, biomolecule and metabolic life detection instruments) and environmental monitoring equipment (passive air particle sampler, particle detectors and environmental monitoring equipment) was deployed in an integrated campaign. Investigations included studying the geochemical signatures of chloride and sulphate evaporitic minerals, testing methods for life detection and planetary protection around human-tended operations, and investigations on the radiation environment of the deep subsurface. The MINAR analogue activity occurs in an active mine, showing how the development of space exploration technology can be used to contribute to addressing immediate Earth-based challenges. During the campaign, in collaboration with European Space Agency (ESA), MINAR was used for astronaut familiarization with future exploration tools and techniques. The campaign was used to develop primary and secondary school and primary to secondary transition curriculum materials on-site during the campaign which was focused on a classroom extra vehicular activity simulation.
OBJECTIVES/SPECIFIC AIMS: The aims of this study are 2-fold: (1) to determine if maternal schistosomiasis affects maternal immunity to tetanus and/or transplacental transfer of antitetanus toxoid (TT) immunoglobulin G (IgG) from mother to infant and (2) determine the influence of maternal schistosomiasis on infant BCG vaccine immunogenicity. METHODS/STUDY POPULATION: The study will utilize blood samples from a historic cohort of 100 mother-infant pairs from Kisumu, Kenya, a schistosomiasis-endemic area. For the first aim, we will evaluate maternal schistosomal circulating anodic antigen, which has improved sensitivity and specificity to detect active schistosomiasis from serum, and antisoluble egg antigen IgG positivity compared with quantitative maternal anti-TT IgG at delivery and anti-TT IgG cord blood to maternal blood ratio (cord:maternal ratio). For the second aim, we will evaluate association between maternal schistosomiasis as detected by circulating anodic antigen and antisoluble egg antigen IgG at delivery and infant BCG-specific Th1-cytokine positive CD4+ cells at 10 weeks following BCG vaccination at birth. RESULTS/ANTICIPATED RESULTS: We hypothesize that active maternal schistosomiasis will be associated with decreased maternal anti-TT IgG and reduced efficiency of transplacental transfer, as measured by infant cord blood to maternal blood ratio of anti-TT IgG. We also expect that maternal schistosomiasis will be associated with decreased infant immunogenicity to BCG vaccine. DISCUSSION/SIGNIFICANCE OF IMPACT: This is a formative study on infant vaccine immunity using laboratory methodology not previously applied. Understanding infant immunity in the setting of maternal schistosomiasis will inform vaccination strategies and tailor vaccine development in schistosome-endemic areas such as Kenya, where neither TB nor neonatal tetanus have been eradicated. Additionally, our results will inform public health policies to consider integration of antischistosomal agents in antenatal care.
Traumatic events are associated with increased risk of psychotic experiences, but it is unclear whether this association is explained by mental disorders prior to psychotic experience onset.
To investigate the associations between traumatic events and subsequent psychotic experience onset after adjusting for post-traumatic stress disorder and other mental disorders.
We assessed 29 traumatic event types and psychotic experiences from the World Mental Health surveys and examined the associations of traumatic events with subsequent psychotic experience onset with and without adjustments for mental disorders.
Respondents with any traumatic events had three times the odds of other respondents of subsequently developing psychotic experiences (OR=3.1, 95% CI 2.7–3.7), with variability in strength of association across traumatic event types. These associations persisted after adjustment for mental disorders.
Exposure to traumatic events predicts subsequent onset of psychotic experiences even after adjusting for comorbid mental disorders.
This article describes a formal proof of the Kepler conjecture on dense sphere packings in a combination of the HOL Light and Isabelle proof assistants. This paper constitutes the official published account of the now completed Flyspeck project.
Impairments in learning and recall have been well established in amnestic mild cognitive impairment (aMCI). However, a relative dearth of studies has examined the profiles of memory strategy use in persons with aMCI relative to those with Alzheimer's disease (AD). Participants with aMCI, nonamnestic MCI, AD, and healthy older adults were administered the California Verbal Learning Test-II (CVLT-II). Measures of semantic clustering and recall were obtained across learning and delayed recall trials. In addition, we investigated whether deficits in semantic clustering were related to progression from healthy aging to aMCI and from aMCI to AD. The aMCI group displayed similar semantic clustering performance as the AD participants, whereas the AD group showed greater impairments on recall relative to the aMCI participants. Control participants who progressed to aMCI showed reduced semantic clustering at the short delay at baseline compared to individuals who remained diagnostically stable across follow-up visits. These findings show that the ability to engage in an effective memory strategy is compromised in aMCI, before AD has developed, suggesting that disruptions in semantic networks are an early marker of the disease. (JINS, 2014, 20, 1–11)
Several N-nitroso compounds (NOC) have been shown to be carcinogenic in a variety of laboratory animals, but evidence of their carcinogenicity in humans is lacking. We aimed to examine the association between NOC intake and colorectal cancer (CRC) risk and possible effect modification by vitamins C and E and protein in a large case–control study carried out in Newfoundland and Labrador and Ontario, Canada. A total of 1760 case patients with pathologically confirmed adenocarcinoma and 2481 population controls were asked to complete a self-administered FFQ to evaluate their dietary intakes 1 year before diagnosis (for cases) or interview (for controls). Adjusted OR and 95 % CI were calculated across the quintiles of NOC (measured by N-nitrosodimethylamine (NDMA)) intake and relevant food items using unconditional logistic regression. NDMA intake was found to be associated with a higher risk of CRC (highest v. lowest quintiles: OR 1·42, 95 % CI 1·03, 1·96; P for trend = 0·005), specifically for rectal carcinoma (OR 1·61, 95 % CI 1·11, 2·35; P for trend = 0·01). CRC risk also increased with the consumption of NDMA-containing meats when the highest tertile was compared with the lowest tertile (OR 1·47, 95 % CI 1·03, 2·10; P for trend = 0·20). There was evidence of effect modification between dietary vitamin E and NDMA. Individuals with high NDMA and low vitamin E intakes had a significantly increased risk than those with both low NDMA and low vitamin E intakes (OR 3·01, 95 % CI 1·43, 6·51; P for interaction = 0·017). The present results support the hypothesis that NOC intake may be positively associated with CRC risk in humans. Vitamin E, which inhibits nitrosation, could modify the effect of NDMA on CRC risk.
The goal of this brief review is to address the role of the ageing gut in the genesis of malnutrition in the elderly. We assess the burden of malnutrition in the elderly, exploring the role of comorbid conditions and neurohumoral changes that take place to contribute towards the process of anorexia associated with ageing. Following this, the review assesses physiological changes that occur in each part of the gastrointestinal (GI) tract and what implication they may have in clinical practice. In the oropharynx and the oesophagus, changes in swallowing and oesophageal motility associated with ageing can be demonstrated using physiological testing. However, in the absence of comorbid disease, they often have little, if any, clinical significance. In the stomach, reduced fundal compliance may contribute to early satiety; however, the primary change is hypochlorhydria, which may predispose to malabsorption or bacterial overgrowth further along the GI tract. Almost uniquely, the small bowel, particularly its absorptive function, is unaffected by age and we review the literature demonstrating this. In the colon, there is evidence of a prolonged transit time related to a reduction in both neurotransmitters and receptors. Although this may cause symptoms, this aspect is unlikely to contribute to malnutrition. In addition, we assess the potential changes in the gut microbiome and how this may interact with the immune system in the process of ‘inflamm-ageing’. We conclude by summarising the main changes and their impact for the clinician along with recommendations for future areas of research.
The discovery of a pulsar or pulsars orbiting near the Galactic Center (GC) could offer an unprecedented probe of strong-field gravity, the properties of our galaxy's supermassive black hole and insights into the paradoxical star formation history of the region. However, searching for pulsars near the GC is severely hampered by the large electron densities along our line of sight and the scattering-induced pulse broadening of the pulsar emission observed through it. As the broadened pulse length approaches the pulsar period, the periodicity in pulsar emission becomes nearly undetectable. Searches extended to higher frequencies, in an effort to reduce scattering, suffer from reduced intrinsic flux, higher system temperatures and increased atmospheric opacity. We are currently attempting to mitigate the challenges associated with searching for pulsars near the GC by employing new wide bandwidth receivers, upgraded IF distribution systems and novel digital spectrometers in a GC pulsar search campaign at the Green Bank Telescope in West Virginia, USA.
Our search will cover two frequency bands, from 12-15 GHz (Ku Band) and 18-26 GHz (K Band), during a total of approximately 30 hours of observations, with expected characteristic 10-sigma sensitivities between 5-10 micro-Jy. Our first observations are scheduled for mid-March 2012. Here we will present the status of our observations and initial results.
The success of urban salt marsh restoration depends upon an understanding of the local tidal regime and hydrologic conditions. Reference wetland characteristics can provide biological and physical restoration baselines for a restoration design through the use of techniques such as bio-benchmarking and geomorphologic assessment. Reference site vegetation can be used as indirect indicators of local tidal elevations and duration of flooding of each tidal zone. Reference sites can also provide landscape allometry to generate geomorphologic ratios that can be applied to the restoration site. Through the use of field measurements, aerial photographs, and GIS technology, relationships can be identified for tidal channel width, depth, diurnal tidal prism, and marsh area. Calculating a hydrologic budget for freshwater is critical to estimate salinity concentrations and their effect on the restoration wetland. This information, along with field measurements of salinity, can be used to predict salinity ranges resulting from the interaction of freshwater sources and will help determine the target vegetation communities. Preconstruction planning is not always sufficient to understand site conditions, especially in urban areas. Flexibility in design, even during the construction phase, may be required to assure project success. During excavation of fill, conditions were found at specific locations that would reduce the likelihood of reestablishing historic functions and values of the tidal marsh. Designs were altered at one low marsh area, which was redesigned as mudflat; and a second low marsh area that was changed to a freshwater fen.
Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders.
To examine joint associations of 12 childhood adversities with first onset of 20 DSM–IV disorders in World Mental Health (WMH) Surveys in 21 countries.
Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM–IV disorders with the WHO Composite International Diagnostic Interview (CIDI).
Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries.
Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.
This study is concerned with the effects of particle–particle collisions and the two-way coupling on the dispersed and carrier phase turbulence fluctuations in a channel flow. The time history of the instantaneous turbulent velocity vector was generated by the two-way coupled direct numerical simulation of the Navier–Stokes equations via a pseudo-spectral method. The particle equation of motion included the wall-corrected nonlinear drag force and the wall-induced and shear-induced lift force. The effect of particles on the flow was included in the analysis via a feedback force that acted on the computational grid points. Several simulations for different particle relaxation times and particle mass loadings were performed, and the effects of particle–particle collisions, particle feedback force and inter-particle interactions on the particle deposition velocity, fluid and particle fluctuating velocities, and particle concentration profiles were determined. The effect of particle aerodynamic interactions was also examined for certain cases.
The simulation results indicated that when particle–particle collisions were included in the computation but two-way coupling effects were ignored, the particle normal fluctuating velocity increased in the wall region causing an increase in the particle deposition velocity. When the particle collisions were neglected but the particle–fluid two-way coupling effects were accounted for, the two-way coupling and the particle normal fluctuating velocity decreased near the wall causing a decrease in the particle deposition velocity. In the case of the four-way coupling in which both inter-particle collisions and two-way coupling effects were present, it was found that the particle deposition velocity increased compared with the one-way coupling case. When the particle aerodynamic interactions were added to the four-way coupled case (termed six-way coupled case), no significant changes in the mean fluid and particle velocities and the fluid and particle fluctuating velocities were obtained.
The results for the particle concentration profile indicated that the inclusion of two-way coupling or inter-particle collisions into the computation reduced the accumulation of particles near the wall. It was also observed that particle–particle collisions and two-way coupling weakened the preferential distribution of particles.
Sonal Patel, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
Joanne Garver, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
Michael Gallo, Epic Therapeutics, Inc. 220 Norwood Park Norwood, MA 02062 USA,
Maria Hackett, Novartis Institutes for Biomedical Research 250 Massachusetts Avenue Cambridge, MA 02139 USA,
Stephen McLaughlin, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
Steven R. Gullans, RxGen, Inc. New Haven, CT USA,
Mark Nadel, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
John Harris, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
Duncan Whitney, US Genomics, Inc. 12 Gill Street, Suite 4700 Woburn, MA 01801 USA,
Lori A. Neely, Technology & Pre-Development Millipore Corp. 80 Ashby Rd. Bedford, MA 01730 USA
Deemed the “breakthrough of the year” by Science magazine in 2002, research into the biology of small RNA regulation has grown exponentially in recent years; however, the field is relatively nascent in terms of identifying and characterizing the universe of miRNAs and their expression in various biological states. According to the miRNA registry (release 6.0, www.sanger.ac.uk/Software/Rfam/mirna/index.shtml); of the 319 predicted human miRNAs the expressions of 234 have been experimentally verified by Northern blot, cloning, or microarray. Further, the total number of miRNAs within a genome is unknown. Thus, sensitive, specific, quantitative, and rapid methods for measuring the expression levels of miRNAs would significantly advance the field.
The short 21 nucleotide nature of these molecules makes them difficult to study via conventional techniques. They are not easily amplified which makes miRNA microarrays and quantitative PCR technically challenging. Despite these challenges, several groups have undertaken miRNA microarray studies to quantify miRNA gene expression. Their approaches are similar in requiring up-front enrichment for small RNAs, reverse transcription, PCR amplification, labeling, and clean-up steps. While the arrays are superior at large scale screening they lack the ability to finely discriminate expression levels and are at best semi-quantitative. Theoretically the most sensitive technique to quantify miRNAs is reverse transcription RT-PCR (real time RT-PCR). However, this method is difficult in both assay (probe) design and execution. Tissue samples must be devoid of enzyme inhibitors to enable efficient reverse transcription and amplification steps (Tichopad et al., 2004).
This paper summarises the way equality has featured in the disciplines of social policy and political theory leading up to the presentation of a new egalitarianian framework for thinking about and acting for equality. The paper presents a broadly chronological, integrated review of the place of equality within the subjects concerned. The longstanding problems of universalism and targeting are themes which recur throughout, and in New Labour's approach to equality and social justice.