STAT

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed.

Interest in multioutput kernel methods is increasing, whether under the guise of multitask learning, multisensor networks or structured output data. From the Gaussian process perspective a multioutput Mercer kernel is a covariance function over correlated output functions. One way of constructing such kernels is based on convolution processes (CP). A key problem for this approach is efficient inference. Alvarez and Lawrence (2009) recently presented a sparse approximation for CPs that enabled efficient inference. In this paper, we extend this work in two directions: we introduce the concept of variational inducing functions to handle potential non-smooth functions involved in the kernel CP construction and we consider an alternative approach to approximate inference based on variational methods, extending the work by Titsias (2009) to the multiple output case. We demonstrate our approaches on prediction of school marks, compiler performance and financial time series.

In this paper, we introduce a new extension of the Singular Spectrum Analysis (SSA) called functional SSA to analyze functional time series. The new methodology is developed by integrating ideas from functional data analysis and univariate SSA. We explore the advantages of the functional SSA in terms of simulation results and two real data applications. We compare the proposed approach with Multivariate SSA (MSSA) and dynamic Functional Principal Component Analysis (dFPCA). The results suggest that further improvement to MSSA is possible, and the new method provides an attractive alternative to the dFPCA approach that is used for analyzing correlated functions. We implement the proposed technique to an application of remote sensing data and a call center dataset. We have also developed an efficient and user-friendly R package and a shiny web application to allow interactive exploration of the results.

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longit...

IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical “type 2” immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle...

STAT6 has an important role in the IL-4 / IL-13 signalling pathway. Genome - wide association studies have shown that particular polymorphism (SNP) or haplotype variants of STAT6 as well as epigenetic gene modifications are associated with IgE level and asthma in childhood. A review of the available literature was performed to map out the function and signalling pathway of STAT6, studies of STAT6 SNPs association with susceptibility to asthma and atopy, covering the years 1997 - 2012 were summarized, and the value of epigenetic and epistatic influences on STAT6 and their relevance to the development of the studied phenotype (atopy or asthma) were determined. There are 2 SNPs (rs71802646 and rs320411) with clinical association and proven functional effect on STAT6 expression. The effect of STAT6 SNPs cumulates in haplotypes and more potently during interaction with SNPs in the genes from the signalling pathway (IL4, IL4Ra, and IL13). Expression of STAT6 is also influenced by DNA meth...

The pervasive use of prevalent cohort studies on disease duration increasingly calls for an appropriate methodology to account for the biases that invariably accompany samples formed by such data. It is well-known, for example, that subjects with shorter lifetime are less likely to be present in such studies. Moreover, certain covariate values could be preferentially selected into the sample, being linked to the long-term survivors. The existing methodology for estimating the propensity score using data collected on prevalent cases requires the correct conditional survival/hazard function given the treatment and covariates. This requirement can be alleviated if the disease under study has stationary incidence, the so-called stationarity assumption. We propose a nonparametric adjustment technique based on a weighted estimating equation for estimating the propensity score which does not require modeling the conditional survival/hazard function when the stationarity assumption holds. T...

The signal transducer and activator of transcription 3 (STAT3) transduces stress signals from the plasma membrane to the nucleus but has recently also been identified in mitochondria. Inhibition of cardiomyocyte mitochondrial STAT3 with the STAT3-specific inhibitor Stattic decreases ADP-stimulated respiration and enhances calcium-induced mitochondrial permeability transition pore (MPTP) opening. The aim of the present study was to analyze whether or not these effects of STAT3 inhibition by Stattic are mediated by the formation of reactive oxygen species (ROS).
The H2O2 formation from isolated rat left ventricular mitochondria was measured continuously in the presence of the complex 1 substrates glutamate and malate using the H2O2 indicator Amplex UltraRed. Stattic dose-dependently increased mitochondrial ROS formation (slope of Amplex UltraRed fluorescence/time; DMSO: 0.39±0.01; 1 µM Stattic: 0.40±0.03; 10 µM Stattic: 0.71±0.04; 25 µM Stattic: 1.43±0.05; 50 µM Stattic: 3.53±0.23; 100 µM Stattic: 9.23±0.69, n=5 mitochondrial preparations, p<0.05 for 10-100 µM Stattic). The increase in the ROS signal by 100 µM Stattic was abolished in the presence of the ROS scavenger N-acetylcysteine (Nac, 0.46±0.02, n=7, p<0.05).

Mitochondria treated with 100 µM Stattic produced less ATP than control mitochondria (86±3 arbitrary units (a.u.) vs. 128±7 a.u., n=9, p<0.05). Again, in the presence of Nac ATP production was similar between Stattic-treated and control mitochondria (142±4 a.u. vs. 147±12 a.u., n=5, p=ns).

MPTP opening was induced by lower amounts of calcium in Stattic-treated than in control mitochondria (in nmol CaCl2/mg protein, Stattic: 507±57, n=7; control: 857±70, n=7, p<0.05). There was no difference in calcium-induced MPTP opening between Stattic-treated (833±57, n=6) and control mitochondria (921±75, n=7, p=ns) in the presence of Nac.

Taken together, our data show that inhibition of mitochondrial STAT3 by Stattic impacts on mitochondrial ATP production and MPTP opening through enhanced ROS formation.

Poxviruses currently are known to disrupt Jak-STAT signal transduction induced by interferon (IFN) through two distinct mechanisms: (1) secreted poxviral IFN decoy receptors that prevent the initiation of IFN signaling from type I or II receptors at the cell surface; and (2) poxviral phosphatase that dephosphorylates STAT1 intracellularly. Here, we report a novel mechanism by which poxviruses can inhibit Jak-STAT signaling in response to type I IFN. Myxoma virus (MV) is a highly species-restricted member of the poxvirus family that infects only rabbits under the natural setting. Interestingly, primary human fibroblasts support a permissive MV infection that is only partially sensitive to the antiviral state induced by type I IFN. In this study we show that when type I IFN is added to primary human fibroblasts following MV infection, the tyrosine phosphorylation of the Janus kinase Tyk2 is specifically blocked, thereby preventing the subsequent activation of downstream STAT1 and STAT...

Rheumatoid arthritis (RA) is a multifactorial disease that is increasing in incidence worldwide. It is associated with a complex mode of inheritance, with many genes being involved in the development and progression of the disease. Genome-wide association studies in ...

Summary
Estabilshment, activity and dissolution of religious communities is achieved
in accordance with a series of legal rules adopted by the Soviet state that
made up the socalled „Law of religions”. Between legislative acts constituting
the „law cults” are two main important: „The Decree on Separation of Church
from State and School from Church” adopted by the Council of People’s Commissars
of the Russian Soviet Federative Socialist Republic on January (20 February),
1918 came into force on January 23 (February 5) of the same year, on
the day of official publication, and „On Religious Associations”, Resolution of
the Central Executive Committee and SNK of the RSFSR Aprilie 8, 1929.
In this article examines how to set up and liquidation of religious communities
in accordance with these two laws, and other that regulate religious
activity of communities during 1944-1965 in the USSR, including the Moldavian
SSR.

β-Cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for β-cell apoptosis by studying the sensitivity of β-cells from STAT-1 knockout (−/−) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1−/− mice were completely resistant to interferon (IFN)-γ (studied in combination with interleukin [IL]-1β)-mediated cell death (92 ± 4% viable cells in STAT-1−/− mice vs. 56 ± 3% viable cells in wild-type controls, P ≤ 0.001) and had preserved insulin release after exposure to IL-1β and IFN-γ. Moreover, analysis of cell death in cytokine-exposed purified β-cells confirmed that protection was due to absence of STAT-1 in the β-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducibl...

Identification of genes/proteins involved in pluripotency and their inter-relationships is important for understanding the induction/loss and maintenance of pluripotency. With the availability of large volume of data on interaction/regulation of pluripotency scattered across a large number of biological databases and hundreds of scientific journals, it is required a systematic integration of data which will create a complete view of pluripotency network. Describing and interpreting such a network of interaction and regulation (i.e., stimulation and inhibition) links are essential tasks of computational biology, an important first step in systems-level understanding of the underlying mechanisms of pluripotency. To address this, we have assembled a network of 166 molecular interactions, stimulations and inhibitions, based on a collection of research data from 147 publications, involving 122 human genes/proteins, all in a standard electronic format, enabling analyses by readily availab...

Previous studies indicate that Stat5 expression is required for mast cell development, survival, and IgE-mediated function. Stat5 tyrosine phosphorylation is swiftly and transiently induced by activation of the high affinity IgE receptor, FcεRI. However, the mechanism for this mode of activation remains unknown. In this study we observed that Stat5 co-localizes with FcεRI in antigen-stimulated mast cells. This localization was supported by cholesterol depletion of membranes, which ablated Stat5 tyrosine phosphorylation. Through the use of various pharmacological inhibitors and murine knockout models, we found that IgE-mediated Stat5 activation is dependent upon Fyn kinase, independent of Syk, PI3K, Akt, BTK, and JAK2, and enhanced in the context of Lyn kinase deficiency. Stat5 immunoprecipitation revealed that un-phosphorylated protein pre-associates with Fyn, and that this association diminishes significantly during mast cell activation. SHP-1 tyrosine phosphatase deficiency modest...

The root cause for most cases of autosomal-dominant polycystic kidney disease (ADPKD) is mutations in the polycystin-1 (PC1) gene. While PC1 has been implicated in a perplexing variety of protein interactions and signaling pathways, what its normal function is and why its disruption leads to the proliferation of renal epithelial cells are unknown. Recent results suggest that PC1 is involved in mechanotransduction by primary cilia measuring the degree of luminal fluid flow. PC1 has also recently been shown to regulate the mTOR and signal transducers and activators of transcription (STAT) 6 pathways. These two pathways are normally dormant in the healthy kidney but are activated in response to injury and appear to drive a proliferative repair response. This review develops the idea that a critical function of PC1 and primary cilia in the adult kidney may be to sense renal injury by detecting changes in luminal fluid flow and to trigger proliferation. Constitutive activation of these p...

Corticosteroids are potent anti-inflammatory and immunosuppressive agents which down-regulate cytokine production and action. Yet, contradictory results have been reported for their effects on the interleukin (IL)-4-mediated response. Using type II Fc receptor for IgE/CD23 as a target gene, here we report that corticosteroids at 10(-4)-10(-6) M inhibit the IL-4 signaling pathway in human primary immune cells by down-regulation of the IL-4-induced IL-4 receptor expression and STAT6 activation. Although functional antagonism between steroid receptor and STAT6 for their transcriptional activity has been recently described, this is the first report that steroid inhibits the IL-4-induced STAT6 activity at the level of tyrosine phosphorylation and target DNA binding.