Lamellar Structures of MUC2-Rich Mucin: A Potential Role in Governing the Barrier and Lubricating Functions of Intestinal Mucus

Mucus is a ubiquitous feature of mammalian wet epithelial surfaces, where it lubricates and forms a selective barrier that excludes a range of particulates, including pathogens, while hosting a diverse commensal microflora. The major polymeric component of mucus is mucin, a large glycoprotein formed by several MUC gene products, with MUC2 expression dominating intestinal mucus. A satisfactory answer to the question of how these molecules build a dynamic structure capable of playing such a complex role has yet to be found, as recent reports of distinct layers of chemically identical mucin in the colon and anomalously rapid transport of nanoparticles through mucus have emphasized. Here we use atomic force microscopy (AFM) to image a MUC2-rich mucus fraction isolated from pig jejunum. In the freshly isolated mucin fraction, we find direct evidence for trigonally linked structures, and their assembly into lamellar networks with a distribution of pore sizes from 20 to 200 nm. The networks are two-dimensional, with little interaction between lamellae. The existence of persistent cross-links between individual mucin polypeptides is consistent with a non-self-interacting lamellar model for intestinal mucus structure, rather than a physically entangled polymer network. We only observe collapsed entangled structures in purified mucin that has been stored in nonphysiological conditions

The AMBRE Project: Parameterisation of FGK-type stars from the ESO:HARPS archived spectra

The AMBRE project is a collaboration between the European Southern Observatory (ESO) and the Observatoire de la Cote d'Azur (OCA). It has been established to determine the stellar atmospheric parameters (effective temperature, surface gravity, global metallicities and abundance of alpha-elements over iron) of the archived spectra of four ESO spectrographs. The analysis of the ESO:HARPS archived spectra is presented. The sample being analysed (AMBRE:HARPS) covers the period from 2003 to 2010 and is comprised of 126688 scientific spectra corresponding to 17218 different stars. For the analysis of the spectral sample, the automated pipeline developed for the analysis of the AMBRE:FEROS archived spectra has been adapted to the characteristics of the HARPS spectra. Within the pipeline, the stellar parameters are determined by the MATISSE algorithm, developed at OCA for the analysis of large samples of stellar spectra in the framework of galactic archaeology. In the present application, MATISSE uses the AMBRE grid of synthetic spectra, which covers FGKM-type stars for a range of gravities and metallicities. We first determined the radial velocity and its associated error for the ~15% of the AMBRE:HARPS spectra, for which this velocity had not been derived by the ESO:HARPS reduction pipeline. The stellar atmospheric parameters and the associated chemical index [alpha/Fe] with their associated errors have then been estimated for all the spectra of the AMBRE:HARPS archived sample. Based on quality criteria, we accepted and delivered the parameterisation of ~71% of the total sample to ESO. These spectra correspond to ~10706 stars; each are observed between one and several hundred times. This automatic parameterisation of the AMBRE:HARPS spectra shows that the large majority of these stars are cool main-sequence dwarfs with metallicities greater than -0.5 dex

Advanced numerical and statistical techniques to assess erosion and flood risk in coastal zones

Throughout history, coastal zones have been vulnerable to the dual risks of erosion and flooding. With climate change likely to exacerbate these risks in the coming decades, coasts are becoming an ever more critical location on which to apply hydro-morphodynamic models blended with advanced numerical and statistical techniques, to assess risk. We implement a novel depth-averaged hydro-morphodynamic model using a discontinuous Galerkin based finite element discretisation within the coastal ocean model {\em Thetis}. Our model is the first with this discretisation to simulate both bedload and suspended sediment transport, and is validated for test cases in fully wet and wet-dry domains. These test cases show our model is more accurate, efficient and robust than industry-standard models. Additionally, we use our model to implement the first fully flexible and freely available adjoint hydro-morphodynamic model framework which we then successfully use for sensitivity analysis, inversion and calibration of uncertain parameters. Furthermore, we implement the first moving mesh framework with a depth-averaged hydro-morphodynamic model, and show that mesh movement can help resolve the multi-scale issues often present in hydro-morphodynamic problems, improving their accuracy and efficiency. We present the first application of the multilevel Monte Carlo method (MLMC) and multilevel multifidelity Monte Carlo method (MLMF) to industry-standard hydro-morphodynamic models as a tool to quantify uncertainty in erosion and flood risk. We use these methods to estimate expected values and cumulative distributions of variables which are of interest to decision makers. MLMC, and more notably MLMF, significantly reduce computational cost compared to the standard Monte Carlo method whilst retaining the same level of accuracy, enabling in-depth statistical analysis of complex test cases that was previously unfeasible. The comprehensive toolkit of techniques we develop provides a crucial foundation for researchers and stakeholders seeking to assess and mitigate coastal risks in an accurate and efficient manner.Open Acces

First Order Premelting Transition of Vortex Lattices

Vortex lattices in the high temperature superconductors undergo a first order phase transition which has thus far been regarded as melting from a solid to a liquid. We point out an alternative possibility of a two step process in which there is a first order transition from an ordinary vortex lattice to a soft vortex solid followed by another first order melting transition from the soft vortex solid to a vortex liquid. We focus on the first step. This premelting transition is induced by vacancy and interstitial vortex lines. We obtain good agreement with the experimental transition temperature versus field, latent heat, and magnetization jumps for YBCO and BSCCO.Comment: revised version replaces 9705092, 5 pages, Latex, 2 postscript figures, defect line wandering is included, 2 step melting is propose

Haploinsufficiency and the sex chromosomes from yeasts to humans.

BACKGROUND: Haploinsufficient (HI) genes are those for which a reduction in copy number in a diploid from two to one results in significantly reduced fitness. Haploinsufficiency is increasingly implicated in human disease, and so predicting this phenotype could provide insights into the genetic mechanisms behind many human diseases, including some cancers. RESULTS: In the present work we show that orthologues of Saccharomyces cerevisiae HI genes are preferentially retained across the kingdom Fungi, and that the HI genes of S. cerevisiae can be used to predict haploinsufficiency in humans. Our HI gene predictions confirm known associations between haploinsufficiency and genetic disease, and predict several further disorders in which the phenotype may be relevant. Haploinsufficiency is also clearly relevant to the gene-dosage imbalances inherent in eukaryotic sex-determination systems. In S. cerevisiae, HI genes are over-represented on chromosome III, the chromosome that determines yeast's mating type. This may be a device to select against the loss of one copy of chromosome III from a diploid. We found that orthologues of S. cerevisiae HI genes are also over-represented on the mating-type chromosomes of other yeasts and filamentous fungi. In animals with heterogametic sex determination, accumulation of HI genes on the sex chromosomes would compromise fitness in both sexes, given X chromosome inactivation in females. We found that orthologues of S. cerevisiae HI genes are significantly under-represented on the X chromosomes of mammals and of Caenorhabditis elegans. There is no X inactivation in Drosophila melanogaster (increased expression of X in the male is used instead) and, in this species, we found no depletion of orthologues to yeast HI genes on the sex chromosomes. CONCLUSION: A special relationship between HI genes and the sex/mating-type chromosome extends from S. cerevisiae to Homo sapiens, with the microbe being a useful model for species throughout the evolutionary range. Furthermore, haploinsufficiency in yeast can predict the phenotype in higher organisms.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Evaluating the engagement of seldom heard groups in commissioning health services.

This report presents the findings of an evaluation of public engagement (PE) conducted by NHS Sheffield (formally known as Sheffield Primary Care Trust, and referred to in this report as the PCT). The focus of the evaluation was on engagement with “harder to reach” or “seldom heard” communities to inform the World Class Commissioning decisions made by the PCT (Department of Health, 2007). The evaluation took place between December 2008 and August 2009 and was conducted by a small team at Sheffield Hallam University. With World Class Commissioning the obligation for the PCT to engage with the public and health service users, and to be equitable in this activity, came together under a banner of commissioning (Department of Health, 2007). This is aligned with a commitment to the involvement of citizens in order to drive up the efficiency or effectiveness of services, improve health and meet personalisation and patient-centred care targets. (Department of Health 2006, 2008). Nationally the status and nature of public engagement has increased. However, PCTs are struggling with engagement of seldom heard groups, and demonstrating how public engagement impacts upon commissioning decisions

Multiple frequencies in the basal ganglia in Parkinson's disease

In recent years, the authors have developed what appears to be a very successful phenomenological model for analyzing the role of deep brain stimulation (DBS) in alleviating the symptoms of Parkinson's disease. In this paper, we extend the scope of the model by using it to predict the generation of new frequencies from networks tuned to a specific frequency, or indeed not self-oscillatory at all. We have discussed two principal cases: firstly where the constituent systems are coupled in an excitatory-excitatory fashion, which we designate by ``+/+''; and secondly where the constituent systems are coupled in an excitatory-inhibitory fashion, which we designate ``+/-''. The model predicts that from a basic system tuned to tremor frequency we can generate an unlimited range of frequencies. We illustrate in particular, starting from systems which are initially non-oscillatory, that when the coupling coefficient exceeds a certain value, the system begins to oscillate at an amplitude which increases with the coupling strength. Another very interesting feature, which has been shown by colleagues of ours to arise through the coupling of complicated networks based on the physiology of the basal ganglia, can be illustrated by the root locus method which shows that increasing and decreasing frequencies of oscillation, existing simultaneously, have the property that their geometric mean remains substantially constant as the coupling strength is varied. We feel that with the present approach, we have provided another tool for understanding the existence and interaction of pathological oscillations which underlie, not only Parkinson's disease, but other conditions such as Tourette's syndrome, depression and epilepsy

Chronology Protection in Galileon Models and Massive Gravity

Galileon models are a class of effective field theories that have recently received much attention. They arise in the decoupling limit of theories of massive gravity, and in some cases they have been treated in their own right as scalar field theories with a specific nonlinearly realized global symmetry (Galilean transformation). It is well known that in the presence of a source, these Galileon theories admit superluminal propagating solutions, implying that as quantum field theories they must admit a different notion of causality than standard local Lorentz invariant theories. We show that in these theories it is easy to construct closed timelike curves (CTCs) within the {\it naive} regime of validity of the effective field theory. However, on closer inspection we see that the CTCs could never arise since the Galileon inevitably becomes infinitely strongly coupled at the onset of the formation of a CTC. This implies an infinite amount of backreaction, first on the background for the Galileon field, signaling the break down of the effective field theory, and subsequently on the spacetime geometry, forbidding the formation of the CTC. Furthermore the background solution required to create CTCs becomes unstable with an arbitrarily fast decay time. Thus Galileon theories satisfy a direct analogue of Hawking's chronology protection conjecture.Comment: 34 pages, no figure

Family in Rehabilitation, Empowering Carers for Improved Malnutrition Outcomes: Protocol for the FREER Pilot Study

Interventions to improve the nutritional status of older adults and the integration of formal and family care systems are critical research areas to improve the independence and health of aging communities and are particularly relevant in the rehabilitation setting.The primary outcome aimed to determine if the FREER (Family in Rehabilitation: EmpowERing Carers for improved malnutrition outcomes) intervention in malnourished older adults during and postrehabilitation improve nutritional status, physical function, quality of life, service satisfaction, and hospital and aged care admission rates up to 3 months postdischarge, compared with usual care. Secondary outcomes evaluated include family carer burden, carer services satisfaction, and patient and carer experiences. This pilot study will also assess feasibility and intervention fidelity to inform a larger randomized controlled trial.This protocol is for a mixed-methods two-arm historically-controlled prospective pilot study intervention. The historical control group has 30 participants, and the pilot intervention group aims to recruit 30 patient-carer pairs. The FREER intervention delivers nutrition counseling during rehabilitation, 3 months of postdischarge telehealth follow-up, and provides supportive resources using a novel model of patient-centered and carer-centered nutrition care. The primary outcome is nutritional status measured by the Scored Patient-Generated Subjective Global Assessment Score. Qualitative outcomes such as experiences and perceptions of value will be measured using semistructured interviews followed by thematic analysis. The process evaluation addresses intervention fidelity and feasibility.Recruitment commenced on July 4, 2018, and is ongoing with eight patient-carer pairs recruited at the time of manuscript submission.This research will inform a larger randomized controlled trial, with potential for translation to health service policies and new models of dietetic care to support the optimization of nutritional status across a continuum of nutrition care from rehabilitation to home.Australian New Zealand Clinical Trials Registry Number (ACTRN) 12618000338268; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374608&isReview=true (Archived by WebCite at http://www.webcitation.org/74gtZplU2).DERR1-10.2196/12647