Circadian control of interferon-sensitive gene expression in murine skin.

The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factor IFN regulatory factor 7 (Irf7), were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lacking Bmal1 systemically had exacerbated and arrhythmic ISG/Irf7 expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day-dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment

The Ising Spin Glass in dimension four

The critical behaviors of the bimodal and Gaussian Ising spin glass (ISG) models in dimension four are studied through extensive numerical simulations, and from an analysis of high temperature series expansion (HTSE) data of Klein {\it et al.} (1991). The simulations include standard finite size scaling measurements, thermodynamic limit regime measurements, and analyses which provide estimates of critical exponents without any consideration of the critical temperature. The higher order HTSE series for the bimodal model provide accurate estimates of the critical temperature and critical exponents. These estimates are independent of and fully consistent with the simulation values. Comparisons between ISG models in dimension four show that the critical exponents and the critical constants for dimensionless observables depend on the form of the interaction distribution of the model.Comment: 10 pages, 15 figure

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription

Insulin secretory granules labelled with phogrin-fluorescent proteins show alterations in size, mobility and responsiveness to glucose stimulation in living β-cells

The intracellular life of insulin secretory granules (ISGs) from biogenesis to secretion depends on their structural (e.g. size) and dynamic (e.g. diffusivity, mode of motion) properties. Thus, it would be useful to have rapid and robust measurements of such parameters in living β-cells. To provide such measurements, we have developed a fast spatiotemporal fluctuation spectroscopy. We calculate an imaging-derived Mean Squared Displacement (iMSD), which simultaneously provides the size, average diffusivity, and anomalous coefficient of ISGs, without the need to extract individual trajectories. Clustering of structural and dynamic quantities in a multidimensional parametric space defines the ISGs’ properties for different conditions. First, we create a reference using INS-1E cells expressing proinsulin fused to a fluorescent protein (FP) under basal culture conditions and validate our analysis by testing well-established stimuli, such as glucose intake, cytoskeleton disruption, or cholesterol overload. After, we investigate the effect of FP-tagged ISG protein markers on the structural and dynamic properties of the granule. While iMSD analysis produces similar results for most of the lumenal markers, the transmembrane marker phogrin-FP shows a clearly altered result. Phogrin overexpression induces a substantial granule enlargement and higher mobility, together with a partial de-polymerization of the actin cytoskeleton, and reduced cell responsiveness to glucose stimulation. Our data suggest a more careful interpretation of many previous ISG-based reports in living β-cells. The presented data pave the way to high-throughput cell-based screening of ISG structure and dynamics under various physiological and pathological conditions

Finding Low-Temperature States with Parallel Tempering, Simulated Annealing and Simple Monte Carlo

Monte Carlo simulation techniques, like simulated annealing and parallel tempering, are often used to evaluate low-temperature properties and find ground states of disordered systems. Here we compare these methods using direct calculations of ground states for three-dimensional Ising diluted antiferromagnets in a field (DAFF) and three-dimensional Ising spin glasses (ISG). For the DAFF, we find that, with respect to obtaining ground states, parallel tempering is superior to simple Monte-Carlo and to simulated annealing. However, equilibration becomes more difficult with increasing magnitude of the externally applied field. For the ISG with bimodal couplings, which exhibits a high degeneracy, we conclude that finding true ground states is easy for small systems, as is already known. But finding each of the degenerate ground states with the same probability (or frequency), as required by Boltzmann statistics, is considerably harder and becomes almost impossible for larger systems.Comment: 14 pages, 9 figures. Accepted for publication at Int. J. of Mod. Phys. C, issue 14(3

Immunomodulatory Function of Interleukin 28B During Primary Infection With Cytomegalovirus

Background. Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication. Methods. We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs). Results. Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher "antiviral” ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01). Conclusions. We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication contro

Suppression and enhancement of the critical current in multiterminal S/N/S mesoscopic structures

We analyse the measured critical current $I_{m\text{}}$ in a mesoscopic 4-terminal S/N/S structure. The current through the S/N interface is shown to consist not only of the Josephson component $I_{c}\sin \phi ,$ but also a phase-coherent part $I_{sg}\cos \phi$ of the subgap current. The current $I_{m}$ is determined by the both components $I_{c}$ and $I_{sg},$ and depends in a nonmonotonic way on the voltage $V$ between superconductors and normal reservoirs reaching a maximum at $V\cong \Delta /e$. The obtained theoretical resultas are in qualitative agreement with recent experimental data.Comment: 4 page, 3 figures. To be puplished in PRB Rapid co