Ex Vivo T Cell Cytokine Expression Predicts Survival in Patients with Severe Alcoholic Hepatitis

( Ashwin D. Dhanda ),( Euan Yates ),( Lauren P. Schewitz-bowers ),( Philippa J. Lait ),( Richard W. J. Lee ),( Matthew E. Cramp ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2020 Gut and Liver Vol.14 No.2

Alcoholic hepatitis (AH) is an acute inflammatory liver condition with high early mortality rate. Steroids improve short-term survival but nonresponders have the worst outcomes. There is a clinical need to identify these high-risk individuals at the time of presentation. T cells are implicated in AH and steroid responsiveness. We measured ex vivo T cell cytokine expression as a candidate biomarker of outcomes in patients with AH. Consecutive patients (bilirubin >80 μmol/L and ratio of aspartate aminotransferase to alanine aminotransferase >1.5 who were heavy alcohol consumers with discriminant function [DF] ≥32), were recruited from University Hospitals Plymouth NHS Trust. T cells were obtained and stimulated ex vivo. Cytokine expression levels were determined by flow cytometry and protein multiplex analysis. Twenty-three patients were recruited (10 male; median age 51 years; baseline DF 67; 30% 90-day mortality). Compared to T cells from nonsurvivors at day 90, T cells from survivors had higher baseline baseline intracellular interleukin (IL)-10:IL-17A ratio (0.43 vs 1.20, p=0.02). Multiplex protein analysis identified interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α) as independent predictors of 90-day mortality (p=0.04, p=0.01, respectively). The ratio of IFNγ to TNF-α was predictive of 90-day mortality (1.4 vs 0.2, p=0.03). These data demonstrate the potential utility of T cell cytokine release assays performed on pretreatment blood samples as biomarkers of survival in patients with severe AH. Our key findings were that intracellular IL-10:IL-17A and IFNγ:TNF-α in culture supernatants were predictors of 90-day mortality. This offers the promise of developing T cell-based diagnostic tools for risk stratification. (Gut Liver 2020;14:265-268)

Diurnal variation of default mode network in patients with restless legs syndrome

Ku, Jeonghun,Lee, Yeong Seon,Chang, Hyuk Won,Earley, Christopher J.,Allen, Richard P.,Cho, Yong Won Elsevier 2018 SLEEP MEDICINE Vol.41 No.-

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>Restless legs syndrome (RLS) patients compared to controls have been found to have abnormal patterns in the default mode network (DMN) in the morning when symptom threshold is the highest and symptoms are least likely to occur. If these morning abnormalities in DMN are pertinent to disease expression, then similar or further detectable differences may be expected on a nighttime assessment when RLS symptom threshold is at its lowest. The purpose of this study was to elucidate the potential neural mechanisms underlying the circadian aspect of RLS symptom expression by assessing diurnal changes in DMN.</P> <P><B>Methods</B></P> <P>Fifteen drug-naïve subjects with idiopathic RLS and 15 age- and gender-matched healthy subjects had fMRI scans in the morning and evening. The DMN patterns were compared both for differences between morning and evening and between RLS and controls.</P> <P><B>Results</B></P> <P>RLS patients compared to the healthy controls showed significant differences in morning and evening DMN. In particular, RLS patients showed consistent increased connectivity in the parietal lobule in both the morning and evening. In contrast, connectivity in the thalamus was increased in the morning and reduced in the evening. In addition, there were negative correlations between thalamic connectivity and the Korean versions of the international RLS scale and the quality-of-life subscore.</P> <P><B>Conclusions</B></P> <P>The results indicated diurnal disturbances of the DMN in RLS subjects are consistent with both the circadian rhythm and severity of RLS. The circadian expression of RLS may relate to changes in arousal cortical-activation thresholds occurring with diurnal changes in the thalamic circuits of the DMN.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Diurnal changes in the brain with RLS symptoms could elucidate symptom dynamics. </LI> <LI> Daytime DMN, thalamic, and sensorimotor networks suggest solutions for RLS symptoms. </LI> <LI> Evening thalamic reduction with sustained sensorimotor activation controls symptom emergence. </LI> <LI> The results suggest RLS is a disorder of the disturbed sensory activation/threshold. </LI> <LI> The results could provide clinical provision for symptom emergence and treatment. </LI> </UL> </P>

Experience-Driven Plasticity in Binocular Vision

Klink, P. Christiaan,Brascamp, Jan W.,Blake, Randolph,van Wezel, Richard J.A. Elsevier 2010 Current biology Vol.20 No.16

<P><B>Summary</B></P><P>Experience-driven neuronal plasticity allows the brain to adapt its functional connectivity to recent sensory input. Here we use binocular rivalry [<ce:cross-ref refid='bib1'>1</ce:cross-ref>], an experimental paradigm in which conflicting images are presented to the individual eyes, to demonstrate plasticity in the neuronal mechanisms that convert visual information from two separated retinas into single perceptual experiences. Perception during binocular rivalry tended to initially consist of alternations between exclusive representations of monocularly defined images, but upon prolonged exposure, mixture percepts became more prevalent. The completeness of suppression, reflected in the incidence of mixture percepts, plausibly reflects the strength of inhibition that likely plays a role in binocular rivalry [<ce:cross-ref refid='bib2'>2</ce:cross-ref>]. Recovery of exclusivity was possible but required highly specific binocular stimulation. Documenting the prerequisites for these observed changes in perceptual exclusivity, our experiments suggest experience-driven plasticity at interocular inhibitory synapses, driven by the correlated activity (and also the lack thereof) of neurons representing the conflicting stimuli. This form of plasticity is consistent with a previously proposed but largely untested anti-Hebbian learning mechanism for inhibitory synapses in vision [<ce:cross-refs refid='bib3 bib4'>3, 4</ce:cross-refs>]. Our results implicate experience-driven plasticity as one governing principle in the neuronal organization of binocular vision.</P> <P><B>Graphical Abstract</B></P><P><ce:figure></ce:figure></P><P><B>Highlights</B></P><P>► Binocular rivalry reveals plasticity in binocular fusion ► Perceptual coherence deteriorates during extended visual rivalry ► We provide psychophysical evidence for plasticity in human vision ► Efficacy of interocular inhibition depends on recent perceptual history</P>

Planar Alignment of Columnar Discotic Liquid Crystals by Isotropic Phase Dewetting on Chemically Patterned Surfaces

Bramble, Jonathan P.,Tate, Daniel J.,Revill, Derek J.,Sheikh, Khizar H.,Henderson, James R.,Liu, Feng,Zeng, Xiangbing,Ungar, Goran,Bushby, Richard J.,Evans, Stephen D. WILEY‐VCH Verlag 2010 Advanced Functional Materials Vol.20 No.6

<P><B>Abstract</B></P>10.1002/adfm.200902140.abs<P>A novel method of creating planar aligned columnar discotic liquid crystals (cDLCs) on surfaces, which also gives control over the azimuthal angle, is presented. Surfaces are chemically patterned with stripes via microcontact printing of organothiol self‐assembled monolayers (SAMs) on gold, or via deep UV patterning of organosilane SAMs on silicon. These are then used to isolate long droplets of cDLCs by dewetting in the isotropic phase. Upon cooling from the isotropic into the hexagonal columnar phase, polarizing microscopy reveals that the cDLC aligns in a planar orientation. Results for three triphenylene derivatives (HAT‐6, HHTT, H7T) and for a phthalocyanine derivative (8H<SUB>2</SUB>Pc) are presented. H7T and HAT‐6 are found to align with the director perpendicular to the stripe direction, but HHTT and 8H<SUB>2</SUB>Pc align parallel to the stripe direction. This relatively simple new method for creating planar aligned columnar phases of DLCs gives control over the azimuthal angle: a condition required for organic field‐effect transistor applications of cDLCs.</P>

Dlg5 Regulates Dendritic Spine Formation and Synaptogenesis by Controlling Subcellular <i>N</i>-Cadherin Localization

Wang, Shih-Hsiu J.,Celic, Ivana,Choi, Se-Young,Riccomagno, Martin,Wang, Qiang,Sun, Lu O.,Mitchell, Sarah P.,Vasioukhin, Valera,Huganir, Richard L.,Kolodkin, Alex L. Society for Neuroscience 2014 The Journal of neuroscience Vol.34 No.38

<P>Most excitatory synapses in the mammalian brain are formed on dendritic spines, and spine density has a profound impact on synaptic transmission, integration, and plasticity. Membrane-associated guanylate kinase (MAGUK) proteins are intracellular scaffolding proteins with well established roles in synapse function. However, whether MAGUK proteins are required for the formation of dendritic spines <I>in vivo</I> is unclear. We isolated a novel <I>disc large-5</I> (<I>Dlg5</I>) allele in mice, <I>Dlg5</I><SUP>LP</SUP>, which harbors a missense mutation in the DLG5 SH3 domain, greatly attenuating its ability to interact with the DLG5 GUK domain. We show here that DLG5 is a MAGUK protein that regulates spine formation, synaptogenesis, and synaptic transmission in cortical neurons. DLG5 regulates synaptogenesis by enhancing the cell surface localization of <I>N</I>-cadherin, revealing a key molecular mechanism for regulating the subcellular localization of this cell adhesion molecule during synaptogenesis.</P>

Autorotation of square plates, with application to windborne debris

P. Martinez-Vazquez,M. Sterling,C.J. Baker,A.D. Quinn,P.J. Richards 한국풍공학회 2011 Wind and Structures, An International Journal (WAS Vol.14 No.2

This paper presents the results of measurements relating to the aerodynamic forces on flat square plates which were allowed to rotate at different speeds about their horizontal axis, by modifying the velocity of the incoming flow. A 1 m square test-sheet and a 0.3 m square test-sheet were fitted with a number of pressure sensors in order to obtain information relating to the instantaneous pressure distribution acting on the test-sheet; a compact gyroscope to record the angular velocity during the rotational motion was also implemented. Previous work on autorotation has illustrated that the angular velocity varies with respect to the torque induced by the wind, the thickness and aspect ratio of the testsheet, any frictional effects present at the bearings, and the vorticity generated through the interaction between the plate and the wind flow. The current paper sets out a method based on the solution of the equation of motion of a rotating plate which enables the determination of angular velocities on autorotating elements to be predicted. This approach is then used in conjunction with the experimental data in order to evaluate the damping introduced by the frictional effects at the bearings during steady autorotation.

Replication of the 2,6-Diamino-4-hydroxy-<i>N</i>⁵-(methyl)-formamidopyrimidine (MeFapy-dGuo) Adduct by Eukaryotic DNA Polymerases

Christov, Plamen P.,Yamanaka, Kinrin,Choi, Jeong-Yun,Takata, Kei-ichi,Wood, Richard D.,Guengerich, F. Peter,Lloyd, R. Stephen,Rizzo, Carmelo J. American Chemical Society 2012 Chemical research in toxicology Vol.25 No.8

<P><I>N</I><SUP>6</SUP>-(2-Deoxy-<SMALL>d</SMALL>-<I>erythro</I>-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-<I>N</I>-methylformamidopyrimidine (MeFapy-dGuo) has been identified as a stable DNA adduct that arises from the reaction of DNA with a variety of methylating agents. Since this lesion persists in DNA and may contribute to the overall mutagenesis from electrophilic methylating agents, the MeFapy-dGuo lesion was incorporated into oligonucleotides, and its replication bypass was examined in vitro with a panel of eukaryotic high fidelity (hPols α, β, and δ/PCNA) and translesion (hPols η, κ, ι, Rev1, ν, and yPol ζ) polymerases to address its miscoding potential. The MeFapy-dGuo was found to be a strong block to the high fidelity polymerases at either the insertion or the extension step. Efficient translesion synthesis was observed for hPols η and κ, and the combined activities of hRev1 and yPol ζ. The nucleotide sequences of the extension products were determined by mass spectrometry. The error-free extension product was the most abundant product observed for each polymerase. Misreplication products, which included misinsertion of Thy, Gua, and Ade opposite the MeFapy-dGuo lesion, as well as an interesting one-nucleotide deletion product, were observed when hPols η and κ were employed; these events accounted for 8–29% of the total extension products observed. The distribution and abundance of the misreplication products were dependent on the polymerases and local sequence context of the lesion. Collectively, these data suggest that although MeFapy-dGuo adducts represent a relatively minor proportion of the total alkylated lesions, their miscoding potentials could significantly contribute to genomic instability.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/crtoec/2012/crtoec.2012.25.issue-8/tx300113e/production/images/medium/tx-2012-00113e_0001.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/tx300113e'>ACS Electronic Supporting Info</A></P>

A 6 m cube in an atmospheric boundary layer flow -Part 2. Computational solutions

Richards, P.J.,Quinn, A.D.,Parker, S. Techno-Press 2002 Wind and Structures, An International Journal (WAS Vol.5 No.2

Computation solutions for the flow around a cube, which were generated as part of the Computational Wind Engineering 2000 Conference Competition, are compared with full-scale measurements. The three solutions shown all use the RANS approach to predict mean flow fields. The major differences appear to be related to the use of the standard $k-{\varepsilon}$, the MMK $k-{\varepsilon}$ and the RNG $k-{\varepsilon}$ turbulence models. The inlet conditions chosen by the three modellers illustrate one of the dilemmas faced in computational wind engineering. While all modeller matched the inlet velocity profile to the full-scale profile, only one of the modellers chose to match the full-scale turbulence data. This approach led to a boundary layer that was not in equilibrium. The approach taken by the other modeller was to specify lower inlet turbulent kinetic energy level, which are more consistent with the turbulence models chosen and lead to a homogeneous boundary layer. For the $0^{\circ}$ case, wind normal to one face of the cube, it is shown that the RNG solution is closest to the full-scale data. This result appears to be associated with the RNG solution showing the correct flow separation and reattachment on the roof. The other solutions show either excessive separation (MMK) or no separation at all (K-E). For the $45^{\circ}$ case the three solutions are fairly similar. None of them correctly predicting the high suctions along the windward edges of the roof. In general the velocity components are more accurately predicted than the pressures. However in all cases the turbulence levels are poorly matched, with all of the solutions failing to match the high turbulence levels measured around the edges of separated flows. Although all of the computational solutions have deficiencies, the variability of results is shown to be similar to that which has been obtained with a similar comparative wind tunnel study. This suggests that the computational solutions are only slightly less reliable than the wind tunnel.

Structural origins of enhanced capacity retention in novel copolymerized sulfur-based composite cathodes for high-energy density Li-S batteries

Oleshko, Vladimir P.,Kim, Jenny,Schaefer, Jennifer L.,Hudson, Steven D.,Soles, Christopher L.,Simmonds, Adam G.,Griebel, Jared J.,Glass, Richard S.,Char, Kookheon,Pyun, Jeffrey Cambridge University Press (Materials Research Soc 2015 MRS Communications Vol.5 No.3

<▼1><B>Abstract</B><P/></▼1><▼2><P>Poly[sulfur-random-1,3-diisopropenylbenzene (DIB)] copolymers synthesized via inverse vulcanization form electrochemically active polymers used as cathodes for high-energy density Li-S batteries, capable of enhanced capacity retention (1005 mAh/g at 100 cycles) and lifetimes of over 500 cycles. In this prospective, we demonstrate how analytical electron microscopy can be employed as a powerful tool to explore the origins of the enhanced capacity retention. We analyze morphological and compositional features when the copolymers, with DIB contents up to 50% by mass, are blended with carbon nanoparticles. Replacing the elemental sulfur with the copolymers improves the compatibility and interfacial contact between active sulfur compounds and conductive carbons. There also appears to be improvements of the cathode mechanical stability that leads to less cracking but preserving porosity. This compatibilization scheme through stabilized organosulfur copolymers represents an alternative strategy to the nanoscale encapsulation schemes which are often used to improve the cycle life in high-energy density Li-S batteries.</P></▼2>

Plenary Lectures 1 : Molecular and cellular approaches to Long-term modifications of synaptic function

( Richard W. Tsien ),( Y. J. Liao ),( Y. Q. Cao ),( E. S. Piedras Renteria ),( P. Safa ),( E. S. Boyden III ),( G. B. Smith ),( G. Chen ),( N. C. Harata ),( J. L. Pyle ),( M. Diehn ),( L. L. Glickfeld 한국생화학분자생물학회 (구 한국생화학회) 2004 생화학분자생물학회 춘계학술발표논문집 Vol.2004 No.-