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Abstract Propylene glycol:water mixtures are usually employed as heat transfer fluids because of their protection against low freezing temperatures and non-toxicity. They are used as working fluids in different applications, like those based on renewable sources such as solar thermal or geothermal energy. In this work, the convection heat transfer coefficients and the pressure drops of various functionalized graphene nanoplatelet nanofluids with a propylene glycol:water mixture at 30:70% mass ratio as base fluid have been experimentally determined. Thus, the heat transfer performance of nanoadditive mass concentrations up to 1.0% at different working temperatures from (298.15–313.15) K and flow rates from (0.2–0.7) m3·h−1 has been evaluated by means of an experimental setup whose main element is a double pipe heat exchanger of stainless steel. Enhancements of the convection heat transfer coefficient reaching 15.3% have been found for the 0.75% mass concentration. Furthermore, a dimensionless analysis has been carried out and new correlations were provided in order to predict Nusselt number and friction factor as a function of other dimensionless parameters. Maximum deviations for Nusselt number and friction factor of 2.5% and 1.5% were achieved, respectively. Finally, thermal performance factors were also obtained for each condition with the aim of evaluating the thermal effectiveness of all the prepared nanofluids with respect to the base fluid. Graphical abstract Image 1 Highlights • Heat transfer of graphene nanoplatelet nanofluids based on propylene glycol-water. • Analysis of experimental convection heat transfer coefficients and pressure drops. • Convection heat transfer coefficient increases 15.3% for 0.75 wt% nanofluid. • 0.50 wt% nanofluid achieves maximum thermal performance factor of 1.074. • Models for Nusselt number and Darcy friction factor with deviations of 2.5 and 1.5%. [ABSTRACT FROM AUTHOR]

The thermal conductivity of the heat transfer fluids commonly used in industrial processes is a major concern in the continuous searching of their performance improvement. During last decades, dispersions of high thermal conductivity nanoparticles in conventional fluids, nanofluids, have received increasingly attention to achieve this aim. The thermophysical properties, not commonly available in the literature, are necessary to describe their thermo-fluid behaviour. Thus, characterization studies become necessary to evaluate the potential heat transfer enhancements. This work presents the thermophysical profile according to the properties with a noticeable influence on the heat transfer capability of different functionalized graphene nanoplatelet dispersions (0.25, 0.50, 0.75 and 1.0) wt% in a propylene glycol-water mixture at (30:70)% mass ratio, usually employed in thermal facilities. Initially, nanofluid stability was investigated optimizing the pH value by analysing zeta potential measurements. Then, densities, heat capacities, thermal conductivities, and dynamic viscosities were experimentally determined throughout the temperature range from (293.15 to 323.15) K. Density was studied by using a pycnometric technique and results were used to analyze the isobaric thermal expansivity behaviour. A differential scanning calorimeter was utilized to obtain heat capacities and thermal conductivities were measured for the nanopowder, base fluid and nanofluids through devices based on the guarded heat flow meter method and the transient hot wire technique. Furthermore, rheological behaviour was analysed by means of a rotational rheometer with cone-plate geometry. Conductivity enhancements up to 16% with respect to base fluid were achieved. Finally, potential enhancements of heat transfer performance in laminar and turbulent flow were investigated through an analysis of different figures of merit based on the experimental results. [ABSTRACT FROM AUTHOR]

The frequency and the gravity of allergic reactions to insulin have decreased substantially with the availability of recombinant DNA-human insulins. Today, the frequency of immediate reactions is estimated to be on the order of 10%. Most of these allergic reactions are related to components of these preparations other than insulin. The manifestations are usually benign and localized to the injection site. True insulin allergies are very rare. We report three cases of patients who presented generalized immediate allergic manifestations after insulin injections. Intradermal skin tests with a panel of recombinant DNA-human insulins were negative in nonallergic diabetic controls and non-diabetic controls but positive in our three patients, suggesting the occurrence of IgE-dependant systemic allergy to recombinant DNA-human insulin. [Copyright &y& Elsevier]

Summary Identifying novel targets for therapy in allergic disease: protein interactions inside the cell Therapy of allergic disease currently relies on pharmacological manipulation of mediators or immunotherapy. Drugs have been developed to target specific mediators and their receptors: for example antihistamines blocking the H1 receptor have been refined to maximize antagonism and reduce central side-effects or adverse effects of activity on other receptors such as muscarinic cholinergic receptors. Traditional pharmacological approaches identify new surface receptors against which chemists will then design or screen compounds for activity: examples are H 3 or H 4 histamine receptors. With the advent of the sequenced human genome we are faced with a vast array of genes and proteins that interact to define normal physiology or indeed pathology. A major challenge to biotechnology is to evolve novel techniques to understand the function and interaction of these myriad proteins. One particular area of current interest is the signalling cascades downstream of surface receptors. For many years pathways have appeared overlapping and to offer little chance of specific intervention. However, greater understanding of the complexity and integration of signalling, together with the possibility of directing drugs to specific cells has aroused considerable interest in this area for novel therapeutics. Indeed, targeting events within the cell has been done for many years with steroids. Here, Jan Tavernier and colleagues describe some signalling pathways relevant to allergic disease and potential methods for understanding protein interactions that allow mapping of the cascades. In particular they describe an elegant new system of analysis of protein–protein interactions in a mammalian system, which they have developed, termed MAPPIT. The basis of the system is an engineered receptor with JAK kinase but which lacks STAT activation sites.... [ABSTRACT FROM AUTHOR]

As tumour necrosis serum kills malarial parasites in vitro and inhibits the multiplication of some species of Plasmodium in mice, we examined the effect of recombinant mouse tumour necrosis factor (rTNF) on P. yoelii both in vitro and in vivo. Parasites incubated overnight with rTNF showed no loss of viability, but repeated injection of rTNF into infected mice reduced parasitaemia and significantly prolonged survival of mice infected with a lethal variant of the parasite. We conclude that TNF acts on blood-stage malaria in vivo via a host cell and that another molecule in tumour necrosis serum is involved in killing the parasite in vitro. [ABSTRACT FROM AUTHOR]

Examines the role of cytokines in the pathogenesis of asthma. Aspects of the cytokine, tumor necrosis factor α; Inhibitory effect of pharmacological agents on late asthmatic reaction; Relationship between airway inflammation and bronchial hyperresponsiveness in asthma.

Several papers highlight methodological challenges related to the lifecycle assessment (LCA) of fruit production systems. These concern both the limited number of impact categories assessed in current LCA literature and the narrow view on the full production phase of an orchard cycle. This article addresses these challenges and contributes to improving the scientific knowledge on impacts associated with less productive years within an orchard cycle, and how these affect the impact associated with an entire fruit growing cycle. Using apple as a case study, an LCA is performed to obtain the impacts associated with young and old low productive trees, alongside those associated with trees in full production. Using the ILCD impact assessment method, the LCA is based on a large dataset of apple orchards in Flanders (Belgium), covering three production systems (conventional, integrated and organic production) and accounting for input and yield variability. The annual median impact values are used to describe a “typical” orchard for each orchard phase and production system. In conventional farming, lowest annual median impacts are mostly found in the full production phase while highest impacts are observed in the old low productive orchards. In integrated and organic production on the other hand, the lowest annual median impacts mostly occur in the old low productive orchards while highest impacts are found for the young low productive trees. Results for organic farming must however be interpreted with care, following the small sample size of organic producers. To calculate the impacts associated with a full orchard cycle, an orchard model was built based on the annual median impact within each apple bearing orchard phase and production system and using weighting factors based on the yields obtained within each of the orchard phases. Across the three production systems, the two low production phases are responsible for 27 to 38% of the calculated orchard cycle impact. Calculated impacts for the entire orchard cycle are, on average across the impact categories, higher than full production impacts in conventional and integrated farming, while lower in the case of organic farming. A mere focus on high productive trees leads to an underestimation of, on average, 18% in conventional farming and 11% integrated farming, versus an overestimation of 11% for organic farming. Inclusion of non-productive phases such as nursery and planting and destruction of the orchard, would further alter the orchard cycle impacts. [ABSTRACT FROM AUTHOR]

Protein interactions underlie the structural and functional integrity of many subcellular processes. The notion that most of the proteins within a cell are part of higher order complexes regulating signal transduction, gene expression, apoptosis and other crucial events, becomes generally accepted. Existing methodologies for large-scale protein interaction mapping include yeast two-hybrid, phage display and mass spectrometric analysis. Although these approaches have found wide application, each of them suffers from intrinsic limitations, not at least from the fact that interactions are analyzed in a non-physiological context. We have developed a cytokine receptor-based two-hybrid method in mammalian cells. Incorporation of an interaction trap in a signalling-deficient receptor allows identification of protein-protein interactions using a STAT-dependent complementation assay. Interaction between ‘bait’ and ‘prey’ leads to ligand-dependent STAT activation, which is detected by the use of STAT-dependent reporter/selector genes. Using this Mammalian Protein-Protein Interaction Trap (MAPPIT) we were able to demonstrate both modification-independent and phosphorylation-dependent interactions. MAPPIT can be used as screening tool, either to detect novel protein-protein interactions, or to search for inhibitors of known interactions. This MAPPIT procedure places protein-protein interactions in their normal physiological context and may be particularly instrumental for the in situ analysis of signal transduction pathways. [ABSTRACT FROM AUTHOR]

Highlights: [•] XBP1 splicing and RIDD activities are differentially regulated functions of the UPR transducer IRE1. [•] RIDD is a conserved ancestral mechanism regulating proteostasis in different eukaryotic phyla. [•] RIDD has a basal activity that is required to maintain ER homeostasis. [•] XBP1 splicing and RIDD produce opposite effects on cell fate in cells subjected to ER stress. [Copyright &y& Elsevier]

Commercial broiler chickens are exposed to a number of potential stressors prior to slaughter, including catching, crating, and transportation. To ameliorate animal welfare and prevent product quality loss during these processes, numerous scientific studies have been performed. As a result, different technical innovations have been presented such as mechanical catching instead of manual catching. The success of a catching machine as an alternative for manual catching of broilers will not only depend on its economic, animal, and human welfare benefits but also on its acceptance by society and consumers. The aim of this research was to assess if individuals' subjective perceptions of catching methods align with objective scientific facts. This research was focused on questions and issues related to the consumers' expected bottlenecks and motives for accepting these technologies after being exposed to video segments of each catching method. In general, the gap between consumer perception and scientific evidence related to manual and mechanical catching is limited. For those bottlenecks where science is inconclusive, respondents also have no explicit preference. Despite absence of major gaps between consumer perception and expert knowledge, preferences of particular consumer segments do not align well with scientific evidence. This holds in particular for female, younger, urban individuals who attach high importance to animal welfare issues. [ABSTRACT FROM AUTHOR]

Growing interest in ameliorating animal welfare has prompted numerous studies that compare various aspects of manual and mechanical catching. In general, mechanical catching has been adopted as a realistic alternative for manual catching. The success of a catching machine as an alternative for manual catching does not only depend on its practical applicability, but also on its acceptance by "the general public." In the history of technological change, public perception of new technologies has often been ambivalent. Against this background, it is important to know how consumers perceive the production methods. This paper provides an evaluation of the preferences for catching methods by "society" to investigate whether there is a shift in preference due to the confrontation with video segments and the potential effect of awareness and importance attached to animal welfare on preference. Data were gathered through a questionnaire-based survey, including 450 respondents, performed in Belgium. For this study, the data indicated that when subjects were provided information concerning catching methods of broilers, they liked the technology much more. However, for those respondents without prior awareness of both catching methods or with high importance attached to animal welfare, giving information could not convince them of the advantage of using a mechanical catching machine. It is obvious that preference varies with the awareness and experience of the respondents. Future research should move forward from simple assessments of consumer concerns about the technologies and focus more directly on questions and issues related to the consumer's expected bottlenecks of these technologies. In this way, working at a better understanding can directly influence the acceptance of these technologies. [ABSTRACT FROM AUTHOR]

To investigate the role of IL-4 in vivo in allergic asthma, we developed a murine model of allergen-induced airway inflammation. Repeated daily exposures of actively immunized C57BL/6 mice to aerosolized ovalbumin (OVA) induced a peribronchial inflammation and an increase in eosinophils and lymphocytes in bronchoalveolar-lavage (BAL) fluid. In IL-4 deficient (IL4-/-) mice, treated in the same way, there were substantially fewer eosinophils in BAL and much less peribronchial inflammation compared with wild type mice. In this model, mast cell deficient (W/Wv) mice developed a similar degree of BAL eosinophilia and peribronchial inflammation as wild type mice, demonstrating that the mast cell is not required for the induction of chronic airway inflammation. In contrast, BAL eosinophilia and airway inflammation were absent in OVA-treated MHC ClassII deficient(B6.Aa-/-) mice which lack mature CD4+ T lymphocytes. In conclusion, these results indicate that IL-4 is a central mediator of allergic airway inflammation, regulating antigen-induced eosinophil recruitment into the airways by a T cell dependent mechanism. [ABSTRACT FROM AUTHOR]

The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease. [ABSTRACT FROM AUTHOR]

1. Due to intensive selection, broiler chickens became the most efficient meat-producing animals because of their fast growth, supported by a virtually unlimited voluntary feed intake. These characteristics cause many problems in the management of broiler breeder hens because of the negative correlation between muscle growth and reproduction effectiveness. 2. This problem, namely the fast muscle growth versus reproduction health paradox, induces a second paradox, acceptable reproduction and health versus hunger stress and impaired welfare, because broiler breeder hens require dedicated programmes of feed restriction (1) to maximise egg and chick production and (2) to avoid metabolic disorders and mortality in broiler breeders. 3. Given that poultry selection is a global large-scale business and chickens are a prolific species, improvement in profit can only be obtained by selecting on feed conversion and/or for higher breast meat percentage, which will intensify the broiler-breeder paradox. 4. New feeding strategies are being studied, but it is questionable if the paradox can be solved by management tools alone. Because breeding and selection are long-term processes, involving animals, farmers, consumers, industry, environment etc., a more sustainable breeding goal needs to be determined by a multidisciplinary approach and an open debate between several actors in the discussion. 5. Using dwarf broiler breeder hens could be one alternative, because dwarf hens combine relatively good reproductive fitness with ad libitum feeding. Another possibility is to accept lower broiler productivity by assigning economic values to welfare and including integrity traits in an extended breeding goal. [ABSTRACT FROM AUTHOR]

Background: Given the key role of interleukin-5 (IL-5) in eosinophil function, we investigated the regulated expression of the membrane-anchored (TM-IL-5Rα) isoform, or a secreted (SOL IL-5Rα) isoform, on both protein and transcript level in vitro and in vivo. Methods: A real-time PCR, FACS and ELISA were established to determine IL-5Rα isoform expression in peripheral blood and nasal tissue from control subjects and nasal polyp (NP) patients with or without asthma. Human peripheral blood eosinophils were incubated with IL-5 and were analyzed for SOL-IL-5Rα and TM-IL-5Rα mRNA and protein levels in comparison with CD-69 expression. Results: SOL-IL-5Rα and TM-IL-5Rα mRNA and protein expression was significantly increased in NP vs controls. In polyp tissue, SOL-IL-5Rα expression correlated to disease severity and eosinophils counts, whereas TM-IL-5Rα levels were inversely correlated to eosinophils counts and SOL-IL-5Rα expression. FACS analysis revealed increased CD-69 and decreased TM-IL-5Rα expression in NP tissue eosinophils vs blood eosinophils. Incubation of blood eosinophils with IL-5 caused up-regulation of CD-69 and down-regulation of TM-IL-5Rα after 2 and 24 h. Conclusion: The expression of SOL-IL-5Rα and TM-IL-5Rα differs according to the eosinophil activation state and localization in the body (blood vs tissue) and may therefore be involved in the fine-tuning of the eosinophil homeostasis. Exposure of eosinophils to IL-5 reduces their responsiveness to IL-5 by regulated expression of the IL-5Rα isoforms. Since, TM-IL-5Rα is down-regulated and SOL-IL-5Rα (antagonistic) is upregulated in NP tissue, our findings are important to understand the clinical trials with anti-IL-5 in humans. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-κB (NF-κB). TLR, IL-1R and TNF-R signaling to NF-κB converge on a common IκB kinase complex that phosphorylates the NF-κB inhibitory protein IκBα. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-κB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways. [ABSTRACT FROM AUTHOR]

Signals induced by granulocyte colony-stimulating factor (G-CSF), the major cytokine involved in neutrophil development, are tightly controlled by ligand-induced receptor internalization. Truncated G-CSF receptors (G-CSF-Rs) that fail to internalize show sustained proliferation and defective differentiation signaling. Steady-state forward routing also determines cell surface levels of cytokine receptors, but mechanisms controlling this are poorly understood. Here, we show that WD40 and suppressor of cytokine signaling (SOCS) box protein-2 (Wsb-2), an SOCS box-containing WD40 protein with currently unknown function, binds to the COOH-terminal region of G-CSF-R. Removal of this region did not affect internalization, yet resulted in increased membrane expression of G-CSF-R and enhanced proliferation signaling at the expense of differentiation induction. Conversely, Wsb-2 binding to the G-CSF-R reduced its cell surface expression and inhibited proliferation signaling. These effects depended on the SOCS box involved in ubiquitylation and on cytosolic lysines of G-CSF-R and imply a major role for ubiquitylation through the G-CSF-R C-terminus in forward routing of the receptor. Importantly, the Wsb-2 gene is commonly disrupted by virus integrations in mouse leukemia. We conclude that control of forward routing of G-CSF-R is essential for a balanced response of myeloid progenitors to G-CSF and suggest that disturbance of this balance may contribute to myeloid leukemia.Oncogene (2007) 26, 1985–1994. doi:10.1038/sj.onc.1210004; published online 25 September 2006 [ABSTRACT FROM AUTHOR]

Abstract: The adipocyte-secreted hormone leptin participates in the regulation of hematopoiesis and enhances proliferation of hematopoietic cells. We used an adaptation of the MAPPIT mammalian two-hybrid method to study leptin signalling in a hematopoietic setting. We confirmed the known interactions of suppressor of cytokine signalling 3 (SOCS3) and STAT5 with the Y985 and Y1077 motifs of the leptin receptor, respectively. We also provide evidence for novel interactions at the Y1077 motif, including phospholipase C gamma and several members of the SOCS protein family, further underscoring the important role of the Y1077 motif in leptin signalling. [Copyright &y& Elsevier]

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists. [Copyright &y& Elsevier]

Background: Alternative splicing of the interleukin-5 receptor alpha (IL-5Rα )-subunit leads to the generation of a signalling, membrane-anchored (TM) isoform, or a secreted [soluble (SOL)], antagonistic variant. Given the key role of IL-5 in eosinophil function, we investigated SOL IL-5Rα expression pattern in an eosinophil-associated disease such as nasal polyposis (NP). Methods: An SOL IL-5Rα enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction (PCR) were established and applied in serum, nasal secretion and nasal tissue of controls (n = 12), and NP patients (n = 42) with or without asthma. Results: Analysis of serum, nasal secretion, and nasal tissue samples revealed that SOL IL-5Rα protein concentrations were significantly increased in NP vs control tissue. Within the NP group, there was a significant up-regulation of SOL IL-5Rα in patients with systemic airway disease. These findings were confirmed at the mRNA level, using an optimized real-time reverse-transcriptase PCR procedure. Conclusions: This report demonstrates SOL IL-5Rα transcript and protein up-regulation in NP. Soluble IL-5Rα differentiates nasal polyps with or without concomitant asthma. As SOL IL-5Rα is strongly up-regulated for disease and has antagonistic properties in vitro , our studies shed new light on the mechanisms of specific immunomodulatory therapies, such as anti-IL-5. [ABSTRACT FROM AUTHOR]

Alors que l'obésité induit une altération de l'équilibre postural, cet effet se voit renforcer chez 50 % de cette population obèse à cause de douleur chronique. La pratique de l'hypnose clinique apparaît être une méthode efficace pour soulager la douleur. L'objectif de cette étude est de quantifier les effets d'un programme de trois semaines d'hypnose clinique sur le contrôle postural de patients douloureux chroniques obèses. Un groupe suivant un programme de trois séances d'hypnose (GH : n = 14 ; 55,6 ± 6,5 ans ; 11 femmes), et un groupe contrôle suivant un programme d'éducation thérapeutique du patient (GETP : n = 12 ; 47,3 ± 14,7 ans ; 9 femmes) ont réalisé des tests d'équilibre en condition bipodale les yeux ouverts (YO) et les yeux fermés (YF) (3 essais de 30 secondes par condition). Le score de douleur moyenne (échelle visuelle analogique [EVA] de 0 à 10) a été évalué avant et après l'intervention. Les paramètres posturographiques de vitesse moyenne, et d'amplitude antéropostérieure, du déplacement du centre de pression ont été recueillis via une plateforme stabilométrique. Nos résultats indiquent une diminution significative du score de douleur moyenne seulement pour le GH (p < 0,001). Alors qu'aucune différence significative n'est observé pour GETP, l'analyse statistique révèle une diminution significative de l'amplitude antéropostérieure en condition YO (−17 %, p < 0,05) et YF (−15 %, p < 0,05) pour le GH. Notre étude indique que la diminution de douleur induite par un programme d'hypnose clinique permet d'améliorer le contrôle postural. La diminution de la douleur pourrait être à l'origine d'une amélioration de l'intégration sensorielle, notamment au niveau proprioceptif. [ABSTRACT FROM AUTHOR]

The activity of Signal Transducer and Activator of Transcription (STAT) proteins is regulated by a multitude of posttranslational modifications, which control different aspects of signal transduction. In particular, lysine acetylation and deacetylation has emerged as a critical modification, regulating the activity of all seven STAT members. Unlike tyrosine phosphorylation/dephosphorylation, which mainly acts as an on/off switch of STAT activity, the control exerted by acetylation appears multifaceted and by far more complex, exerting distinct and even opposed regulation to different STAT members. We observed that type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide siRNA screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as a novel regulator of STAT activity. Sin3a directly interacts with STAT3 and controls its acetylation status, its nuclear accumulation and DNA binding, strongly influencing the transcription of a subset of STAT3-responsive genes. Interfering with Sin3a expression restores, at least partially, the STAT3 transcriptional blockade observed upon IFN treatment. Strikingly, Sin3a exerts opposed regulation on ISGF3 activity, as it is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. We conclude that Sin3a contributes to the regulation of the balance between the activities of different STAT members, and interfering with its activity or expression may re-direct cytokine signals, favoring the onset of pathological conditions, such as autoimmune syndromes, inflammation and cancer. [ABSTRACT FROM AUTHOR]

Introduction: Tyrosine phosphorylation is a hallmark for activation of Signal Transducer and Activator of Transcription (STAT) proteins, but their transcriptional activity also depends on other secondary modifications. Type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Methods: Simultaneous treatment with IFNa2 and Trichostatin A, as well as combined HDAC1/HDAC2 silencing, restores STAT3-dependent reporter gene and endogenous genes expression, strongly suggesting that HDAC1 and HDAC2 are directly involved in repressing IFNa-activated STAT3. We used the IFN-dependent STAT3 transcriptional blockade as read-out for a genome-wide RNAi repressor screen. Results: Quite significantly, we identified multiple partners of the Sin3a/HDAC transcriptional repressor complex as negative regulators of STAT3 transcriptional activity, regardless to the STAT3 activating stimulus. Sin3a directly interacts with STAT3 and controls its acetylation status, its nuclear accumulation and DNA binding, strongly influencing the transcription of a subset of STAT3-responsive genes. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. Conclusion: The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch. [ABSTRACT FROM AUTHOR]