發作性血色素尿症ニ就テ

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain and exists in two functional stoichiometries: (α4)3(β2)2 and (α4)2(β2)3. A distinct feature of the (α4)3(β2)2 receptor is the biphasic activation response to the endogenous agonist acetylcholine, where it is activated with high potency and low efficacy when two α4-β2 binding sites are occupied and with low potency/high efficacy when a third α4-α4 binding site is occupied. Further, exogenous ligands can bind to the third α4-α4 binding site and potentiate the activation of the receptor by ACh that is bound at the two α4-β2 sites. We propose that perturbations of the recently described pre-activation step when a third binding site is occupied are a key driver of these distinct activation properties. To investigate this, we used a combination of simple linear kinetic models and voltage clamp electrophysiology to determine whether transitions into the pre-activated state were increased when three binding sites were occupied. We separated the binding at the two different sites with ligands selective for the α4-β2 site (Sazetidine-A and TC-2559) and the α4-α4 site (NS9283) and identified that when a third binding site was occupied, changes in the concentration-response curves were best explained by an increase in transitions into a pre-activated state. We propose that perturbations of transitions into a pre-activated state are essential to explain the activation properties of the (α4)3(β2)2 receptor by acetylcholine and other ligands. Considering the widespread clinical use of benzodiazepines, this discovery of a conserved mechanism that benzodiazepines and ACh potentiate receptor activation via a third binding site can be exploited to develop therapeutics with similar properties at other cys-loop receptors

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

LRRK2 protein is expressed prominently in immune cells, cell types whose contribution to LRRK2-associated genetic Parkinson's disease (PD) is increasingly being recognised. We investigated the effect of inflammatory stimuli using RAW264.7 murine macrophage cells as model systems. A detailed time course of TLR2 and TLR4 stimulation was investigated through measuring LRRK2 phosphorylation at its specific phospho-sites, and Rab8 and Rab10 phosphorylation together with cytokine release following treatment with LPS and zymosan. LRRK2 phosphorylation at Ser935, Ser955 and Ser973 was increased significantly over untreated conditions at 4-24h in both WT-LRRK2 and T1348N-LRRK2 cell lines to similar extents although levels of Ser910 phosphorylation were maintained at higher levels throughout. Importantly we demonstrate that LPS stimulation significantly decreased phospho-Rab10 but not phospho-Rab8 levels over 4-24h in both WT-LRRK2 and T1348N-LRRK2 cell lines. The dephosphorylation of Rab10 was not attributed to its specific phosphatase, PPM1H as the levels remained unaltered with LPS treatment. MAPK phosphorylation occurred prior to LRRK2 phosphorylation which was validated by blocking TLR4 and TLR2 receptors with TAK242 or Sparstolonin B respectively. A significant decrease in basal level of TNFα release was noted in both T1348N-LRRK2 and KO-LRRK2 cell lines at 48h compared to WT-LRRK2 cell line, however LPS and zymosan treatment did not cause any significant alteration in the TNFα and IL-6 release between the three cell lines. In contrast, LPS and zymosan caused significantly lower IL-10 release in T1348N-LRRK2 and KO-LRRK2 cell lines. A significant decrease in phospho-Rab10 levels was also confirmed in human IPS-derived macrophages with TLR4 activation. Our data demonstrates for the first time that LRRK2-dependent Rab10 phosphorylation is modulated by LPS stimulation, and that cytokine release may be influenced by the status of LRRK2. These data provide further insights into the function of LRRK2 in immune response, and has relevance for understanding cellular dysfunctions when developing LRRK2-based inhibitors for clinical treatment

On the origin of ambiguity in efficient communication

This article studies the emergence of ambiguity in communication through the concept of logical irreversibility and within the framework of Shannon's information theory. This leads us to a precise and general expression of the intuition behind Zipf's vocabulary balance in terms of a symmetry equation between the complexities of the coding and the decoding processes that imposes an unavoidable amount of logical uncertainty in natural communication. Accordingly, the emergence of irreversible computations is required if the complexities of the coding and the decoding processes are balanced in a symmetric scenario, which means that the emergence of ambiguous codes is a necessary condition for natural communication to succeed.Comment: 28 pages, 2 figure

Incontinence-associated dermatitis: reducing adverse events

Incontinence-associated dermatitis (IAD) is a common problem in patients with faecal and/or urinary incontinence. Urine alters the normal skin flora and increases permeability of the stratum corneum and faecal enzymes on the skin contribute to skin damage. Faecal bacteria can then penetrate the skin, increasing the risk of secondary infection. However, IAD can be prevented and healed with timely and appropriate skin cleansing and skin protection. This includes appropriate use of containment devices. This article also looks at HARTMANN incontinence pads that have been developed to absorb the fluids that cause IAD and maintain the skin's acidic pH. The acidic pH of the skin contributes to its barrier function and defence against infection. Therefore, maintaining an acidic pH will help protect the skin from damage

Embedded Microbubbles for Acoustic Manipulation of Single Cells and Microfluidic Applications.

Acoustically excited microstructures have demonstrated significant potential for small-scale biomedical applications by overcoming major microfluidic limitations. Recently, the application of oscillating microbubbles has demonstrated their superiority over acoustically excited solid structures due to their enhanced acoustic streaming at low input power. However, their limited temporal stability hinders their direct applicability for industrial or clinical purposes. Here, we introduce the embedded microbubble, a novel acoustofluidic design based on the combination of solid structures (poly(dimethylsiloxane)) and microbubbles (air-filled cavity) to combine the benefits of both approaches while minimizing their drawbacks. We investigate the influence of various design parameters and geometrical features through numerical simulations and experimentally evaluate their manipulation capabilities. Finally, we demonstrate the capabilities of our design for microfluidic applications by investigating its mixing performance as well as through the controlled rotational manipulation of individual HeLa cells

A Compromise between Neutrino Masses and Collider Signatures in the Type-II Seesaw Model

A natural extension of the standard $SU(2)_{\rm L} \times U(1)_{\rm Y}$ gauge model to accommodate massive neutrinos is to introduce one Higgs triplet and three right-handed Majorana neutrinos, leading to a $6\times 6$ neutrino mass matrix which contains three $3\times 3$ sub-matrices $M_{\rm L}$, $M_{\rm D}$ and $M_{\rm R}$. We show that three light Majorana neutrinos (i.e., the mass eigenstates of $\nu_e$, $\nu_\mu$ and $\nu_\tau$) are exactly massless in this model, if and only if $M_{\rm L} = M_{\rm D} M_{\rm R}^{-1} M_{\rm D}^T$ exactly holds. This no-go theorem implies that small but non-vanishing neutrino masses may result from a significant but incomplete cancellation between $M_{\rm L}$ and $M_{\rm D} M_{\rm R}^{-1} M_{\rm D}^T$ terms in the Type-II seesaw formula, provided three right-handed Majorana neutrinos are of ${\cal O}(1)$ TeV and experimentally detectable at the LHC. We propose three simple Type-II seesaw scenarios with the $A_4 \times U(1)_{\rm X}$ flavor symmetry to interpret the observed neutrino mass spectrum and neutrino mixing pattern. Such a TeV-scale neutrino model can be tested in two complementary ways: (1) searching for possible collider signatures of lepton number violation induced by the right-handed Majorana neutrinos and doubly-charged Higgs particles; and (2) searching for possible consequences of unitarity violation of the $3\times 3$ neutrino mixing matrix in the future long-baseline neutrino oscillation experiments.Comment: RevTeX 19 pages, no figure

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation

Simulated distributions from negative experiments highlight the importance of the body mass index distribution in explaining depression–body mass index genetic risk score interactions

This is the final version. Available on open access from Oxford University Press via the DOI in this record. Data availability: All data from UK Biobank are publicly available; the negative experiments algorithm can be found here https://github.com/drar wood/gags.Abstract. Background: Depression and obesity are complex global health problems. Recent studies suggest a genetic predisposition to obesity might be accentuated in people with depression, but these analyses are prone to bias. Here, we tested the hypothesis that depression accentuates genetic susceptibility to obesity and applied negative control experiments to test whether any observed interactions were real or driven by confounding and statistical biases. Methods: We used data from upto 378,000 Europeans in UK Biobank, a 73 variant Body Mass Index (BMI) genetic risk score, 2 depression measures (depressive symptoms (DS), major depression (MD)) and an antidepressant usage variable available. We tested whether a) depression and b) antidepressant treatment accentuated genetic susceptibility to obesity. Finally, we performed negative control experiments by sampling individuals at random so that they had BMI distributions identical to depression cases and controls. Results: Depression was associated with an accentuation of an individuals genetic risk of obesity with evidence of interactions for both DS and MD (Pinteraction=7x10-4 and 7x10-5 respectively). Antidepressant usage within DS cases accentuated genetic obesity risk (Pinteraction=9x10-4), but not for MD (Pinteraction=0.13). Negative control experiments suggested that the observed interactions for MD (empirical-P =0.067) may be driven by statistical biases or confounding factors but were not possible with the larger DS groups. Antidepressant usage interaction also appears to be driven by statistical artefacts (empirical-P=0.510 using MD and 0.162 using DS). Conclusion: We have highlighted the importance of running negative experiments to confirm putative interactions in gene-environment studies. We provide some tentative evidence that depression accentuates an individual’s genetic susceptibility to higher BMI but demonstrated that the BMI distributions within cases and controls might drive these interactions.Academy of Medical SciencesEuropean Research Council (ERC

The biomechanics of amnion rupture: an X-ray diffraction study

Pre-term birth is the leading cause of perinatal and neonatal mortality, 40% of which are attributed to the pre-term premature rupture of amnion. Rupture of amnion is thought to be associated with a corresponding decrease in the extracellular collagen content and/or increase in collagenase activity. However, there is very little information concerning the detailed organisation of fibrillar collagen in amnion and how this might influence rupture. Here we identify a loss of lattice like arrangement in collagen organisation from areas near to the rupture site, and present a 9% increase in fibril spacing and a 50% decrease in fibrillar organisation using quantitative measurements gained by transmission electron microscopy and the novel application of synchrotron X-ray diffraction. These data provide an accurate insight into the biomechanical process of amnion rupture and highlight X-ray diffraction as a new and powerful tool in our understanding of this process

The Complete transmission spectrum of WASP-39b with a precise water constraint

This is the author accepted manuscript. The final version is available from American Astronomical Society via the DOI in this record.WASP-39b is a hot Saturn-mass exoplanet with a predicted clear atmosphere based on observations in the optical and infrared. Here we complete the transmission spectrum of the atmosphere with observations in the near-infrared (NIR) over three water absorption features with the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) G102 (0.8-1.1 microns) and G141 (1.1-1.7 microns) spectroscopic grisms. We measure the predicted high amplitude H2O feature centered at 1.4 microns, and the smaller amplitude features at 0.95 and 1.2 microns, with a maximum water absorption amplitude of 2.4 planetary scale heights. We incorporate these new NIR measurements into previously published observational measurements to complete the transmission spectrum from 0.3-5 microns. From these observed water features, combined with features in the optical and IR, we retrieve a well constrained temperature Teq = 1030(+30,-20) K, and atmospheric metallicity 151 (+48,-46)x solar which is relatively high with respect to the currently established mass-metallicity trends. This new measurement in the Saturn-mass range hints at further diversity in the planet formation process relative to our solar system giants.This work is based on observations made with the NASA/ESA Hubble Space Telescope that were obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc. These observations are associated with programs GO-14169 (PI. HR Wakeford) and GO-14260 (PI. D Deming). D.K.S., H.R.W., T.E., B.D., and N.N., acknowledge funding from the European Research Council (ERC) under the European Unions Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 336792. J.G. acknowledges support from Leverhulme Trust. A.L.C. acknowledges support from the STFC. H.R.W. also acknowledges support from the Giacconi Fellowship at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc