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High salt concentration has been shown to induce increased electrochemical stability in organic solvent-based electrolytes. Accompanying the change in bulk properties is a structural ordering on mesoscopic length scales and changes in the ion transport mechanism have also been suggested. Here we investigate the local structure and dynamics in highly concentrated acetonitrile electrolytes as a function of salt concentration. Already at low concentrations ordering on microscopic length scales in the electrolytes is revealed by small angle X-ray scattering, as a result of correlations of Li+ coordinating clusters. For higher salt concentrations a charge alternation-like ordering is found as anions start to take part in the solvation. Results from quasi-elastic neutron spectroscopy reveal a jump diffusion dynamical process with jump lengths virtually independent of both temperature and Li-salt concentration. The jump can be envisaged as dissociation of a solvent molecule or anion from a particular Li+ solvation structure. The residence time, 50-800 ps, between the jumps is found to be highly temperature and Li-salt concentration dependent, with shorter residence times for higher temperature and lower concentrations. The increased residence time at high Li-salt concentration can be attributed to changes in the interaction of the solvation shell as a larger fraction of TFSI anions take part in the solvation, forming more stable solvation shells.

A detailed understanding of the local dynamics in ionic liquids remains an important aspect in the design of new ionic liquids as advanced functional fluids. Here, we use small-angle X-ray scattering and quasi-elastic neutron spectroscopy to investigate the local structure and dynamics in a model ionic liquid as a function of temperature and pressure, with a particular focus on state points (P,T) where the macroscopic dynamics, i.e., conductivity, is the same. Our results suggest that the initial step of ion transport is a confined diffusion process, on the nanosecond timescale, where the motion is restricted by a cage of nearest neighbors. This process is invariant considering timescale, geometry, and the participation ratio, at state points of constant conductivity, i.e., state points of isoconductivity. The connection to the nearest-neighbor structure is underlined by the invariance of the peak in the structure factor corresponding to nearest-neighbor correlations. At shorter timescales, picoseconds, two localized relaxation processes of the cation can be observed, which are not directly linked to ion transport. However, these processes also show invariance at isoconductivity. This points to that the overall energy landscape in ionic liquids responds in the same way to density changes and is mainly governed by the nearest-neighbor interactions.

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar. Disclosure E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

Room temperature ionic liquids are considered to have huge potential for practical applications such as batteries. However, their high viscosity presents a significant challenge to their use changing from niche to ubiquitous. The modelling and prediction of viscosity in ionic liquids is the subject of an ongoing debate involving two competing hypotheses: molecular and local mechanisms

The Piezo-electric Shear Gauge (PSG) [Christensen & Olsen, Rev. Sci. Instrum. 66, 5019, 1995] is a rheometric technique developed to measure the complex shear modulus of viscous liquids near their glass transition temperature. We report recent advances to the PSG technique: 1) The data extraction procedure is optimized which extends the upper limit of the frequency range of the method to between 50 and 70 kHz. 2) The measuring cell is simplified to use only one piezo-electric ceramic disc instead of three. We present an implementation of this design intended for liquid samples. Data obtained with this design revealed that a soft extra spacer is necessary to allow for thermal contraction of the sample in the axial direction. Model calculations show that flow in the radial direction is hindered by the confined geometry of the cell when the liquid becomes viscous upon cooling. The method is especially well-suited for -- but not limited to -- glassy materials., 21 pages, 15 figures. Final revision before publication

The aging rate of glasses has traditionally been modeled as a function of temperature, T, and fictive temperature, while density, ρ, is not explicitly included as a parameter. However, this description does not naturally connect to the modern understanding of what governs the relaxation rate in equilibrium. In equilibrium, it is well known that the relaxation rate, γ eq, depends on temperature and density. In addition, a large class of systems obeys density scaling, which means the rate specifically depends on the scaling parameter, Γ = e( ρ)/ T, where e( ρ) is a system specific function. This paper presents a generalization of the fictive temperature concept in terms of a fictive scaling parameter, Γ fic, and a density scaling conjecture for aging glasses in which the aging rate depends on Γ and Γ fic.

In studies of glass-forming liquids, one of the important questions is to understand to which degree chemically different classes of liquids have the same type of dynamics. In this context, room-temperature ionic liquids are interesting because they exhibit both van der Waals and Coulomb interactions. In this work we study the $\ensuremath{\alpha}$ relaxation and faster relaxation dynamics in the room-temperature ionic liquid 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14-TFSI). The paper presents quasielastic neutron and shear mechanical spectroscopy data measured over seven decades in frequency (${10}^{\ensuremath{-}3}\ensuremath{-}{10}^{4}$ Hz). The use of these two methods in combination reveal the $\ensuremath{\alpha}$ relaxation and four separate, faster modes. Two of these faster modes, based on the partial deuterations, can be assigned to the methyl group and the methyl end of the butyl chain of the cation. The neutron data are also used to determine the mean-square displacement (MSD) on the nanosecond timescale. It is shown that the temperature dependence of the MSD can account for the super-Arrhenius behavior of the $\ensuremath{\alpha}$ relaxation as predicted by the shoving model [Dyre, Rev. Mod. Phys. 78, 953 (2006)], similarly to what is seen in simpler glass-forming liquids.

The coupling behavior of time scales of structural relaxation is investigated on the basis of five different response functions for 1,2,6-hexanetriol, a hydrogen-bonded liquid with a minor secondary contribution, and 2,6,10,15,19,23-hexamethyl-tetracosane (squalane), a van der Waals bonded liquid with a prominent secondary relaxation process. Time scales of structural relaxation are derived as inverse peak frequencies for each investigated response function. For 1,2,6-hexanetriol, the time-scale indices are temperature-independent, while a decoupling of time scales is observed for squalane in accordance with literature. An alternative evaluation approach is made on the squalane data, extracting time scales from the terminal relaxation mode instead of the peak position, and in this case temperature-independent coupling is also found for squalane, despite its strong secondary relaxation contribution. Interestingly, the very same ordering of response-function-specific time scales is observed for these two liquids, which is also consistent with the observation made for simple van der Waals bonded liquids reported previously [Jakobsen \textit{et al.}, J. Chem. Phys. \textbf{136}, 081102 (2012)]. This time-scale ordering is based on the following response functions, from fast to slow dynamics: shear modulus, bulk modulus, dielectric permittivity, longitudinal thermal expansivity coefficient, and longitudinal specific heat. These findings indicate a general relation between the time scales of different response functions and, as inter-molecuar interactions apparently play a subordinate role, suggest a rather generic nature of the process of structural relaxation.

This paper presents data for the physical aging of the density of squalane upon both non-linear and nearly linear temperature jumps from states of thermal equilibrium. Invoking the single-parameter-aging scenario [Hecksher et al., J. Chem. Phys. 142, 241103 (2015); Proc. Natl. Acad. Sci. U. S. A. 116, 16736–16741 (2019)], the linear-response aging relaxation function is extracted from the data. Based on this, it is shown that the relaxation toward equilibrium follows a simple exponential function at long times; a stretched-exponential function provides a poor fit. This demonstrates the existence of a terminal relaxation rate for the physical aging of squalane, corresponding to an effective long-time cutoff in the spectrum of structural relaxation times.

We report on dielectric test measurements of a rectangular flat sample holder which serves as capacitor and which is aimed for simultaneous neutron and dielectric (n-DE) spectroscopy of acidic liquid samples. We describe technical details of the sample holder assembly and the dielectric and neutron equipment as well as the sample preparation procedure of the air sensitive acidic samples. The sample holder was characterised off-line from the neutron spectrometer by dielectric spectroscopy, but using the standard IN16B cryofurnace with a dielectric sample stick with 4-wire connection and a Novocontrol equipment, previously setup by a collaborative effort between ILL and Roskilde University. Temperature-dependent dielectric scans on standard samples (glycerol, glycerol-water, and Milli-Q water) were measured in the frequency range between 0.27 Hz and 1 MHz. Step-like temperature changes allowed to probe the temperature equilibrium conditions and continuous temperature changes were made to mimic typical IN16B backscattering neutron fixed window scans. Both type of scans were carried out in cooling and in heating. The standard samples show that our dielectric setup with flat sample holder is well suited for simultaneous n-DE-experiments. On the other hand, the dielectric scan on phosphoric acid reveals the limitations of our setup in case of high sample conductivities, but also shows that the DC-conductivity can still be accessed in a sufficiently wide low temperature range where the onset of conductivity can be simultaneously probed with the change in proton dynamics as seen by neutron spectroscopy.

Recent experimental results for the structure in the ionic liquid PYR14+TFSI− have shown invariance in the main structure factor peak along curves of equal electrical conductivity [Hansen et al., Phys. Chem. Chem. Phys. 22, 14169 (2020)]. The charge peak decreases slightly with increasing temperature at fixed conductivity, however. For simple liquids, curves with invariant dynamics and structure, known as isomorphs, can be identified as configurational adiabats. While liquids with strong-Coulomb interactions do not have good isomorphs, ionic liquids could be an intermediate case with approximate isomorphs along which some aspects of structure and dynamics are invariant. We study a simple molten salt model using molecular dynamics simulations to test this hypothesis. Simple measures of structure and dynamics are investigated along with one transport property, the shear viscosity. We find that there is a substantial degree of invariance of the self-intermediate scattering function, the mean square displacement, and the viscosity along configurational adiabats over a wide range of densities for the three adiabats simulated. The density range studied is more than a factor of two and extends from the strong-Coulomb regime at low densities to the weak-Coulomb regime at high densities. The structure is not invariant over the full range of density, but in the weak-Coulomb regime, we see behavior similar to that seen experimentally over density changes of order 15%. In view of the limited structural invariance but substantial dynamical invariance, we designate the configurational adiabats as isodynes.

Our aim here is to gain new insight into the nature of the crystalline phase formed in supercooled glycerol near the glass transition temperature and to establish the interrelationship between the kinetics of crystal growth and fundamental dynamic properties. The liquid’s dynamics and the crystalline development in glycerol, a hydrogen-bonded liquid, is studied by means of dielectric spectroscopy. We monitored the kinetics of crystallization by isothermal treatment at temperatures between 220 and 240 K (Tg = 185 K). Given the thermal protocol employed, we stimulated the growth of the crystalline phase from pre-existing nuclei, in such a way that the observed kinetics is dominated by the crystal growth step. Our experimental results are discussed in terms of the classical theory of crystallization which predicts a significant correlation between the liquid’s diffusion and the crystal growth rate. The coupling between dynamic properties, such as dielectric α relaxation time, viscosity, and self-diffusion co...

Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5+ B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5+ B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.

G protein-coupled receptors (GPCRs) constitute a large protein family of seven transmembrane (7TM) spanning proteins that regulate multiple physiological functions. GPR87 is overexpressed in several cancers and plays a role in tumor cell survival. Here, the basal activity of GPR87 was investigated in transiently transfected HEK293 cells, revealing ligand-independent coupling to Gαi, Gαq and Gα12/13. Furthermore, GPR87 showed a ligand-independent G protein-dependent activation of the downstream transcription factors CREB, NFκB, NFAT and SRE. In tetracycline-induced Flp-In T-Rex-293 cells, GPR87 induced cell clustering presumably through Gα12/13 coupling. In a foci formation assay using retrovirally transduced NIH3T3 cells, GPR87 showed a strong in vitro transforming potential, which correlated to the in vivo tumor induction in nude mice. Importantly, we demonstrate that the transforming potential of GPR87 was correlated to the receptor signaling, as the signaling-impaired mutant R139A (Arg in the conserved "DRY"-motif at the bottom of transmembrane helix 3 of GPR87 substituted to Ala) showed a lower in vitro cell transformation potential. Furthermore, R139A lost the ability to induce cell clustering. In summary, we show that GPR87 is active through several signaling pathways and that the signaling activity is linked to the receptor-induced cell transformation and clustering. The robust surface expression of GPR87 and general high druggability of GPCRs make GPR87 an attractive future anticancer target for drugs that - through inhibition of the receptor signaling - will inhibit its transforming properties.

A large class of liquids obey density scaling characterized by an exponent, which quantifies the relative roles of temperature and density for the dynamics. We present experimental evidence that the density-scaling exponent γ is state-point dependent for the glass formers tetramethyl-tetraphenyl-trisiloxane (DC704) and 5-polyphenyl ether (5PPE). A method is proposed that from dynamic and thermodynamic properties at equilibrium estimates the value of γ. The method applies at any state point of the pressure-temperature plane, both in the supercooled and the normal liquid regimes. We find that γ is generally state-point dependent, which is confirmed by reanalyzing data for 20 metallic liquids and two model liquids.

Controlling crystallization and glass-forming tendencies of molecular liquids is of great scientific and practical importance. In the present work, we show that a lot can be learned regarding this process by introducing temperature and pressure as thermodynamic control variables. For the glass-forming liquid ketoprofen and its non-hydrogen bonded analogue, we have investigated changes in the crystallization rate along different isolines located in the two-dimensional T–p phase space. This has included isobaric (p = const), isothermal (T = const), and isochronal (τα = const) data. Our results reveal that the crystallization tendency of the investigated liquids can be tuned by moving along specific thermodynamic pathways. In particular, we highlight that among considered isolines the overall crystallization rate is the least affected by the density increase for the isochronal (T, p) state points. Interestingly, for various thermodynamic conditions with the same τα the estimated value of the thermodynamic dr...

The relaxation dynamics in two van der Waals bonded liquids and one hydrogen-bonding molecular liquid are studied as a function of pressure and temperature by incoherent neutron scattering using simultaneous dielectric spectroscopy. The dynamics are studied in a range of alpha relaxation times from pico- to milliseconds, primarily in the equilibrium liquid state. In this range, we find that isochronal superposition and density scaling work not only for the two van der Waals liquids but also for the hydrogen-bonding liquid, though the density scaling exponent is much smaller for the latter. Density scaling and isochronal superposition are seen to break down for intra-molecular dynamics when it is separated in time from the alpha relaxation, in close agreement with previous observations from molecular dynamics simulations.

Glass formers show motional processes over an extremely broad range of timescales, covering more than ten orders of magnitude, meaning that a full understanding of the glass transition needs to comprise this tremendous range in timescales. Here we report simultaneous dielectric and neutron spectroscopy investigations of three glass-forming liquids, probing in a single experiment the full range of dynamics. For two van der Waals liquids, we locate in the pressure–temperature phase diagram lines of identical dynamics of the molecules on both second and picosecond timescales. This confirms predictions of the isomorph theory and effectively reduces the phase diagram from two to one dimension. The implication is that dynamics on widely different timescales are governed by the same underlying mechanisms., Glass formers show dynamics over a broad range of timescales, presenting a hurdle to understanding the glass transition. Here, the authors find that the dynamics of glass-forming liquids are governed by the same mechanisms over different timescales, effectively reducing the phase diagram from two to one dimension.

In this article we report on the design, manufacture and testing of a high-pressure cell for doing simultaneous dielectric and neutron spectroscopy. This cell is a unique tool for studying dynamics on different timescales, from kilo- to picoseconds, covering universal features such as the alpha relaxation and fast vibrations at the same time. The cell, constructed in cylindrical geometry, is made in high-strength aluminum alloy and operates up to 500 MPa in a temperature range between roughly 2 and 320 K. In order to measure the scattered neutron intensity and the sample capacitance simultaneously, a cylindrical capacitor is positioned within the bore of the high-pressure container. The capacitor consists of two concentric electrodes separated by insulating spacers. The performance of this setup has been successfully verified by collecting simultaneous dielectric and neutron spectroscopy data on dipropylene glycol, using both backscattering and time-of-flight instruments. We have carried out the experiments at different combinations of temperature and pressure in both supercooled liquid and glassy state., A.S. and H.W.H. contributed equally to this work

The relaxation dynamics in two van der Waals bonded liquids and one hydrogen-bonding molecular liquid are studied as a function of pressure and temperature by incoherent neutron scattering using simultaneous dielectric spectroscopy. The dynamics are studied in a range of alpha relaxation times from pico- to milliseconds, primarily in the equilibrium liquid state. In this range, we find that isochronal superposition and density scaling work not only for the two van der Waals liquids but also for the hydrogen-bonding liquid, though the density scaling exponent is much smaller for the latter. Density scaling and isochronal superposition are seen to break down for intra-molecular dynamics when it is separated in time from the alpha relaxation, in close agreement with previous observations from molecular dynamics simulations.

International audience; Glycerol-water mixtures were studied at molar concentrations ranging from $x_\text{gly} = 1$ (pure glycerol) to $x_\text{gly}=0.3$ using shear mechanical spectroscopy. We observed a low frequency mode in neat glycerol, similar to what is usually reported for monohydroxy alcohols. This mode has no dielectric counterpart and disappears with increased water concentration. We propose that the hydrogen-bonded network formed between glycerol molecules is responsible for the observed slow mode and that water acts as a plasticizer for the overall dynamics and as a lubricant softening the hydrogen-bonding contribution to the macroscopic viscosity of this binary system.

In this paper, we study crystallization behavior and molecular dynamics in the supercooled liquid state of the pharmaceutically important compound ketoprofen at various thermodynamic conditions. Dielectric relaxation for a racemic mixture was investigated in a wide range of temperatures and pressures (up to 350 MPa), whereas crystallization kinetics for racemic and single enantiomers was studied along a (T, p) curve characterized by the same structural relaxation time, τα ≅ 10–6 s, a so-called isochrone. The aim was to investigate the effect of pressure on the crystallization tendencies of pure enantiomers and their 50–50 equimolar mixture in the metastable supercooled liquid state. Crystallization kinetic studies revealed that at the same isochronal conditions the behavior of the S-enantiomer and R,S-racemic mixture of ketoprofen is entirely different. This was examined in the context of previous results and in view of the possibility of inducing changes in the enantiomeric composition or enantiomers sep...

This paper derives a prediction for the variation of the amplitude of the dielectric loss from isomorph theory, and presents an experimental test of the prediction performed by measuring the dielectric-relaxation behavior of the van der Waals liquid 5-phenyl-4-ether (5PPE). The liquid is studied at isochronal states in the temperature range $266-333$ K and pressure range $0.1-300$ MPa, for relaxation times around $10^{-3}$ s and $10^{-4}$ s. From the isomorph statement that there is structural and dynamic invariance of isomorph states in reduced units for Roskilde simple liquids we derive four equivalent isomorph-invariant terms, one of which is used in analyzing our data. It is the frequency-dependent term $\chi_{e}(f) \rho^{\gamma-1}$, with electric susceptibility $\chi_{e}$, density $\rho$, and density-scaling factor $\gamma$. Due to the unique design of our experimental setup, we obtain dielectric loss data where the amplitude is reproducible $\pm 0.1 \%$. We moreover find that the empty capacitance of the capacitor cell is stable within $\pm 0.3 \%$ in our measuring range and can be assumed to be constant. Using this we predict for two isomorph states there is $-C_{2}"(f)= -C_{1}"(f) \left(\rho_1 / \rho_2 \right)^{\gamma-1}$ to scale the negative imaginary capacitance, where $C_{1}$ is the capacitance measurement at ambient pressure and $C_{2}$ is the predicted capacitance at elevated pressure. We visually compare the predicted and measured plots and there is good match between the two plots among the 42 pairs of isochronal states from the measurement.

The linear volume relaxation and the nonlinear volume aging of a glass-forming liquid are measured, directly compared, and used to extract the out-of-equilibrium relaxation time. This opens a window to investigate how the relaxation time depends on temperature, structure, and volume in parts of phase space that are not accessed by the equilibrium liquid. It is found that the temperature dependence of relaxation time is non-Arrhenius even in the isostructural case---challenging the Adam-Gibbs entropy model. Based on the presented data and the idea that aging happens through quasiequilibrium states, we suggest a mapping of the out-of-equilibrium states during isobaric aging to the equilibrium phase diagram. This mapping implies the existence of isostructural lines in the equilibrium phase diagram. The relaxation time is found to depend on the bath temperature, density, and a just single structural parameter, referred to as an effective temperature.

The seven transmembrane G protein-coupled receptor Epstein-Barr virus (EBV) induced gene 2 (EBI2; also known as GPR183) was identified in 1993 on the basis of its substantial upregulation in EBV-infected cells. It is primarily expressed in lymphoid cells; most abundantly in B cells. EBI2 is central for the positioning of B cells within the lymphoid organs, a process that is regulated in part by a chemotactic gradient formed by the endogenous lipid agonists, and in part by a fine-tuned regulation of EBI2 cell surface expression. The most potent endogenous EBI2 agonist is 7α, 25-dihydroxyxcholesterol (7α,25-OHC), yet many structurally related oxysterols can bind to an EBI2 pocket that is defined by the upper parts of the transmembrane helices and extracellular receptor regions. EBI2 signals via Gαi, as well as via G protein-independent pathways like β-arrestin recruitment. The concerted action of these pathways leads to cell migration. By genetically interfering with its up- and downregulation, EBI2 was also recently shown to induce cell proliferation, an action that could be inhibited by small molecule antagonists. Here, we focus on the oxysterol–EBI2 axis in immune control, including its role in the EBV life cycle. We also summarize the structural and functional properties of EBI2 interaction with oxysterol agonists and small molecule antagonists and discuss EBI2 as therapeutic target for diseases of the immune system.

Physical aging of glycerol following temperature jumps is studied by dielectric spectroscopy at temperatures just below the glass transition temperature. The data are analyzed using two single-parameter aging tests developed by Hecksher et al. [J. Chem. Phys. 142, 241103 (2015)]. We generalize these tests to include jumps ending at different temperatures. Moreover, four times larger jumps than previously are studied. The single-parameter aging tests are here for the first time applied to a hydrogen-bonded liquid. We conclude that glycerol obeys single-parameter aging to a good approximation., 20 pages, 8 figures

The Epstein–Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK682753A, which blocks oxysterol-induced G-protein activation, β-arrestin recruitment and B-cell chemotaxis. We furthermore demonstrate that activation triggers pertussis toxin-sensitive MAP kinase phosphorylation, which is also inhibited by GSK682753A. Thus, EBI2 signalling in B cells mediates key phenotypic functions via signalling pathways amenable to manipulation providing additional therapeutic options for inhibiting EBI2 activity., Highlights • The antagonist GSK682753A inhibits EBI2 activation. • It potently suppresses G protein activation, β-arrestin recruitment and migration. • EBI2 activation induces pertussis toxin (ptx)-sensititve MAP kinase phosphorylation.

The temperature dependence of the high-frequency shear modulus measured in the kHz range is compared to the mean-squared displacement measured in the nanosecond range for the two van der Waals bonded glass-forming liquids cumene and 5PPE. This provides an experimental test for the assumption connecting two versions of the shoving model for the non-Arrhenius temperature dependence of the relaxation time in glass formers. The two versions of the model are also tested directly and both are shown to work well for these liquids., Comment: 7 pages, 6 figures

Background and purpose Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes. Experimental approach The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gα(i) signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148. Key results All compounds were highly potent inverse agonists with EC(50) values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC(50) values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [(125)I]-CCL1 (K(i) 3.4-842 nM), whereas the affinities measured against [(125)I]-MC148 were less widely spread (K(i) 0.37-27 nM), and matched the inverse agonist potencies. Conclusion and implications Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties.

Background: EBI2 was recently deorphanized as the first oxysterol-activated receptor, but the binding mode remains unknown. Results: Mutational analysis showed that substitution of Arg-87, Tyr-112, Tyr-116, and Tyr-260 abolished agonist binding and EBI2 activation. Conclusion: Oxysterol binding is dependent on residues in TM-II, -III, and -VI. Significance: This is the first study to examine the binding mode of these novel 7TM receptor agonists., Oxysterols are oxygenated cholesterol derivates that are emerging as a physiologically important group of molecules. Although they regulate a range of cellular processes, only few oxysterol-binding effector proteins have been identified, and the knowledge of their binding mode is limited. Recently, the family of G protein-coupled seven transmembrane-spanning receptors (7TM receptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol (7α,25-OHC). Nothing is known about the binding mode, however. Using mutational analysis, we identify here four key residues for 7α,25-OHC binding: Arg-87 in TM-II (position II:20/2.60), Tyr-112 and Tyr-116 (positions III:09/3.33 and III:13/3.37) in TM-III, and Tyr-260 in TM-VI (position VI:16/6.51). Substituting these residues with Ala and/or Phe results in a severe decrease in agonist binding and receptor activation. Docking simulations suggest that Tyr-116 interacts with the 3β-OH group in the agonist, Tyr-260 with the 7α-OH group, and Arg-87, either directly or indirectly, with the 25-OH group, although nearby residues likely also contribute. In addition, Tyr-112 is involved in 7α,25-OHC binding but via hydrophobic interactions. Finally, we show that II:20/2.60 constitutes an important residue for ligand binding in receptors carrying a positively charged residue at this position. This group is dominated by lipid- and nucleotide-activated receptors, here exemplified by the CysLTs, P2Y12, and P2Y14. In conclusion, we present the first molecular characterization of oxysterol binding to a 7TM receptor and identify position II:20/2.60 as a generally important residue for ligand binding in certain 7TM receptors.

Under standing the origin of the dramatic temperature and density dependence of the relaxation time of glass-forming liquids is a fundamental challenge in glass science. The recently established ‘density-scaling’ relation quantifies the relative importance of temperature and density for the relaxation time in terms of a material-dependent exponent. We show that this exponent for approximate single-parameter liquids can be calculated from thermoviscoelastic linear-response data at a single state point, for instance an ambient-pressure state point. This prediction is confirmed for the van der Waals liquid tetramethyl-tetraphenyl-trisiloxane. Consistent with this, a compilation of literature data for the Prigogine‐Defay ratio shows that van der Waals liquids and polymers are approximate single-parameter systems, whereas associated and network-forming liquids are not.

The mechanism that leads to different fragility values upon approaching the glass transition remains a topic of active discussion. Many researchers are trying to find an answer in the properties of the frozen glassy state. Following this approach, we focus here on a previously proposed relationship between the fragility of glass-formers and their nonergodicity factor, determined by inelastic X-ray scattering (IXS) in the glass. We extend this molecular liquid study to two model polymers; polystyrene (PS) and poly- isobutylene (PIB);for which we change the molecular weight. Polymers offer the opportunity to change the fragilitywithoutalteringthechemicalstructure,justbychangingthechainlength.Thus,wespecificallychose PS and PIB because they exhibit opposite dependences of fragility with molecular weight. Our analysis for thesetwopolymersrevealsnouniquecorrelationbetweenthefragilityandthenonergodicityparameter.Even after a recently suggested correction for a possible contribution of the β relaxation, the correlation is not restored. We discuss possible causes for the failure of the "fragility-nonergodicity factor" correlation, emphasizing the features that are specific to polymers. We speculate that polymers might have specific contributions to fragility related to the chain connectivity that are absent in nonpolymeric systems.

For the flow around a circular cylinder, the steady flow changes its topology at a Reynolds number around 6 where the flow separates and a symmetric double separation zone is created. At the bifurcation point, the flow topology is locally degenerate, and by a bifurcation analysis we find all possible streamline patterns which can occur as perturbations of this flow. We show that there is no a priori topological limitation from further assuming that the flow fulfils the steady Navier–Stokes equations or from assuming that a Hopf bifurcation occurs close to the degenerate flow.The steady flow around a circular cylinder experiences a Hopf bifurcation for a Reynolds number about 45–49. Assuming that this Reynolds number is so close to the value where the steady separation occurs that the flow here can be considered a perturbation of the degenerate flow, the topological bifurcation diagram will contain all possible instantaneous streamline patterns in the periodic regime right after the Hopf bifurcation. On the basis of the spatial and temporal symmetry associated with the circular cylinder and the structure of the topological bifurcation diagram, two periodic scenarios of instantaneous streamline patterns are conjectured. We confirm numerically the existence of these scenarios, and find that the first scenario exists only in a narrow range after the Hopf bifurcation whereas the second one persists through the entire range of Re where the flow can be considered two-dimensional. Our results corroborate previous experimental and computational results.

Isothermal crystallization of the mono-hydroxyl alcohol n-butanol was studied with dielectric spectroscopy in real time. The crystallization was carried out using two different sample cells at 15 temperatures between 120 K and 134 K. Crystallization is characterized by a decrease of the dielectric intensity. In addition, a shift in relaxation times to shorter times was observed during the crystallization process for all studied temperatures. The two different sample environments induced quite different crystallization behaviors, consistent and reproducible over all studied temperatures. An explanation for the difference was proposed on the background of an Avrami analysis and a Maxwell-Wagner analysis. Both types of analysis suggest that the morphology of the crystal growth changes from a higher dimension to a lower at a point during the crystallization. More generally, we conclude that a microscopic interpretation of crystallization measurements requires multiple probes, sample cells, and protocols.

Being present in around 90% of the worldwide population, Epstein-Barr virus (EBV) is an exceptionally prevalent virus. This highly successful virus establishes a latent infection in resting memory B cells and is maintained in a balance between viral homeostasis on one side and antiviral defense of the immune system on the other side. The life cycle of EBV is dependent on many viral proteins, but EBV also regulates a number of endogenous proteins. 7TM receptors and ligands of viral and host origin are examples of such proteins. 7TM receptors are highly druggable and they are among the most popular class of investigational drug targets. The 7TM receptor encoded by EBV-BILF1, is known to downregulate cell surface MHC class I expression as part of the immune evasion strategy of EBV. However, the functional impact of the relationship between EBV and the regulated endogenous 7TM receptors and ligands is still unclear. This is for instance the case for the most upregulated 7TM receptor EBI2 (EBV-induced gene 2 or GPR183). Whereas some regulated genes have been suggested to be involved in the EBV life cycle, others could also be important for the antiviral immune defense. As many of these 7TM receptors and ligands have been shown to be modulated in EBV-associated diseases, targeting these could provide an efficient and specific way to inhibit EBV-associated disease progression. Here, we will review current knowledge on EBV infection, the immune defense against EBV and 7TM receptors and ligands being either encoded or manipulated by EBV.

We present a simple method for fast and cheap thermal analysis on supercooled glass-forming liquids. This "Thermalization Calorimetry" technique is based on monitoring the temperature and its rate of change during heating or cooling of a sample for which the thermal power input comes from heat conduction through an insulating material, i.e., is proportional to the temperature difference between sample and surroundings. The monitored signal reflects the sample's specific heat and is sensitive to exo- and endothermic processes. The technique is useful for studying supercooled liquids and their crystallization, e.g., for locating the glass transition and melting point(s), as well as for investigating the stability against crystallization and estimating the relative change in specific heat between the solid and liquid phases at the glass transition., Comment: 17 pages, 9 figures, minor changes

Being present in around 90% of the worldwide population, Epstein–Barr virus (EBV) is an exceptionally prevalent virus. This highly successful virus establishes a latent infection in resting memory B cells and is maintained in a balance between viral homeostasis on one side and antiviral defense of the immune system on the other side. The life cycle of EBV is dependent on many viral proteins, but EBV also regulates a number of endogenous proteins. 7TM receptors and ligands of viral and host origin are examples of such proteins. 7TM receptors are highly druggable and they are among the most popular class of investigational drug targets. The 7TM receptor encoded by EBV-BILF1, is known to downregulate cell surface MHC class I expression as part of the immune evasion strategy of EBV. However, the functional impact of the relationship between EBV and the regulated endogenous 7TM receptors and ligands is still unclear. This is for instance the case for the most upregulated 7TM receptor EBI2 (EBV-induced gene 2 or GPR183). Whereas some regulated genes have been suggested to be involved in the EBV life cycle, others could also be important for the antiviral immune defense. As many of these 7TM receptors and ligands have been shown to be modulated in EBV-associated diseases, targeting these could provide an efficient and specific way to inhibit EBV-associated disease progression. Here, we will review current knowledge on EBV infection, the immune defense against EBV and 7TM receptors and ligands being either encoded or manipulated by EBV.

Influence of pressure on fast dynamics and elastic properties in polyisobutylene is studied using Raman, Brillouin and neutron scattering spectroscopy. Analysis of the results shows that the boson peak frequency increases with pressure stronger than the longitudinal sound velocity measured by Brillouin scattering. Moreover, the boson peak intensity decreases under pressure stronger in Raman scattering than in neutron scattering suggesting a decrease in the light-to-vibrations coupling coefficient C ( ν ). The strong decrease of the microscopic peak intensity under pressure in Raman spectra supports this suggestion. We argue that variations in C ( ν ) might be related to amplitude of structural fluctuations. We speculate that change in disorder and/or overall density under pressure is the main cause for the observed variations.

A liquid obeys isochronal superposition if its dynamics is invariant along the isochrones in the thermodynamic phase diagram (the curves of constant relaxation time). This paper introduces two quantitative measures of isochronal superposition. The measures are used to test the following six liquids for isochronal superposition: 1,2,6 hexanetriol, glycerol, polyphenyl ether, diethyl phthalate, tetramethyl tetraphenyl trisiloxane, and dibutyl phthalate. The latter four van der Waals liquids obey isochronal superposition to a higher degree than the two hydrogen-bonded liquids. This is a predic- tion of the isomorph theory, and it confirms findings by other groups.

Based on previous works on polymers by Bauer et al. [Phys. Rev. E 61, 1755 (2000)], this paper describes a capacitative method for measuring the dynamical expansion coefficient of a viscous liquid. Data are presented for the glass-forming liquid tetramethyl tetraphenyl trisiloxane (DC704) in the ultraviscous regime. Compared to the method of Bauer et al., the dynamical range has been extended by making time-domain experiments and by making very small and fast temperature steps. The modeling of the experiment presented in this paper includes the situation in which the capacitor is not full because the liquid contracts when cooling from room temperature down to around the glass-transition temperature, which is relevant when measuring on a molecular liquid rather than a polymer.