Model-based meta-analysis to optimise S. aureus-targeted therapies for atopic dermatitis

Several clinical trials of Staphylococcus aureus (S. aureus)-targeted therapies for atopic dermatitis (AD) have demonstrated conflicting results regarding whether they improve AD severity scores. This study performs a model-based meta-analysis to investigate possible causes of these conflicting results and suggests how to improve the efficacies of S. aureus-targeted therapies. We developed a mathematical model that describes systems-level AD pathogenesis involving dynamic interactions between S. aureus and Coagulase Negative Staphylococcus (CoNS). Our model simulation reproduced the clinically observed detrimental effects of application of S. hominis A9 (ShA9) and flucloxacillin on AD severity and showed that these effects disappeared if the bactericidal activity against CoNS was removed. A hypothetical (modelled) eradication of S. aureus by 3.0 log10 CFU/cm2, without killing CoNS, achieved comparable EASI-75 to dupilumab. This efficacy was potentiated if dupilumab was administered in conjunction with S. aureus eradication (EASI-75 at week 16; S. aureus eradication: 66.7%, dupilumab 61.6% and combination: 87.8%). The improved efficacy was also seen for virtual dupilumab poor responders. Our model simulation suggests that killing CoNS worsens AD severity and that S. aureus-specific eradication without killing CoNS could be effective for AD patients, including dupilumab poor responders. This study will contribute to design promising S. aureus-targeted therapy

Polar Antiferromagnets Produced with Orbital-Order

Polar magnetic states are realized in pseudocubic manganite thin films fabricated on high-index substrates, in which a Jahn-Teller (JT) distortion remains an active variable. Several types of orbital-orders were found to develop large optical second harmonic generation, signaling broken-inversion-symmetry distinct from their bulk forms and films on (100) substrates. The observed symmetry-lifting and first-principles calculation both indicate that the modified JT q2 mode drives Mn-site off-centering upon orbital order, leading to the possible cooperation of "Mn-site polarization" and magnetism.Comment: 5 pages, 4 figure

Near-Optimal Scheduling for LTL with Future Discounting

We study the search problem for optimal schedulers for the linear temporal logic (LTL) with future discounting. The logic, introduced by Almagor, Boker and Kupferman, is a quantitative variant of LTL in which an event in the far future has only discounted contribution to a truth value (that is a real number in the unit interval [0, 1]). The precise problem we study---it naturally arises e.g. in search for a scheduler that recovers from an internal error state as soon as possible---is the following: given a Kripke frame, a formula and a number in [0, 1] called a margin, find a path of the Kripke frame that is optimal with respect to the formula up to the prescribed margin (a truly optimal path may not exist). We present an algorithm for the problem; it works even in the extended setting with propositional quality operators, a setting where (threshold) model-checking is known to be undecidable

Layer dynamics of a freely standing smectic-A film

We study the hydrodynamics of a freely-standing smectic-A film in the isothermal, incompressible limit theoretically by analyzing the linearized hydrodynamic equations of motion with proper boundary conditions. The dynamic properties for the system can be obtained from the response functions for the free surfaces. Permeation is included and its importance near the free surfaces is discussed. The hydrodynamic mode structure for the dynamics of the system is compared with that of bulk systems. We show that to describe the dynamic correlation functions for the system, in general, it is necessary to consider the smectic layer displacement $u$ and the velocity normal to the layers, $v_z$, together. Finally, our analysis also provides a basis for the theoretical study of the off-equilibrium dynamics of freely-standing smectic-A films.Comment: 22 pages, 4 figure

An X-Ray Induced Structural Transition in La_0.875Sr_0.125MnO_3

We report a synchrotron x-ray scattering study of the magnetoresistive manganite La_0.875Sr_0.125MnO_3. At low temperatures, this material undergoes an x-ray induced structural transition at which charge ordering of Mn^3+ and Mn^4+ ions characteristic to the low-temperature state of this compound is destroyed. The transition is persistent but the charge-ordered state can be restored by heating above the charge-ordering transition temperature and subsequently cooling. The charge-ordering diffraction peaks, which are broadened at all temperatures, broaden more upon x-ray irradiation, indicating the finite correlation length of the charge-ordered state. Together with the recent reports on x-ray induced transitions in Pr_(1-x)Ca_xMnO_3, our results demonstrate that the photoinduced structural change is a common property of the charge-ordered perovskite manganites.Comment: 5 pages, 4 embedded EPS figures; significant changes in the data analysis mad

Ultrafast Photoinduced Formation of Metallic State in a Perovskite-type Manganite with Short Range Charge and Orbital Order

Femtosecond reflection spectroscopy was performed on a perovskite-type manganite, Gd0.55Sr0.45MnO3, with the short-range charge and orbital order (CO/OO). Immediately after the photoirradiation, a large increase of the reflectivity was detected in the mid-infrared region. The optical conductivity spectrum under photoirradiation obtained from the Kramers-Kronig analyses of the reflectivity changes demonstrates a formation of a metallic state. This suggests that ferromagnetic spin arrangements occur within the time resolution (ca. 200 fs) through the double exchange interaction, resulting in an ultrafast CO/OO to FM switching.Comment: 4 figure

Modeling gene expression regulatory networks with the sparse vector autoregressive model

<p>Abstract</p> <p>Background</p> <p>To understand the molecular mechanisms underlying important biological processes, a detailed description of the gene products networks involved is required. In order to define and understand such molecular networks, some statistical methods are proposed in the literature to estimate gene regulatory networks from time-series microarray data. However, several problems still need to be overcome. Firstly, information flow need to be inferred, in addition to the correlation between genes. Secondly, we usually try to identify large networks from a large number of genes (parameters) originating from a smaller number of microarray experiments (samples). Due to this situation, which is rather frequent in Bioinformatics, it is difficult to perform statistical tests using methods that model large gene-gene networks. In addition, most of the models are based on dimension reduction using clustering techniques, therefore, the resulting network is not a gene-gene network but a module-module network. Here, we present the Sparse Vector Autoregressive model as a solution to these problems.</p> <p>Results</p> <p>We have applied the Sparse Vector Autoregressive model to estimate gene regulatory networks based on gene expression profiles obtained from time-series microarray experiments. Through extensive simulations, by applying the SVAR method to artificial regulatory networks, we show that SVAR can infer true positive edges even under conditions in which the number of samples is smaller than the number of genes. Moreover, it is possible to control for false positives, a significant advantage when compared to other methods described in the literature, which are based on ranks or score functions. By applying SVAR to actual HeLa cell cycle gene expression data, we were able to identify well known transcription factor targets.</p> <p>Conclusion</p> <p>The proposed SVAR method is able to model gene regulatory networks in frequent situations in which the number of samples is lower than the number of genes, making it possible to naturally infer partial Granger causalities without any <it>a priori </it>information. In addition, we present a statistical test to control the false discovery rate, which was not previously possible using other gene regulatory network models.</p

Exploiting the Temporal Logic Hierarchy and the Non-Confluence Property for Efficient LTL Synthesis

The classic approaches to synthesize a reactive system from a linear temporal logic (LTL) specification first translate the given LTL formula to an equivalent omega-automaton and then compute a winning strategy for the corresponding omega-regular game. To this end, the obtained omega-automata have to be (pseudo)-determinized where typically a variant of Safra's determinization procedure is used. In this paper, we show that this determinization step can be significantly improved for tool implementations by replacing Safra's determinization by simpler determinization procedures. In particular, we exploit (1) the temporal logic hierarchy that corresponds to the well-known automata hierarchy consisting of safety, liveness, Buechi, and co-Buechi automata as well as their boolean closures, (2) the non-confluence property of omega-automata that result from certain translations of LTL formulas, and (3) symbolic implementations of determinization procedures for the Rabin-Scott and the Miyano-Hayashi breakpoint construction. In particular, we present convincing experimental results that demonstrate the practical applicability of our new synthesis procedure

Model Checking Branching Properties on Petri Nets with Transits (Full Version)

To model check concurrent systems, it is convenient to distinguish between the data flow and the control. Correctness is specified on the level of data flow whereas the system is configured on the level of control. Petri nets with transits and Flow-LTL are a corresponding formalism. In Flow-LTL, both the correctness of the data flow and assumptions on fairness and maximality for the control are expressed in linear time. So far, branching behavior cannot be specified for Petri nets with transits. In this paper, we introduce Flow-CTL* to express the intended branching behavior of the data flow while maintaining LTL for fairness and maximality assumptions on the control. We encode physical access control with policy updates as Petri nets with transits and give standard requirements in Flow-CTL*. For model checking, we reduce the model checking problem of Petri nets with transits against Flow-CTL* via automata constructions to the model checking problem of Petri nets against LTL. Thereby, physical access control with policy updates under fairness assumptions for an unbounded number of people can be verified.Comment: 23 pages, 5 figure