Virtual screening for inhibitors of the human TSLP:TSLPR interaction

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation

Out-of-equilibrium physics in driven dissipative coupled resonator arrays

Coupled resonator arrays have been shown to exhibit interesting many- body physics including Mott and Fractional Hall states of photons. One of the main differences between these photonic quantum simulators and their cold atoms coun- terparts is in the dissipative nature of their photonic excitations. The natural equi- librium state is where there are no photons left in the cavity. Pumping the system with external drives is therefore necessary to compensate for the losses and realise non-trivial states. The external driving here can easily be tuned to be incoherent, coherent or fully quantum, opening the road for exploration of many body regimes beyond the reach of other approaches. In this chapter, we review some of the physics arising in driven dissipative coupled resonator arrays including photon fermionisa- tion, crystallisation, as well as photonic quantum Hall physics out of equilibrium. We start by briefly describing possible experimental candidates to realise coupled resonator arrays along with the two theoretical models that capture their physics, the Jaynes-Cummings-Hubbard and Bose-Hubbard Hamiltonians. A brief review of the analytical and sophisticated numerical methods required to tackle these systems is included.Comment: Chapter that appeared in "Quantum Simulations with Photons and Polaritons: Merging Quantum Optics with Condensed Matter Physics" edited by D.G.Angelakis, Quantum Science and Technology Series, Springer 201

ERP evidence suggests executive dysfunction in ecstasy polydrug users

Background: Deficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users. Method: Twenty ecstasy–polydrug users, 20 non-ecstasy–polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded. Results: Analysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy–polydrug users

Signatures of a dissipative phase transition in photon correlation measurements

This work was supported by the Swiss National Science Foundation (SNSF) through the National Centre of Competence in Research - Quantum Science and Technology (NCCR QSIT). A.S., C.S., and S.H. acknowledge support by the State of Bavaria and the DFG within the Project Schn1376/3-1.Understanding and characterizing phase transitions in driven-dissipative systems constitutes a new frontier for many-body physics[1-8]. A generic feature of dissipative phase transitions is a vanishing gap in the Liouvillian spectrum [9], which leads to long-lived deviations from the steady state as the system is driven towards the transition. Here, we show that photon correlation measurements can be used to characterize the corresponding critical slowing down of non-equilibrium dynamics. We focus on the extensively studied phenomenon of optical bistability in GaAs cavity polaritons [10,11], which can be described as a first-order dissipative phase transition [12-14]. Increasing the excitation strength towards the bistable range results in an increasing photon-bunching signal along with a decay time that is prolonged by more than nine orders of magnitude as compared with that of single polaritons. In the limit of strong polariton interactions leading to pronounced quantum fluctuations, the mean-field bistability threshold is washed out. Nevertheless, the functional form with which the Liouvillian gap closes as the thermodynamic limit is approached provides a signature of the emerging dissipative phase transition. Our results establish photon correlation measurements as an invaluable tool for studying dynamical properties of dissipative phase transitions without requiring phase-sensitive interferometric measurements.PostprintPeer reviewe

The Pleiotropic CymR Regulator of Staphylococcus aureus Plays an Important Role in Virulence and Stress Response

We have characterized a novel pleiotropic role for CymR, the master regulator of cysteine metabolism. We show here that CymR plays an important role both in stress response and virulence of Staphylococcus aureus. Genes involved in detoxification processes, including oxidative stress response and metal ion homeostasis, were differentially expressed in a ΔcymR mutant. Deletion of cymR resulted in increased sensitivity to hydrogen peroxide-, disulfide-, tellurite- and copper-induced stresses. Estimation of metabolite pools suggests that this heightened sensitivity could be the result of profound metabolic changes in the ΔcymR mutant, with an increase in the intracellular cysteine pool and hydrogen sulfide formation. Since resistance to oxidative stress within the host organism is important for pathogen survival, we investigated the role of CymR during the infectious process. Our results indicate that the deletion of cymR promotes survival of S. aureus inside macrophages, whereas virulence of the ΔcymR mutant is highly impaired in mice. These data indicate that CymR plays a major role in virulence and adaptation of S. aureus for survival within the host

Tensor based multichannel reconstruction for breast tumours identification from DCE-MRIs

A new methodology based on tensor algebra that uses a higher order singular value decomposition to perform three-dimensional voxel reconstruction from a series of temporal images obtained using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is proposed. Principal component analysis (PCA) is used to robustly extract the spatial and temporal image features and simultaneously de-noise the datasets. Tumour segmentation on enhanced scaled (ES) images performed using a fuzzy C-means (FCM) cluster algorithm is compared with that achieved using the proposed tensorial framework. The proposed algorithm explores the correlations between spatial and temporal features in the tumours. The multi-channel reconstruction enables improved breast tumour identification through enhanced de-noising and improved intensity consistency. The reconstructed tumours have clear and continuous boundaries; furthermore the reconstruction shows better voxel clustering in tumour regions of interest. A more homogenous intensity distribution is also observed, enabling improved image contrast between tumours and background, especially in places where fatty tissue is imaged. The fidelity of reconstruction is further evaluated on the basis of five new qualitative metrics. Results confirm the superiority of the tensorial approach. The proposed reconstruction metrics should also find future applications in the assessment of other reconstruction algorithms

Activation of Methanogenesis in Arid Biological Soil Crusts Despite the Presence of Oxygen

Methanogenesis is traditionally thought to occur only in highly reduced, anoxic environments. Wetland and rice field soils are well known sources for atmospheric methane, while aerated soils are considered sinks. Although methanogens have been detected in low numbers in some aerated, and even in desert soils, it remains unclear whether they are active under natural oxic conditions, such as in biological soil crusts (BSCs) of arid regions. To answer this question we carried out a factorial experiment using microcosms under simulated natural conditions. The BSC on top of an arid soil was incubated under moist conditions in all possible combinations of flooding and drainage, light and dark, air and nitrogen headspace. In the light, oxygen was produced by photosynthesis. Methane production was detected in all microcosms, but rates were much lower when oxygen was present. In addition, the δ13C of the methane differed between the oxic/oxygenic and anoxic microcosms. While under anoxic conditions methane was mainly produced from acetate, it was almost entirely produced from H2/CO2 under oxic/oxygenic conditions. Only two genera of methanogens were identified in the BSC-Methanosarcina and Methanocella; their abundance and activity in transcribing the mcrA gene (coding for methyl-CoM reductase) was higher under anoxic than oxic/oxygenic conditions, respectively. Both methanogens also actively transcribed the oxygen detoxifying gene catalase. Since methanotrophs were not detectable in the BSC, all the methane produced was released into the atmosphere. Our findings point to a formerly unknown participation of desert soils in the global methane cycle

Increased sporulation underpins adaptation of Clostridium difficile strain 630 to a biologically–relevant faecal environment, with implications for pathogenicity

Abstract Clostridium difficile virulence is driven primarily by the processes of toxinogenesis and sporulation, however many in vitro experimental systems for studying C. difficile physiology have arguably limited relevance to the human colonic environment. We therefore created a more physiologically–relevant model of the colonic milieu to study gut pathogen biology, incorporating human faecal water (FW) into growth media and assessing the physiological effects of this on C. difficile strain 630. We identified a novel set of C. difficile–derived metabolites in culture supernatants, including hexanoyl– and pentanoyl–amino acid derivatives by LC-MSn. Growth of C. difficile strain 630 in FW media resulted in increased cell length without altering growth rate and RNA sequencing identified 889 transcripts as differentially expressed (p < 0.001). Significantly, up to 300–fold increases in the expression of sporulation–associated genes were observed in FW media–grown cells, along with reductions in motility and toxin genes’ expression. Moreover, the expression of classical stress–response genes did not change, showing that C. difficile is well–adapted to this faecal milieu. Using our novel approach we have shown that interaction with FW causes fundamental changes in C. difficile biology that will lead to increased disease transmissibility

Comparative analyses imply that the enigmatic sigma factor 54 is a central controller of the bacterial exterior

Contains fulltext : 95738.pdf (publisher's version ) (Open Access)BACKGROUND: Sigma-54 is a central regulator in many pathogenic bacteria and has been linked to a multitude of cellular processes like nitrogen assimilation and important functional traits such as motility, virulence, and biofilm formation. Until now it has remained obscure whether these phenomena and the control by Sigma-54 share an underlying theme. RESULTS: We have uncovered the commonality by performing a range of comparative genome analyses. A) The presence of Sigma-54 and its associated activators was determined for all sequenced prokaryotes. We observed a phylum-dependent distribution that is suggestive of an evolutionary relationship between Sigma-54 and lipopolysaccharide and flagellar biosynthesis. B) All Sigma-54 activators were identified and annotated. The relation with phosphotransfer-mediated signaling (TCS and PTS) and the transport and assimilation of carboxylates and nitrogen containing metabolites was substantiated. C) The function annotations, that were represented within the genomic context of all genes encoding Sigma-54, its activators and its promoters, were analyzed for intra-phylum representation and inter-phylum conservation. Promoters were localized using a straightforward scoring strategy that was formulated to identify similar motifs. We found clear highly-represented and conserved genetic associations with genes that concern the transport and biosynthesis of the metabolic intermediates of exopolysaccharides, flagella, lipids, lipopolysaccharides, lipoproteins and peptidoglycan. CONCLUSION: Our analyses directly implicate Sigma-54 as a central player in the control over the processes that involve the physical interaction of an organism with its environment like in the colonization of a host (virulence) or the formation of biofilm