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Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD), is characterized by chronic inflammation of the gastrointestinal tract and associated with aberrant CD4+ T-helper type 1 (Th1) and Th17 responses. Protein kinase 2 (CK2) is a conserved serine-threonine kinase involved in signal transduction pathways, which regulate immune responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3+ regulatory T cells. The function of CK2 in CD4+ T cells during the pathogenesis of CD is unknown. We utilized the T cell-induced colitis model, transferring CD45RBhi-naive CD4+ T cells from CK2αfl/fl controls and CK2αfl/fldLck-Cre mice into Rag1-/- mice. CD4+ T cells from CK2αfl/fldLck-Cre mice failed to induce wasting disease and significant intestinal inflammation, which was associated with decreased interleukin-17A-positive (IL-17A+), interferon-γ-positive (IFN-γ+), and double-positive IL-17A+IFN-γ+ CD4+ T cells in the spleen and colon. We determined that CK2α regulates CD4+ T cell proliferation through a cell-intrinsic manner. CK2α is also important in controlling CD4+ T cell responses by regulating NFAT2, which is vital for T cell activation and proliferation. Our findings indicate that CK2α contributes to the pathogenesis of colitis by promoting CD4+ T cell proliferation and Th1 and Th17 responses, and that targeting CK2 may be a novel therapeutic treatment for patients with CD.

The cGAS–cyclic GMP–AMP (cGAMP)–stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing–remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)–encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing–remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-β. Mechanistically, cGAMP MPs showed both IFN-I–dependent and –independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing–remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.

The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, caspase-1, ASC and NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1β and IL-18 secretion in myeloid cells3–6. Here we reveal an unexpected function of a DNA-binding inflammasome receptor, AIM2 (Absent in Melanoma 2)7–10, in T regulatory cells (Tregs) to restrain two models of autoimmunity (experimental autoimmune encephalomyelitis and T cell-mediated colitis) by studying whole-body and Treg-specific Aim2–/– mice. AIM2 is highly expressed by human and mouse Tregs, with its expression induced by TGF-β and its promoter occupied by transcription factors associated with Tregs, including Runx1, Ets1, Bcl11b and CREB. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates Akt-phosphorylation, mTOR, c-Myc and glycolysis, but promotes lipid oxidative phosphorylation in Tregs. Mechanistically, AIM2 interacts with the RACK1/PP2A-phosphatase complex to restrain Akt-phosphorylation. Lineage tracing demonstrates that AIM2 promotes the stability of Tregs during inflammation. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a T cell-intrinsic role of AIM2 in restraining autoimmunity by diminishing Akt-mTOR signaling and altering immune-metabolism to enhance Treg stability.

An extensive crosstalk between host and intestinal microbiota contributes to the development and maturation of intestinal epithelium and immune system. This review details the interplay between nucleotide-binding domain leucine-rich repeat containing proteins (NLR, or NOD-like receptors) signaling to host-microbiota homeostasis., The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat–containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.

Growing evidence demonstrates that the highly conserved serine/threonine kinase CK2 promotes Th17 cell differentiation while suppressing the generation of Foxp3+ regulatory T cells (Tregs); however, the exact mechanism by which CK2 regulates the Th17/Treg axis remains unclear. CK2 can be composed of three distinct subunits: two catalytic subunits, CK2α and CK2α′, and the regulatory subunit CK2β. We generated mice that lack the major catalytic subunit of CK2, CK2α, specifically in mature T cells using the distal Lck-Cre (CK2α−/−). Importantly, CK2α deficiency resulted in a significant decrease in the overall kinase activity of CK2. Further, CK2α deficiency resulted in a significant defect in Th17 cell polarization and a reciprocal increase in Tregs both in vitro and in vivo in the context of autoimmune neuroinflammation. The transcription factor forkhead box protein O1 (FoxO1) directly inhibits Th17 cell differentiation and is essential for the generation of Tregs. CK2α−/− CD4+ T cells exhibit less phosphorylated FoxO1 and a corresponding increase in the transcription of FoxO1-regulated genes. Treatment of CK2α−/− CD4+ T cells with the FoxO1 inhibitor AS1842856 or short hairpin RNA knockdown of FoxO1 is sufficient to rescue Th17 cell polarization. Through use of a genetic approach to target CK2 kinase activity, the current study provides evidence of a major mechanism by which CK2 regulates the Th17/Treg axis through the inhibition of FoxO1.

The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway is utilized by numerous cytokines and interferons, and is essential for the development and function of both innate and adaptive immunity. Aberrant activation of the JAK/STAT pathway is evident in neuroinflammatory diseases such as Multiple Sclerosis and Parkinson's Disease. Innate immunity is the front line defender of the immune system and is composed of various cell types, including microglia, macrophages and neutrophils. Innate immune responses have both pathogenic and protective roles in neuroinflammation, depending on disease context and the microenvironment in the central nervous system. In this review, we discuss the role of innate immunity in the pathogenesis of neuroinflammatory diseases, how the JAK/STAT signaling pathway regulates the innate immune response, and finally, the potential for ameliorating neuroinflammation by utilization of JAK/STAT inhibitors.

Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE, however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3ΔLysM mice show a hyper-activated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibit enhanced STAT3 activation, a hyper-activated phenotype in response to G-CSF, and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3ΔLysM mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.

Dysregulation of the JAK/STAT signaling pathway is associated with multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Suppressors of cytokine signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3(ΔLysM)), and that this atypical EAE is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE; however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3(ΔLysM) mice show a hyperactivated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibited enhanced signal transducer and activator of transcription 3 (STAT3) activation, a hyperactivated phenotype in response to granulocyte colony–stimulating factor (G-CSF), and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3(ΔLysM) mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are diseases with high mortality. Macrophages and neutrophils are responsible for inflammatory responses in ALI and ARDS, which are characterized by excessive production of proinflammatory mediators in bronchoalveolar lavage fluid (BALF) and plasma. Aberrant activation of the JAK/STAT pathway is critical for persistent inflammation in many conditions such as infection and autoimmunity. Given the importance of the STAT3 transcription factor in activating macrophages and neutrophils and augmenting inflammation, we investigated the therapeutic potential of inhibiting STAT3 activity using the small-molecule STAT3 inhibitor, LLL12. Our results demonstrate that LPS induces STAT3 activation in macrophages in vitro and in CD45+CD11b+ cells from BALF in the LPS-induced ALI model in vivo. LLL12 treatment inhibits LPS-induced lung inflammation in the ALI model, which is accompanied by suppression of LPS-induced STAT3 activation and an inhibition of macrophage and inflammatory cell infiltration in lung and BALF. LLL12 treatment also suppresses expression of proinflammatory genes including IL-1β, IL-6, TNF-α, iNOS, CCL2, and MHC class II in macrophages and inflammatory cells from BALF and serum as determined by ELISA. Furthermore, hyperactivation of STAT3 in LysMCre-SOCS3fl/fl mice accelerates the severity of inflammation in the ALI model. Both pre- and post-LPS treatment with LLL12 decrease LPS-induced inflammatory responses in mice with ALI. Importantly, LLL12 treatment attenuates STAT3 phosphorylation in human peripheral blood mononuclear cells induced by plasma from patients with ARDS, which suggests the feasibility of targeting the STAT3 pathway therapeutically for patients with ALI and ARDS.

Pathogenic CD4+ T cells and myeloid cells play critical roles in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These immune cells secrete aberrantly high levels of pro-inflammatory cytokines that pathogenically bridge the innate and adaptive immune systems and damage neurons and oligodendrocytes. These cytokines include interleukin-2 (IL-2), IL-6, IL-12, IL-21, IL-23, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon-γ (IFN-γ). It is, therefore, not surprising that both the dysregulated expression of these cytokines and the subsequent activation of their downstream signaling cascades is a common feature in MS/EAE. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is utilized by numerous cytokines for signal transduction and is essential for the development and regulation of immune responses. Unbridled activation of the JAK/STAT pathway by pro-inflammatory cytokines has been demonstrated to be critically involved in the pathogenesis of MS/EAE. In this review, we discuss recent advancements in our understanding of the involvement of the JAK/STAT signaling pathway in the pathogenesis of MS/EAE, with a particular focus on therapeutic approaches to target the JAK/STAT pathway.

Although it has historically been studied in the context of cancer, recent literature has highlighted the importance of the highly conserved serine/threonine kinase casein kinase II (CK2) in inflammatory disorders. Most strikingly, CK2 is a major regulator of the Th17–Treg axis relevant to many T cell-driven autoimmune disorders including multiple sclerosis (MS).

// G. Kenneth Gray 1 , Braden C. McFarland 1 , Amber L. Rowse 1 , Sara A. Gibson 1 and Etty N. Benveniste 1 1 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA Correspondence: Etty N. Benveniste, email: // Keywords : breast cancer, CK2, STAT3, NF-κB Received : June 24, 2014 Accepted : July 22, 2014 Published : July 23, 2014 Abstract Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/Akt/mTOR, NF-κB and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-κB and STAT3 activation and inducible NF-κB and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall, these results demonstrate the tremendous potential of CK2 as a clinical target in breast cancer.

A phenol formaldehyde (PF) adhesive was uniformly tagged with iodine such that it yielded sufficient X-ray computed tomography (XCT) gray-scale contrast for material segmentation in reconstructed wood-composite bondlines. Typically, untagged adhesives are organic and have a similar solid-state density as wood cell-walls, and therefore cannot be segmented quantitatively in XCT data. The iodinated PF development involved analysis and comparison of three trial adhesives containing rubidium, bromine, or iodine. Adhesive tag efficacy was measured in terms of X-ray absorption contrast enhancement and tag uniformity along the adhesive polymers. Cured adhesive density, tag element, and concentration were each found to significantly impact XCT contrast results, which in turn agreed with theoretical X-ray attenuation predictions for each resin. Ion chromatography confirmed the absence of free iodide in the liquid PF prior to bonding, and fluorescence microscopy and energy-dispersive spectroscopy (EDS) showed that iodine tags remained associated with the cured adhesive polymers. XCT and EDS results also demonstrated that when contrast agents are simply mixed into resins, rather than attached to the polymer chains, they are free to migrate independent of the penetrating adhesives during bonding. This then can cause complications with quantitative segmentation and analyses. The iodinated PF yielded consistent and uniform XCT gray-scale contrast; its formulation could be adjusted for other viscosity or molecular weight distribution, which would affect its penetration behavior.

Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase composed of two catalytic subunits (α) and/or (α') and two regulatory (β) subunits. The expression and kinase activity of CK2 is elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are highly tumorigenic and promote the resistance of GBM to current therapies. We previously reported that CK2 activity promotes prosurvival signaling in GBM. In this study, the role of CK2 signaling in BTIC function was examined. We found that expression of CK2α was increased in CD133+ BTICs compared to CD133- cells within the same GBM xenolines. Treatment with CX-4945, an ATP-competitive inhibitor of CK2, led to reduced expression of Sox2 and Nestin, transcription factors important for the maintenance of stem cells. Similarly, inhibition of CK2 also reduced the frequency of CD133+ BTICs over the course of 7 days, indicating a role for CK2 in BTIC persistence and survival. Importantly, using an in vitro limiting dilution assay, we found that inhibition of CK2 kinase activity with CX-4945 or siRNA knockdown of the CK2 catalytic subunits reduced neurosphere formation in GBM xenolines of different molecular subtypes. Lastly, we found that inhibition of CK2 led to decreased EGFR levels in some xenolines, and combination treatment with CX-4945 and Gefitinib to inhibit CK2 and EGFR, respectively, provided optimal inhibition of viability of cells. Therefore, due to the integration of CK2 in multiple signaling pathways important for BTIC survival, CK2 is a promising target in GBM.

CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4+ T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4+ T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3+ regulatory T cells (Tregs). These findings were associated with suppression of PI3K/Akt/mTOR activation and STAT3 phosphorylation upon CX-4945 treatment. Furthermore, we demonstrate that CX-4945 treatment inhibits the maturation of Th17 cells into inflammatory IFN-γ–coproducing effector cells. The Th17/Treg axis and maturation of Th17 cells are major contributing factors to the pathogenesis of many autoimmune disorders, including multiple sclerosis. Using a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrate that in vivo administration of CX-4945 targets Akt/mTOR signaling in CD4+ T cells and the Th17/Treg axis throughout disease. Importantly, CX-4945 treatment after disease initiation significantly reduced disease severity, which was associated with a significant decrease in the frequency of pathogenic IFN-γ+ and GM-CSF+ Th17 cells in the CNS. Our data implicate CK2 as a regulator of the Th17/Treg axis and Th17 cell maturation and suggest that CK2 could be targeted for the treatment of Th17 cell–driven autoimmune disorders.

Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that inhibition or genetic haploinsufficiency of protein kinase R-like endoplasmic reticulum kinase (PERK) can selectively control inflammation brought on by ER stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition led to reduced ER stress-induced inflammation (IL-6, CCL2, and CCL20 expression) without compromising prosurvival responses. In contrast, complete loss of PERK blocked canonical PERK-dependent UPR genes and promoted apoptosis. Reversal of eIF2α-mediated translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression, indicating that the selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2α phosphorylation and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally, ER-stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective immunoregulation in the context of ER stress without disrupting normal immune function.

There is evidence that major depressive disorder (MDD) is associated with increased peripheral markers of oxidative stress. To explore oxidation and antioxidant response in MDD, we assayed human dermal fibroblast cultures derived from skin biopsies of age-, race-, and sex-matched individuals in depressed and normal control groups ( n = 16 each group), cultured in glucose and galactose conditions, for relative protein carbonylation (a measure of oxidative stress), glutathione reductase (GR) expression, and total glutathione concentration. In control-group fibroblasts, galactose induced a significant increase from the glucose condition in both protein carbonylation and GR. The cells from the MDD group showed total protein carbonylation and GR expression in the glucose condition that was significantly higher than control cells in glucose and equivalent to controls in galactose. There was a small decrease in protein carbonylation in MDD cells from glucose to galactose and no significant change in GR. There was no difference in total glutathione among any of the groups. Increased protein carbonylation and GR expression, cellular responses to oxidative stress induced by galactose in control fibroblasts, are present in fibroblasts derived from MDD patients and are not explainable by reduced GR or total glutathione in the depressed patients. These studies support the role of oxidative stress in the pathophysiology of MDD. Further confirmation of these findings could lead to the development of novel antioxidant approaches for the treatment of depression.

Like many cancers, glioma cells have an altered metabolic state and utilize glycolysis even in the presence of oxygen, and thus require a large amount of glucose. The ketogenic diet is a high fat, low carbohydrate, low protein diet that limits the amount of glucose, and theoretically starves tumor growth. In addition, recent reports have indicated that the gut microbiome can influence tumor growth as well as the effectiveness of certain therapeutic agents. In this study, we sought to determine if the ketogenic diet is an effective treatment for glioma, and to correlate changes in the healthy gut bacteria in response to the ketogenic diet. In an orthotopic mouse model of glioma, we found that mice fed the ketogenic diet had slightly increased survival compared to mice fed a normal diet. Comparing the composition of gut bacteria from animals on normal versus ketogenic diets, we found significant differences in several key microbes. Interestingly, we observed that there were several long-term ketogenic survivors implanted with intracranial tumors and displayed a significant increase in the percentage of microbes found in the murine gastrointestinal tract (F. rodentium and related microbes). We found that F. rodentium growth does not occur until day 21 on the diet; thus, F. rodentium could be introduced early as a probiotic and enhance anti-tumor effects of the ketogenic diet. Additionally, we found that the ketogenic diet increased the percentage of mature Th17 cells, potentially collaborating with the growth of F. rodentium to decrease tumor growth. No studies have ever evaluated a probiotic for therapeutic efficacy in glioma. As the ketogenic diet is very strict, and can negatively affect quality of life, a ketogenic-diet probiotic (healthy gut bacteria, similar to the probiotics in yogurt) may offer an alternative supplement and patients could possibly eat a modified (less strict) ketogenic diet.

International audience; Phenol formaldehyde (PF) resin containing low molecular weight hydroxymethyl phenol species and a water soluble hindered amine light stabilizer (HALS) was synthesized and used to treat wood veneers. Treated veneers were exposed to natural weathering for 25, 35 and 50 days and the effectiveness of the modified PF resins as photoprotective treatments for wood was assessed. We hypothesized that the photostability of veneers would be positively correlated with concentration of PF resin (10, 20 and 30% w/v) and HALS (1 or 2% w/w) in solutions used to treat veneers. There was an inverse relationship between resin concentration in treatment solutions and tensile strength losses of treated veneers exposed to natural weathering. Mass losses of veneers treated with solutions containing 20 or 30% PF resin were lower than those of veneers treated with 10% PF resin. The addition of 2% HALS to solutions containing 30% PF resin had a significant (p < 0.05) effect at restricting mass and tensile strength losses of treated veneers exposed to the weather for 50 days. A PF resin treatment containing 30% resin and 2% HALS was as effective as chromic acid (a noted photostabilizer for wood) at restricting mass and tensile strength losses of veneers during natural weathering. Treated veneer in a plywood-type composite became darker and redder when exposed outdoors, but the addition of HALS to the resin restricted color changes of veneer treated with 10% PF resin. A 30% PF resin treatment on its own or containing 2% HALS protected wood's cellular structure from destruction during accelerated weathering and restricted, but did not prevent delignification of wood. We conclude that the effectiveness of low molecular weight PF resin as a photoprotective treatment for wood can be improved by increasing the concentration of PF resin and by combining it with a water soluble HALS. (C) 2012 Elsevier Ltd. All rights reserved.

Remarkable increases in the performance of complex systems can be achieved by a collective approach to optimizing individual factors that influence performance. This approach, termed the aggregation of marginal gains, is tested here as a means of improving the performance of exterior clear-coatings. We focused on five factors that influence clear-coating performance: dimensional stability of wood; photostability of the wood surface; moisture ingress via end-grain; coating flexibility and photostability; and finally coating thickness. We performed preliminary research to select effective wood pre-treatments and durable clear-coatings, and then tested coating systems with good solutions to each of the aforementioned issues (factors). Red oak and radiata pine panels were modified with PF-resin, end-sealed, and thick acrylic, alkyd or spar varnishes were applied to the panels. Panels were exposed to the weather and the level of coating defects was assessed every year over a 4-year period. All of the coatings are performing well on PF-modified pine after 4 years’ outdoor exposure. In contrast, coatings failed after 2 years on unmodified pine and they are failing on PF-modified oak. We conclude that our approach shows promise. Future research will build on the current work by developing solutions to additional factors that influence clear-coating performance.

Parkinson’s Disease (PD) is an age-related, chronic neurodegenerative disorder. Activated microglia/macrophages and subsequent neuroinflammation is associated with the pathogenesis of PD. We have recently demonstrated that inhibiting the JAK/STAT pathway prevents neuroinflammation and neurodegeneration in an α-synuclein (α-syn) overexpression PD model by suppressing activation of immune responses. Our previous studies demonstrated that deletion of SOCS3, a negative regulator of the JAK/STAT pathway, in the myeloid cells (LysM-CreSOCS3fl/fl mice) resulted in polarization of the pro-inflammatory M1 macrophage phenotype, which have been implicated in contributing to PD pathogenesis. To better understand the function of M1 polarized macrophages in PD, we utilized the α-syn overexpression model in LysM-CreSOCS3fl/fl mice. Our results indicate that stimulation of SOCS3-deficient macrophages with a combination of α-syn and IFN-γ promotes a more pronounced M1 phenotype and higher levels of expression of MHC Class II, LRRK2, CD40, iNOS, TNF-α and IL-6, compared to SOCS3fl/fl cells. In the in vivo setting, the numbers of activated and infiltrating macrophages are increased in the midbrain of LysM-CreSOCS3fl/fl mice compared to SOCS3fl/fl mice at 4 weeks of a-syn transduction. Furthermore, there is enhanced MHC Class II expression and STAT3 activation in these activated macrophages from LysM-CreSOCS3fl/fl mice. Our novel findings demonstrate that dysregulation of the JAK/STAT pathway in myeloid cells contributes to neuroinflammation in PD by promoting the M1 macrophage phenotype. As such, targeting the JAK/STAT pathway to abrogate neuroinflammation and neurodegeneration may be a therapeutic strategy for PD patients.

The JAK/STAT signaling is critical for the initiation, regulation and termination of immune responses, and dysregulation of JAK/STAT signaling is associated with many pathological conditions such as multiple sclerosis. We previously demonstrated that myeloid lineage–specific deletion of SOCS3, a negative regulator of STAT3, resulted in a severe, non-resolving atypical form of experimental autoimmune encephalomyelitis (EAE). Mice with atypical EAE exhibit ataxia and tremors and are characterized by lesions, inflammatory infiltrates, elevated STAT3 activation, and increased cytokine and chemokine expression in the cerebellum. In the current study, our data indicate that the atypical EAE observed in LysMCre-SOCS3fl/fl mice is associated with elevated pro-inflammatory cytokines and chemokines in the cerebellum and brainstem. Greater numbers of infiltrating neutrophils were found in the cerebellum and brainstem of LysMCre-SOCS3fl/fl mice compared to SOCS3fl/fl mice, however, neutrophil numbers in the periphery were comparable. Infiltrating neutrophils in LysMCre-SOCS3fl/fl mice have hyper-activated STAT3 and express higher levels of IL-6 and CCL2. Recruitment of Ly6Chi monocytes in LysMCre-SOCS3fl/flmice is comparable to SOCS3fl/fl mice. During the peak stage of disease, LysMCre-SOCS3fl/fl mice had increased numbers of both Th1 and Th17 cells, and significantly increased numbers of IFN-γ+IL-17+ T cells in the cerebellum and brainstem, compared to SOCS3fl/fl mice. Depletion of neutrophils in LysMCre-SOCS3fl/fl mice prevented the atypical EAE phenotype, rather, classical EAE was observed. This study illustrates the critical function of neutrophils in the pathogenesis of atypical EAE.

Action Learning is a group process design that was developed for the purpose of solving intractable human problems in organisations. Organisations large and small have successfully used action learning for a variety of purposes: to solve problems, to develop the organisation’s learning capacity, to build teams, to promote personal development and to develop leadership skills (Marquardt, 1999). This article describes a qualitative study that used interviews with experienced action learning coaches to answer the research question: How do action-learning coaches create a climate conducive to learning? The findings indicate that action-learning coaches use themselves as instruments to help unfreeze participants’ behaviour, introduce important changes and then refreeze behaviour at a higher and more effective level of functioning.