Evaluating the Applicability of the Fokker-Planck Equation in Polymer Translocation: A Brownian Dynamics Study

Brownian dynamics (BD) simulations are used to study the translocation dynamics of a coarse-grained polymer through a cylindrical nanopore. We consider the case of short polymers, with a polymer length, N, in the range N=21-61. The rate of translocation is controlled by a tunable friction coefficient, gamma_{0p}, for monomers inside the nanopore. In the case of unforced translocation, the mean translocation time scales with polymer length N as ~ (N-N_p)^alpha, where N_p is the average number of monomers in the nanopore. The exponent approaches the value alpha=2 when the pore friction is sufficiently high, in accord with the prediction for the case of the quasi-static regime where pore friction dominates. In the case of forced translocation, the polymer chain is stretched and compressed on the cis and trans sides, respectively, for low gamma_{0p}. However, the chain approaches conformational quasi-equilibrium for sufficiently large gamma_{0p}. In this limit the observed scaling of with driving force and chain length supports the FP prediction that is proportional to N/f_d for sufficiently strong driving force. Monte Carlo simulations are used to calculate translocation free energy functions for the system. The free energies are used with the Fokker-Planck equation to calculate translocation time distributions. At sufficiently high gamma_{0p}, the predicted distributions are in excellent agreement with those calculated from the BD simulations. Thus, the FP equation provides a valid description of translocation dynamics for sufficiently high pore friction for the range of polymer lengths considered here. Increasing N will require a corresponding increase in pore friction to maintain the validity of the FP approach. Outside the regime of low N and high pore friction, the polymer is out of equilibrium, and the FP approach is not valid.Comment: 13 pages, 11 figure

An exploration of the accentuation effect: errors in memory for voice fundamental frequency (F0) and speech rate

The accentuation effect demonstrates how memory often reflects category typical representations rather than the specific features of learned items. The present study investigated the impact of manipulating fundamental frequency (F0) and speech rate (syllables per second) on immediate target matching performance (selecting a voice from a pair to match a previously heard target voice) for a range of synthesised voices. It was predicted that when participants were presented with high or low frequency target voices, voices even higher or lower in frequency would be selected. The same pattern was also predicted for speech rate. Inconsistent with the accentuation account, the results showed a general bias to select voices higher in frequency for high, moderate, and low frequency target voices. For speech rate, listeners selected voices faster in rate for slow rate target voices. Overall it seems doubtful that listeners rely solely on categorical information about voices during recognition

Earwitness memory: factors that influence voice recognition accuracy across the lifespan [poster presentation]

We aimed to explore the effect of change in frequency (F0 in Hz) and speech rate (syllables per second - SPS) on voice recognition accuracy. In part one of our experiment, participants (M=36; F=36; aged 18-30 years) were given a 2AFC voice matching task which involved hearing (binaural headphone presentation) synthesised (using NaturalReader 12) voices (uttering the phrase “spring is the season where flowers appear, summer is the warmest season of the year”). Participants had to identify whether the two voices were the ‘same’ or ‘different’ (using a key press, left/right). There were six target voices (six different identities, three male and three female) in total. In each trial the to be matched voices comprised the original voice or a modulated version (increased/decreased F0 or increased/decreased SPS) of the original voice presented in a random order. In part two of our experiment, the same participants heard the original voice and the modulated versions in a random order. After presenting each voice, participants had to decide whether the voice they heard was ‘male’ or ‘female’ (using a key press, left/right). Results from part one indicated that participants could discriminate a more subtle pitch shift than they could for speech rate. Results from part two indicated that participants correctly identified the sex of the speaker when SPS was modulated for both male and female voices, and when F0 was modulated for male voices. However, participants incorrectly identified a female voice as ‘male’ when F0 decreased. This suggests that both pitch and speech rate variations are important for accurate speaker identification and voice discrimination

Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-gamma in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-gamma production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56 bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-gamma. Blockade of IL-10 +/- TGF-beta restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-gamma, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-gamma persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-beta blockade

Studying the X-ray hysteresis in GX 339-4: the disc and iron line over one decade

We report on a comprehensive and consistent investigation into the X-ray emission from GX 339-4. All public observations in the 11 year RXTE archive were analysed. Three different types of model - single powerlaw, broken powerlaw and a disc + powerlaw - were fitted to investigate the evolution of the disc, along with a fixed gaussian component at 6.4 keV to investigate any iron line in the spectrum. We show that the relative variation in flux and X-ray colour between the two best sampled outbursts are very similar. The decay of the disc temperature during the outburst is clearly seen in the soft state. The expected decay is S_Disc \propto T^4; we measure T^4.75\pm0.23. This implies that the inner disc radius is approximately constant in the soft state. We also show a significant anti-correlation between the iron line significant width and the X-ray flux in the soft state while in the hard state the EW is independent of the flux. This results in hysteresis in the relation between X-ray flux and both line flux and EW. To compare the X-ray binary outburst to the behaviour seen in AGN, we construct a Disc Fraction Luminosity Diagram for GX 339-4, the first for an X-ray binary. The shape qualitatively matches that produced for AGN. Linking this with the radio emission from GX 339-4 the change in radio spectrum between the disc and power-law dominated states is clearly visible.Comment: Accepted for publication in MNRAS, 20 pages, 17 figures. For high-res version see http://www.astro.soton.ac.uk/~r.j.dunn/publications.htm

Cancellation of vorticity in steady-state non-isentropic flows of complex fluids

In steady-state non-isentropic flows of perfect fluids there is always thermodynamic generation of vorticity when the difference between the product of the temperature with the gradient of the entropy and the gradient of total enthalpy is different from zero. We note that this property does not hold in general for complex fluids for which the prominent influence of the material substructure on the gross motion may cancel the thermodynamic vorticity. We indicate the explicit condition for this cancellation (topological transition from vortex sheet to shear flow) for general complex fluids described by coarse-grained order parameters and extended forms of Ginzburg-Landau energies. As a prominent sample case we treat first Korteweg's fluid, used commonly as a model of capillary motion or phase transitions characterized by diffused interfaces. Then we discuss general complex fluids. We show also that, when the entropy and the total enthalpy are constant throughout the flow, vorticity may be generated by the inhomogeneous character of the distribution of material substructures, and indicate the explicit condition for such a generation. We discuss also some aspects of unsteady motion and show that in two-dimensional flows of incompressible perfect complex fluids the vorticity is in general not conserved, due to a mechanism of transfer of energy between different levels.Comment: 12 page

Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids

Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans

Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification

Background. Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. Method. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Results. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Conclusions. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment