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|Erin Moore
Erin Moore is in her fifth season in a support role with the University of Michigan volleyball program. Moore returned to her alma mater in 2006 after spending two years away to play professionally. Moore continues to train during the college season and has played internationally during the spring and summer the last six years.
Moore became the first All-American in Wolverine volleyball history after a record-setting senior campaign in 2003. Moore was a two-time captain with the Wolverines, earning All-Big first team honors in 2002 and 2003, while picking up honorable mention All-Big Ten in 2001.
Moore played professionally for Criollas de Caguas (Puerto Rico), starring on the outside in 2006-07 and helping lead her club to a second place finish in the league. She played two seasons of professional volleyball with Playas Benidorm in Spain (2004-05, 2005-06) starting as an outside hitter and helping the team to a fourth-place finish in the 14-team league. In addition to playing against teams from Spain, Moore and Benidorm competed in CEW Cup tournaments throughout Europe, competing against some of the best professional teams in the world.
Moore holds the U-M single-season record for blocks (161) and still ranks among the top five players all-time in five statistical categories (kills, attack attempts, hitting percentage, total blocks, block assists).
» Learn about Michigan volleyball ticket opportunities for the 2016 season.
Michigan to Play Host to No. 1 Nebraska, Iowa in B1G Opener
Watch: Fifth-Year Senior Captains Lead Michigan into B1G Play
Rosen Report: Week 5 (vs. Nebraska, vs. Iowa)
No. 23 Michigan Defeats Colgate, Sweeps Home Tournament
Michigan Rolls Past Eastern Michigan in Saturday Matinee
No. 23 Michigan Tops Auburn in Home Tournament Opener
U-M to End Non-Conference Play with Michigan/EMU Challenge


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Discover the unknown cuisine of the Chinese nomads, known as the Hakka. Linda Lau Anusasananan, author of The Hakka Cookbook: Chinese Soul Food from around the World, talks about her journey to find her Hakka identity through food.
Linda Lau Anusasananan formerly worked as a food writer and recipe editor for 34 years at Sunset Magazine. There she created and tested thousands of recipes and wrote stories for the home cook. Her work has also appeared in Cooking Light, Yoga Journal, and Flavor and Fortune. For more information about the book, visit: http://TheHakkaCookbook.com
A book sale and signing will follow the program. Cash or check only.
This presentation will be in English.
Upcoming Events
- Intersecting Film, Music and Queerness
- Thursday, September 29, 2016, 6:30 pmMain Library, Latino/Hispanic Rms A & B
- Low Energy Radiation from Our Home and Media Appliances
- Sunday, October 9, 2016, 1:00 pmMain Library, Latino/Hispanic Rms A & B
- The Life and Art of Vincent Van Gogh
- Thursday, October 20, 2016, 7:00 pmSunset, Sunset Children's Area

subset: commoncrawl


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Need to run a Facebook ad
This project received 10 bids from talented freelancers with an average bid price of €56 EUR.Get free quotes for a project like this
Skills Required
Project Budget€8 - €30 EUR
Total Bids10
Project Description
I need someone to create a Facebook ad for me. I have tried using my facebook account myself, but it is now stuck in verifications by Facebook itself.
You will need to:
- create a new Facebook account. The new facebook account will become my property and shall be transferred to me completely.
- create a new ad according to my screenshot / requirements (I already have a target audience defined)
- let it run for 3 days, up to a maximum of 10 dollars a day.
In return, I will pay you the costs for the Facebook ad (maximum 30 dollars) + a fee for your effort.
To apply just write "Good person am I" in the first line of your proposal. Also mention what effort fee you want to get paid.
Note: The money will be paid after the three days, if the ad is displayed constantly by Facebook (without the account being suspended). Before payout the Facebook credentials shall be passed on to me.
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- Times Online


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The stars will shine on these Stars Milk Chocolate Lollipops!
Our Stars Milk Chocolate Lollipop Favors have a variety of star filled designs with your personalized message. Each individually wrapped Personalized Stars Milk Chocolate Lollipop measures 3 inches in diameter x 7 1/2 inches high and are 2.4 ounces of pure chocolate. Give your guests a Stars Milk Chocolate Lollipop Favor as they leave your star themed party! Assembly required. Bows not included.
Lollipop Ordering Instructions:
Please allow ample time for delivery. Our ship date for this product is noted in your shopping cart. Many items are shipped separately, so please allow extra time for these items to arrive. Shipping charges are based on the value of the merchandise and not the number of shipments. For additional shipping information, contact our Customer Service Department at (email@example.com or 1-800-227-2789).


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Experienced Motorcycle Riders
Seeking experienced male and female motorcycle riders. Candidates must have experience with a dirt bike style of motorcycle, have a valid Florida Motorcycle License, and have a clean driving record of 3 years.
Audition will consist of a type out audition. Following the type out audition select candidates will be asked to maneuver a small course to demonstrate skill and bike control.
Candidates must supply a photo, resume listing years of experience, and types of motorcycles ridden, and a valid endorsement at the time of the audition to be eligible to audition.
Candidates must be available for rehearsals from mid-September and for all remaining Halloween Horror Nights® performance dates: 9/29-10/2, 10-6-10/9, 10/12-10/16, 10/20-10/23, and 10/26-10/31.
Please submit a headshot and resume to firstname.lastname@example.com by 5pm on Saturday, October 1st.
Must be at least 18 years of age to audition and be able to provide proof of eligibility to work within the United States. Additional restrictions may apply.


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5 Reviews
This was a nice quick dish for a weeknight meal AND everyone at the table liked it. I did not serve it OVER the broccoli, just on the side of the veg. (personal preferences). After reading from others that the sauce was thin, I added an extra tablespoon of flour to the roux and used only about half of the chicken broth - until it was the consistency I liked. The flavor was very nice and the chicken was moist and tender. Looking forward to the Tetrazzini! Thanks for posting this - I'll be using it often!
On taste--it is a five star. I used Swiss cheese instead of Gruyere for the Divan ($15/lb not in the budget) and it was delicious. But the sauce is definately too watery. I added 2-3 T cornstarch mixed with a little cold water to the sauce and it thickened up nicely. Did this for OAMC and doubled the recipe. We ate one Divan for dinner that night and froze another--recommendation for freezing: since my family doesn't like mushy brocolli, I didn't cook the brocolli, just put the brocolli in and pour the warm sauce and chicken over it. Then it cooks just enough when reheating in the oven.
I thought I followed the recipe properly but the sauce was so watery on the divan I had to make a soup of it. Both recipes taste terrific.
Delicious! Not as easy as I like, but very yummy! A definite favorite.
I made both of these recipes last week and my husband and son could not get enough. We loved the flavor of the wine, cream & nutmeg in the sauce. I recommend them both highly. My son even ate the broccoli! When I try a new recipe I ask them if it is a "Hit" or a "Miss". They rated both of these as a definite "Hit".


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Bim Nuclear Translocation and Inactivation by Viral Interferon Regulatory Factor
Choi, Young Bong
Nicholas, John
PLoS Pathogens
Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8 (HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors (vIRFs 1–4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFβ receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, co-localization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication-induced apoptosis and suggest that inhibitory targeting of vIRF-1:Bim interaction may provide an effective antiviral strategy.
Author Summary
Human herpesvirus 8 (HHV-8) is a pathogen associated with cancers Kaposi's sarcoma (KS), an endothelial cell disease, and B cell malignancies primary effusion lymphoma and multicentric Castleman's disease. KS is particularly prevalent amongst HIV-positive populations in Africa and is a major health concern. Virus productive replication, in addition to latency, is important for maintaining viral load within the host and also for KS pathogenesis. Essential to HHV-8 and other virus replication is the control of innate host defenses, which comprise stress-sensing cellular signaling pathways that result ultimately in programmed cell death (apoptosis). Here we identify a novel mechanism whereby a viral protein, viral interferon regulatory factor-1 (vIRF-1), mediates inhibition of a stress sensor and initiator of apoptosis, Bim, by inducing its translocation to the cell nucleus and thereby sequestration away from the cytoplasmic compartment where it exerts its pro-death activity. We show that vIRF-1:Bim interaction is necessary for efficient HHV-8 productive replication and that it can be blocked using a cell-permeable antagonist of vIRF-1:Bim binding. Our data not only identify previously unsuspected mechanisms of Bim inactivation and vIRF-1 function, but suggest that inhibitory targeting of vIRF-1 interaction with Bim may be of therapeutic benefit.
Related Articles
IRF5 activation in monocytes of SLE patients is triggered by circulating autoantigens independent of type I IFN
Stone, Rivka C.
Feng, Di
Deng, Jing
Singh, Sukhwinder
Yang, Lisong
Fitzgerald-Bocarsly, Patricia
Eloranta, Maija-Leena
Rönnblom, Lars
Barnes, Betsy J.
Arthritis and Rheumatism
Genetic variants of interferon regulatory factor 5 (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). IRF5 regulates the expression of proinflammatory cytokines and type I interferons (IFN) believed to be involved in SLE pathogenesis. The aim of this study was to determine the activation status of IRF5 by assessing its nuclear localization in immune cells of SLE patients and healthy donors, and to identify SLE triggers of IRF5 activation.
IRF5 nuclear localization in subpopulations of peripheral blood mononuclear cells (PBMC) from 14 genotyped SLE patients and 11 healthy controls was assessed using imaging flow cytometry. IRF5 activation and function were examined after ex vivo stimulation of healthy donor monocytes with SLE serum or components of SLE serum. Cellular localization was determined by ImageStream and cytokine expression by Q-PCR and ELISA.
IRF5 was activated in a cell type-specific manner; monocytes of SLE patients had constitutively elevated levels of nuclear IRF5 compared to NK and T cells. SLE serum was identified as a trigger for IRF5 nuclear accumulation; however, neither IFNα nor SLE immune complexes could induce nuclear localization. Instead, autoantigens comprised of apoptotic/necrotic material triggered IRF5 nuclear accumulation in monocytes. Production of cytokines IFNα, TNFα and IL6 in monocytes stimulated with SLE serum or autoantigens was distinct yet correlated with the kinetics of IRF5 nuclear localization.
This study provides the first formal proof that IRF5 activation is altered in monocytes of SLE patients that is in part contributed by the SLE blood environment.
Related Articles
RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE
Stone, Rivka C.
Du, Peicheng
Feng, Di
Dhawan, Kopal
Rönnblom, Lars
Eloranta, Maija-Leena
Donnelly, Robert
Barnes, Betsy J.
PLoS ONE
Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next-generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype.
Related Articles
Multiple Regulatory Domains of IRF-5 Control Activation, Cellular Localization, and Induction of Chemokines That Mediate Recruitment of T Lymphocytes
Barnes, Betsy J.
Kellum, Merrill J.
Field, Ann E.
Pitha, Paula M.
Molecular and Cellular Biology
Transcription factors of the interferon regulatory factor (IRF) family have been identified as critical mediators of early inflammatory gene transcription in infected cells. We recently determined that, besides IRF-3 and IRF-7, IRF-5 serves as a direct transducer of virus-mediated signaling. In contrast to that mediated by the other two IRFs, IRF-5-mediated activation is virus specific. We show that, in addition to Newcastle disease virus (NDV) infection, vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infection activates IRF-5, leading to the induction of IFNA gene subtypes that are distinct from subtypes induced by NDV. The IRF-5-mediated stimulation of inflammatory genes is not limited to IFNA since in BJAB/IRF-5-expressing cells IRF-5 stimulates transcription of RANTES, macrophage inflammatory protein 1β, monocyte chemotactic protein 1, interleukin-8, and I-309 genes in a virus-specific manner. By transient- transfection assay, we identified constitutive-activation (amino acids [aa] 410 to 489) and autoinhibitory (aa 490 to 539) domains in the IRF-5 polypeptide. We identified functional nuclear localization signals (NLS) in the amino and carboxyl termini of IRF-5 and showed that both of these NLS are sufficient for nuclear translocation and retention in infected cells. Furthermore, we demonstrated that serine residues 477 and 480 play critical roles in the response to NDV infection. Mutation of these residues from serine to alanine dramatically decreased phosphorylation and resulted in a substantial loss of IRF-5 transactivation in infected cells. Thus, this study defines the regulatory phosphorylation sites that control the activity of IRF-5 in NDV-infected cells and provides further insight into the structure and function of IRF-5. It also shows that the range of IRF-5 immunoregulatory target genes includes members of the cytokine and chemokine superfamilies.
Related Articles
Genetic variants and disease-associated factors contribute to enhanced IRF-5 expression in blood cells of systemic lupus erythematosus patients
Feng, Di
Stone, Rivka C.
Program, MD/PhD
Eloranta, Maija-Leena
Sangster-Guity, Niquiche
Nordmark, Gunnel
Sigurdsson, Snaevar
Wang, Chuan
Alm, Gunnar
Syvänen, Ann-Christine
Rönnblom, Lars
Barnes, Betsy J.
Arthritis and rheumatism
Genetic variants of the interferon (IFN) regulatory factor 5 (IRF5) gene are associated with systemic lupus erythematosus (SLE) susceptibility. The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFN. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.
IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time PCR, minigene assay, and flow cytometry. The rs2004640, rs10954213, rs10488631 and the CGGGG indel were genotyped in these patients. Genotypes of these polymorphisms defined a common risk and protective haplotype.
IRF-5 expression and alternative splicing were significantly upregulated in SLE patients versus healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 gave the only significant independent association that correlated with increased transcription from non-coding exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG indel, along with type I IFNs in regulating IRF-5 expression.
This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly upregulated in primary blood cells of SLE patients. The risk haplotype is associated with enhanced IRF-5 transcript and protein expression in SLE patients.
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Functional Regulation of MyD88-Activated Interferon Regulatory Factor 5 by K63-Linked Polyubiquitination ▿
Balkhi, Mumtaz Yaseen
Fitzgerald, Katherine A.
Pitha, Paula M.
Molecular and Cellular Biology
Interferon regulatory factor 5 (IRF-5) plays an important role in the innate antiviral and inflammatory response. Specific IRF-5 haplotypes are associated with dysregulated expression of type I interferons and predisposition to autoimmune disorders. IRF-5 is activated by Toll-like receptor 7 (TLR7) and TLR9 via the MyD88 pathway, where it interacts with both MyD88 and the E3 ubiquitin ligase, TRAF6. To understand the role of these interactions in the regulation of IRF-5, we examined the role of ubiquitination and showed that IRF-5 is subjected to TRAF6-mediated K63-linked ubiquitination, which is important for IRF-5 nuclear translocation and target gene regulation. We show that while the murine IRF-5 and human IRF-5 variant 4 (HuIRF-5v4) and HuIRF-5v5 are ubiquitinated, an IRF-5 bone marrow variant mutant containing an internal deletion of 288 nucleotides is not ubiquitinated. Lysine residues at positions 410 and 411 in a putative TRAF6 consensus binding domain of IRF-5 are the targets of K63-linked ubiquitination. Mutagenesis of these two lysines abolished IRF-5 ubiquitination, nuclear translocation, and the IFNA promoter-inducing activity but not the IRF-5-TRAF6 interaction. Finally, we show that IRAK1 associates with IRF-5 and that this interaction precedes and is required for IRF-5 ubiquitination and activation. Thus, our findings offer a new mechanistic insight into IRF-5 gene induction program through hitherto unknown processes of IRF-5 ubiquitination.
Related Articles
The IRF-3 Transcription Factor Mediates Sendai Virus-Induced Apoptosis
Heylbroeck, Christophe
Balachandran, Siddharth
Servant, Marc J.
DeLuca, Carmela
Barber, Glen N.
Lin, Rongtuan
Hiscott, John
Journal of Virology
Virus infection of target cells can result in different biological outcomes: lytic infection, cellular transformation, or cell death by apoptosis. Cells respond to virus infection by the activation of specific transcription factors involved in cytokine gene regulation and cell growth control. The ubiquitously expressed interferon regulatory factor 3 (IRF-3) transcription factor is directly activated following virus infection through posttranslational modification. Phosphorylation of specific C-terminal serine residues results in IRF-3 dimerization, nuclear translocation, and activation of DNA-binding and transactivation potential. Once activated, IRF-3 transcriptionally up regulates alpha/beta interferon genes, the chemokine RANTES, and potentially other genes that inhibit viral infection. We previously generated constitutively active [IRF-3(5D)] and dominant negative (IRF-3 ΔN) forms of IRF-3 that control target gene expression. In an effort to characterize the growth regulatory properties of IRF-3, we observed that IRF-3 is a mediator of paramyxovirus-induced apoptosis. Expression of the constitutively active form of IRF-3 is toxic, preventing the establishment of stably transfected cells. By using a tetracycline-inducible system, we show that induction of IRF-3(5D) alone is sufficient to induce apoptosis in human embryonic kidney 293 and human Jurkat T cells as measured by DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay, and analysis of DNA content by flow cytometry. Wild-type IRF-3 expression augments paramyxovirus-induced apoptosis, while expression of IRF-3 ΔN blocks virus-induced apoptosis. In addition, we demonstrate an important role of caspases 8, 9, and 3 in IRF-3-induced apoptosis. These results suggest that IRF-3, in addition to potently activating cytokine genes, regulates apoptotic signalling following virus infection.
Related Articles
Protection of Irf5-deficient mice from pristane-induced lupus involves altered cytokine production and class switching
Feng, Di
Yang, Lisong
Bi, Xiaohui
Stone, Rivka C.
Patel, Priya
Barnes, Betsy J.
European journal of immunology
Polymorphisms in the transcription factor interferon (IFN) regulatory factor 5 (IRF5) have been identified that show strong association with increased risk of developing the autoimmune disease systemic lupus erythematosus (SLE). A potential pathologic role for IRF5 in SLE development is supported by the fact that increased IRF5 mRNA and protein abundance are observed in primary blood cells of SLE patients that correlate with increased risk of developing the disease. Here, we demonstrate that IRF5 is required for pristane-induced SLE via its ability to control multiple facets of autoimmunity. We show that IRF5 has a distinct influence on pathological hypergammaglobulinemia and provide evidence for its role in regulating IgG1 class switching and antigen specificity. Examination of in vivo cytokine expression (and autoantibody production) identified an imbalance in Irf5−/− mice favoring Th2 polarization. In addition, we provide clear evidence that loss of Irf5 significantly weakens the in vivo type I IFN signature critical for disease pathogenesis in this model of murine lupus. Together, these findings demonstrate the global effect that IRF5 has on autoimmunity and provides significant new insight into how overexpression of IRF5 in blood cells of SLE patients may contribute to disease pathogenesis.
interferon regulatory factor 5 (IRF5, IRF-5); systemic lupus erythematosus (SLE); autoantibody; type I interferon; Th2
Related Articles
Irf8-Regulated Genomic Responses Drive Pathological Inflammation during Cerebral Malaria
Berghout, Joanne
Langlais, David
Radovanovic, Irena
Tam, Mifong
MacMicking, John D.
Stevenson, Mary M.
Gros, Philippe
PLoS Pathogens
Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8R294C) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network.
Author Summary
Cerebral malaria is a severe and often lethal complication from infection with Plasmodium falciparum which is driven in part by pathological host inflammatory response to parasitized red cells′ adherence in the brain microvasculature. However, the pathways that initiate and amplify this pathological neuroinflammation are not well understood. As susceptibility to cerebral malaria is variable and has been shown to be partially heritable, we have studied this from a genetic perspective using a mouse model of infection with P. berghei which induces experimental cerebral malaria (ECM). Here we show that mice bearing mutations in the myeloid transcription factor IRF8 and its heterodimerization partner IRF1 are completely resistant to ECM. We have identified the genes and associated networks that are activated by IRF8 during ECM. Loss-of-function mutations of several IRF8 targets are also shown to be protective. Parallel analysis of lungs infected with Mycobacterium tuberculosis show that IRF8-associated core pathways are also engaged during tuberculosis where they play a protective role. This contrast illustrates the balancing act required by the immune system to respond to pathogens and highlights a lynchpin role for IRF8 in both. Finally, several genes in these networks have been individually associated with chronic or acute inflammatory conditions in humans.
Related Articles
TRIpartite Motif 21 (TRIM21) Differentially Regulates the Stability of Interferon Regulatory Factor 5 (IRF5) Isoforms
Lazzari, Elisa
Korczeniewska, Justyna
Ní Gabhann, Joan
Smith, Siobhán
Barnes, Betsy J.
Jefferies, Caroline A.
PLoS ONE
IRF5 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors activated downstream of the Toll-Like receptors (TLRs). Polymorphisms in IRF5 have been shown to be associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) and other autoimmune conditions, suggesting a central role for IRF5 in the regulation of the immune response. Four different IRF5 isoforms originate due to alternative splicing and to the presence or absence of a 30 nucleotide insertion in IRF5 exon 6. Since the polymorphic region disturbs a PEST domain, a region associated with protein degradation, we hypothesized that the isoforms bearing the insertion might have increased stability, thus explaining the association of individual IRF5 isoforms with SLE. As the E3 ubiquitin ligase TRIpartite Motif 21 (TRIM21) has been shown to regulate the stability and hence activity of members of the IRF family, we investigated whether IRF5 is subjected to regulation by TRIM21 and whether dysregulation of this mechanism could explain the association of IRF5 with SLE. Our results show that IRF5 is degraded following TLR7 activation and that TRIM21 is involved in this process. Comparison of the individual IRF5 variants demonstrates that isoforms generated by alternative splicing are resistant to TRIM21-mediated degradation following TLR7 stimulation, thus providing a functional link between isoforms expression and stability/activity which contributes to explain the association of IRF5 with SLE.
Related Articles
The Ebola Virus VP35 Protein Inhibits Activation of Interferon Regulatory Factor 3
Basler, Christopher F.
Mikulasova, Andrea
Martinez-Sobrido, Luis
Paragas, Jason
Mühlberger, Elke
Bray, Mike
Klenk, Hans-Dieter
Palese, Peter
García-Sastre, Adolfo
Journal of Virology
The Ebola virus VP35 protein was previously found to act as an interferon (IFN) antagonist which could complement growth of influenza delNS1 virus, a mutant influenza virus lacking the influenza virus IFN antagonist protein, NS1. The Ebola virus VP35 could also prevent the virus- or double-stranded RNA-mediated transcriptional activation of both the beta IFN (IFN-β) promoter and the IFN-stimulated ISG54 promoter (C. Basler et al., Proc. Natl. Acad. Sci. USA 97:12289-12294, 2000). We now show that VP35 inhibits virus infection-induced transcriptional activation of IFN regulatory factor 3 (IRF-3)-responsive mammalian promoters and that VP35 does not block signaling from the IFN-α/β receptor. The ability of VP35 to inhibit this virus-induced transcription correlates with its ability to block activation of IRF-3, a cellular transcription factor of central importance in initiating the host cell IFN response. We demonstrate that VP35 blocks the Sendai virus-induced activation of two promoters which can be directly activated by IRF-3, namely, the ISG54 promoter and the ISG56 promoter. Further, expression of VP35 prevents the IRF-3-dependent activation of the IFN-α4 promoter in response to viral infection. The inhibition of IRF-3 appears to occur through an inhibition of IRF-3 phosphorylation. VP35 blocks virus-induced IRF-3 phosphorylation and subsequent IRF-3 dimerization and nuclear translocation. Consistent with these observations, Ebola virus infection of Vero cells activated neither transcription from the ISG54 promoter nor nuclear accumulation of IRF-3. These data suggest that in Ebola virus-infected cells, VP35 inhibits the induction of antiviral genes, including the IFN-β gene, by blocking IRF-3 activation.
Related Articles
Monocytes from Irf5−/− mice have an intrinsic defect in their response to pristane-induced lupus‡
Yang, Lisong
Feng, Di
Bi, Xiaohui
Stone, Rivka C.
Barnes, Betsy J.
Journal of immunology (Baltimore, Md. : 1950)
The transcription factor interferon regulatory factor 5 (IRF5) has been identified as a human systemic lupus erythematosus (SLE) susceptibility gene by numerous joint linkage and genome-wide association studies. Although IRF5 expression is significantly elevated in primary blood cells of SLE patients, it is not yet known how IRF5 contributes to SLE pathogenesis. Recent data from mouse models of lupus indicate a critical role for IRF5 in the production of pathogenic autoantibodies and the expression of Th2 cytokines and type I IFN. In the current study, we examined the mechanism(s) by which loss of Irf5 protects mice from pristane-induced lupus at early time points of disease development. We demonstrate that Irf5 is required for Ly6C(hi) monocyte trafficking to the peritoneal cavity (PC), which is believed to be one of the initial key events leading to lupus pathogenesis in this model. Chemotaxis assays using peritoneal lavage from pristane-injected Irf5+/+ and Irf5−/− littermates support an intrinsic defect in Irf5−/− monocytes. We found the expression of chemokine receptors CXCR4 and CCR2 to be dysregulated on Irf5−/− monocytes and less responsive to their respective ligands, CXCL12 and CCL2. Bone marrow reconstitution experiments further supported an intrinsic defect in Irf5−/− monocytes since Irf5+/+ monocytes were preferentially recruited to the PC in response to pristane. Together, these findings demonstrate an intrinsic role for IRF5 in the response of monocytes to pristane, and their recruitment to the primary site of inflammation that is thought to trigger lupus onset in this experimental model of SLE.
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Rotavirus NSP1 Mediates Degradation of Interferon Regulatory Factors through Targeting of the Dimerization Domain
Arnold, Michelle M.
Barro, Mario
Patton, John T.
Journal of Virology
Rotavirus nonstructural protein NSP1 can inhibit expression of interferon (IFN) and IFN-stimulated gene products by inducing proteasome-mediated degradation of IFN-regulatory factors (IRFs), including IRF3, IRF5, and IRF7. All IRF proteins share an N-terminal DNA-binding domain (DBD), and IRF3, IRF5, and IRF7 contain a similar C-proximal IRF association domain (IAD) that mediates IRF dimerization. An autoinhibitory domain (ID) at the extreme C terminus interacts with the IAD, burying residues necessary for IRF dimerization. Phosphorylation of serine/threonine residues in the ID induces charge repulsions that unmask the IAD, enabling IRF dimerization and subsequent nuclear translocation. To define the region of IRF proteins targeted for degradation by NSP1, we generated IRF3 and IRF7 truncation mutants and transiently expressed each with simian SA11-4F NSP1. These assays indicated that the IAD represented a necessary and sufficient target for degradation. Because NSP1 did not mediate degradation of truncated forms of the IAD, NSP1 likely requires a structurally intact IAD for recognition and targeting of IRF proteins. IRF9, which contains an IAD-like region that directs interactions with signal inducer and activator of transcription (STAT) proteins, was also targeted for degradation by NSP1, while IRF1, which lacks an IAD, was not. Analysis of mutant forms of IRF3 unable to undergo dimerization or that were constitutively dimeric showed that both were targeted for degradation by NSP1. These results indicate that SA11-4F NSP1 can induce degradation of inactive and activated forms of IAD-containing IRF proteins (IRF3 to IRF9), allowing a multipronged attack on IFN-based pathways that promote antiviral innate and adaptive immune responses.
Related Articles
Association of IRF5 polymorphisms with activation of the interferon α pathway
Rullo, Ornella J
Woo, Jennifer M P
Wu, Hui
Hoftman, Alice D C
Maranian, Paul
Brahn, Brittany A
McCurdy, Deborah
Cantor, Rita M
Tsao, Betty P
Annals of the rheumatic diseases
The genetic association of interferon regulatory factor 5 (IRF5) with systemic lupus erythematosus (SLE) susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, a study was undertaken to examine whether such genetic variation predisposes to activation of the interferon α (IFNα) pathway.
Using a computer simulated approach, 14 single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFNα and IFN-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. IFN-inducible gene expression was assessed in LCLs from children with SLE in the presence and absence of IFNα stimulation.
The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU (pc=0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of IFN-inducible genes in LCLs by IFNα.
SNPs of IRF5 in healthy individuals of a number of ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFNα and IFN-inducible chemokine expression. Identifying individuals genetically predisposed to increased IFN-inducible gene and chemokine expression may allow early detection of risk for SLE.
Related Articles
IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus
Niewold, Timothy B
Kelly, Jennifer A
Kariuki, Silvia N
Franek, Beverly S
Kumar, Akaash A
Kaufman, Kenneth M
Thomas, Kenaz
Walker, Daniel
Kamp, Stan
Frost, Jacqueline M
Wong, Andrew K
Merrill, Joan T
Alarcón-Riquelme, Marta E
Tikly, Mohammed
Ramsey-Goldman, Rosalind
Reveille, John D
Petri, Michelle A
Edberg, Jeffrey C
Kimberly, Robert P
Alarcón, Graciela S
Kamen, Diane L
Gilkeson, Gary S
Vyse, Timothy J
James, Judith A
Gaffney, Patrick M
Moser, Kathy L
Crow, Mary K
Harley, John B
Annals of the Rheumatic Diseases
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.
In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.
The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.
SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34
Related Articles
Cis-regulation of IRF5 expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines
Alonso-Perez, Elisa
Suarez-Gestal, Marian
Calaza, Manuel
Kwan, Tony
Majewski, Jacek
Gomez-Reino, Juan J
Gonzalez, Antonio
Arthritis Research & Therapy
Interferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information.
Expression data from four published microarray hybridisation experiments with lymphoblastoid cell lines (57 to 181 cell lines) were retrieved. Genotypes of 109 IRF5 polymorphisms, including four known functional polymorphisms, were considered. The best linear regression models accounting for the IRF5 expression data were selected by using a forward entry procedure. SLE-associated IRF5 haplotypes were correlated with the expression data and with the best cis-regulatory models.
A large fraction of variability in IRF5 expression was accounted for by linear regression models with IRF5 polymorphisms, but at a different level in each expression data set. Also, the best models from each expression data set were different, although there was overlap between them. The SNP introducing an early polyadenylation signal, rs10954213, was included in the best models for two of the expression data sets and in good models for the other two data sets. The SLE risk haplotype was associated with high IRF5 expression in the four expression data sets. However, there was also a trend towards high IRF5 expression with some protective and neutral haplotypes, and the protective haplotypes were not associated with IRF5 expression. As a consequence, correlation between the cis-regulatory best models and SLE-associated haplotypes, regarding either the risk or protective component, was poor.
Our analysis indicates that although the SLE risk haplotype of IRF5 is associated with high expression of the gene, cis-regulation of IRF5 expression is not enough to fully account for IRF5 association with SLE susceptibility, which indicates the need to identify additional functional changes in this gene.
systemic lupus erythematosus; IRF5; lymphoblastoid cell lines; cis-regulation; disease susceptibility; linear regression models
Related Articles
Interferon Regulatory Factor 7 Regulates Expression of Epstein-Barr Virus Latent Membrane Protein 1: a Regulatory Circuit
Ning, Shunbin
Hahn, Angela M.
Huye, Leslie E.
Pagano, Joseph S.
Journal of Virology
We have shown previously that interferon regulatory factor 7 (IRF7), a multifunctional protein intimately involved in latent Epstein-Barr virus (EBV) infection, is induced as well as activated by EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein. Since the LMP1 promoter (LMP1p) contains an interferon-stimulated response element (ISRE), we hypothesized that IRF7 might be able to regulate LMP1 expression and thus participate in a regulatory circuit between these two genes. In this study, IRF7 was shown first to activate LMP1p in transient transfection assays. Compared with EBV nuclear antigen 2 (EBNA2), the most potent viral transactivator of LMP1p, IRF7 has a lesser effect (approximately 10% that of EBNA2) on induction of LMP1p. Study with IRF7 deletion mutants showed that IRF7 functional domains have similar effects on both the beta interferon (IFN-β) and LMP1 promoters in BJAB and 293 cells, and study with IRF7 phosphomimetic mutants showed that IRF7 phosphorylation may be involved in the activation of these two promoters. Further, the ISRE in LMP1p responds to IRF7 induction and IRF7 binds to this element. In the EBV-positive cell line P3HR1, which lacks the complete EBNA2 and EBV-encoded leader protein genes and hence expresses low-level LMP1, IRF7 alone can notably increase the endogenous LMP1 mRNA and protein levels. These results indicate that LMP1 is regulated by this host cell gene in addition to the viral factor, EBNA2, and may help to explain how LMP1 is expressed in type II latency in the absence of EBNA2. Moreover, IRF7 can regulate a viral gene in addition to a host cellular gene such as the IFN-β gene. Together with the previous data that LMP1 can induce IRF7 expression and facilitate IRF7 phosphorylation and nuclear translocation, these results suggest a positive regulatory circuit between IRF7 and LMP1.
Related Articles
Association of Functional Polymorphisms in Interferon Regulatory Factor 2 (IRF2) with Susceptibility to Systemic Lupus Erythematosus: A Case-Control Association Study
Kawasaki, Aya
Furukawa, Hiroshi
Nishida, Nao
Warabi, Eiji
Kondo, Yuya
Ito, Satoshi
Matsumoto, Isao
Kusaoi, Makio
Amano, Hirofumi
Suda, Akiko
Nagaoka, Shouhei
Setoguchi, Keigo
Nagai, Tatsuo
Hirohata, Shunsei
Shimada, Kota
Sugii, Shoji
Okamoto, Akira
Chiba, Noriyuki
Suematsu, Eiichi
Ohno, Shigeru
Katayama, Masao
Okamoto, Akiko
Kono, Hajime
Tokunaga, Katsushi
Takasaki, Yoshinari
Hashimoto, Hiroshi
Sumida, Takayuki
Tohma, Shigeto
Tsuchiya, Naoyuki
PLoS ONE
Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10−4, Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18–1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30–1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10−4, Pc = 0.037, OR 1.53, 95%CI 1.19–1.96) and rs62339994 (dominant model, P = 9.0×10−4, Pc = 0.043, OR 1.46, 95%CI 1.17–1.82). The haplotype carrying both of the risk alleles (rs66801661A–rs62339994A) was significantly increased in SLE (P = 9.9×10−4), while the haplotype constituted by both of the non-risk alleles (rs66801661G–rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10−4). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.
Related Articles
Essential Role of Interferon Regulatory Factor 3 in Direct Activation of RANTES Chemokine Transcription
Lin, Rongtuan
Heylbroeck, Christophe
Genin, Pierre
Pitha, Paula M.
Hiscott, John
Molecular and Cellular Biology
Localized and systemic cytokine production in virus-infected cells play an important role in the outcome of viral infection and pathogenicity. Activation of the interferon regulatory factors (IRF) in turn is a critical mediator of cytokine gene transcription. Recent studies have focused on the 55-kDa IRF-3 gene product as a direct transcriptional regulator of type 1 interferon (IFN-α and IFN-β) activation in response to virus infection. Virus infection induces phosphorylation of IRF-3 on specific C-terminal serine residues and permits cytoplasmic-to-nuclear translocation of IRF-3, activation of DNA binding and transactivation potential, and association with the CBP/p300 coactivator. We previously generated constitutively active [IRF-3(5D)] and dominant-negative forms of IRF-3 that control IFN-β and IFN-α gene expression. In an effort to characterize the range of immunoregulatory genes controlled by IRF-3, we now demonstrate that endogenous human RANTES gene transcription is directly induced in tetracycline-inducible IRF-3(5D)-expressing cells or paramyxovirus-infected cells. We also show that a dominant-negative IRF-3 mutant inhibits virus-induced expression of the RANTES promoter. Specific mutagenesis of overlapping ISRE-like sites located between nucleotides −123 and −96 in the RANTES promoter reduces virus-induced and IRF-3-dependent activation. These studies broaden the range of IRF-3 immunoregulatory target genes to include at least one member of the chemokine superfamily.
Related Articles
Genetic Variation at the IRF7/PHRF1 Locus Is Associated With Autoantibody Profile and Serum Interferon-α Activity in Lupus Patients
Salloum, Rafah
Franek, Beverly S.
Kariuki, Silvia N.
Rhee, Lesley
Mikolaitis, Rachel A.
Jolly, Meenakshi
Utset, Tammy O.
Niewold, Timothy B.
Arthritis and rheumatism
Interferon-α (IFNα) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFNα production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFNα production and whether autoantibodies are important to this phenomenon.
We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFNα were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped.
In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti–double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFNα in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 × 10−5 in anti-dsDNA–positive patients and P = 0.99 in anti-dsDNA–negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFNα only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA–rs702966 C allele interaction on serum levels of IFNα was observed, similar to the other patient groups (overall joint analysis P = 1.0 × 10−6). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFNα level in anti-dsDNA–positive patients.
Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFNα, providing a biologic relevance for this locus at the protein level in human SLE in vivo.
Related Articles
Interferon Regulatory Factor 5 in the Pathogenesis of Systemic Lupus Erythematosus
Cham, Candace M.
Ko, Kichul
Niewold, Timothy B.
Clinical and Developmental Immunology
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple genetic risk factors, high levels of interferon alpha (IFN-α), and the production of autoantibodies against components of the cell nucleus. Interferon regulatory factor 5 (IRF5) is a transcription factor which induces the transcription of IFN-α and other cytokines, and genetic variants of IRF5 have been strongly linked to SLE pathogenesis. IRF5 functions downstream of Toll-like receptors and other microbial pattern-recognition receptors, and immune complexes made up of SLE-associated autoantibodies seem to function as a chronic endogenous stimulus to this pathway. In this paper, we discuss the physiologic role of IRF5 in immune defense and the ways in which IRF5 variants may contribute to the pathogenesis of human SLE. Recent data regarding the role of IRF5 in both serologic autoimmunity and the overproduction of IFN-α in human SLE are summarized. These data support a model in which SLE-risk variants of IRF5 participate in a "feed-forward" mechanism, predisposing to SLE-associated autoantibody formation, and subsequently facilitating IFN-α production downstream of Toll-like receptors stimulated by immune complexes composed of these autoantibodies.
Related Articles
Structural and Functional Analysis of Interferon Regulatory Factor 3: Localization of the Transactivation and Autoinhibitory Domains
Lin, Rongtuan
Mamane, Yael
Hiscott, John
Molecular and Cellular Biology
The interferon regulatory factor 3 (IRF-3) gene encodes a 55-kDa protein which is expressed constitutively in all tissues. In unstimulated cells, IRF-3 is present in an inactive cytoplasmic form; following Sendai virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues located in the carboxy terminus. Virus-induced phosphorylation of IRF-3 leads to cytoplasmic to nuclear translocation of phosphorylated IRF-3, association with the transcriptional coactivator CBP/p300, and stimulation of DNA binding and transcriptional activities of virus-inducible genes. Using yeast and mammalian one-hybrid analysis, we now demonstrate that an extended, atypical transactivation domain is located in the C terminus of IRF-3 between amino acids (aa) 134 and 394. We also show that the C-terminal domain of IRF-3 located between aa 380 and 427 participates in the autoinhibition of IRF-3 activity via an intramolecular association with the N-terminal region between aa 98 and 240. After Sendai virus infection, an intermolecular association between IRF-3 proteins is detected, demonstrating a virus-dependent formation of IRF-3 homodimers; this interaction is also observed in the absence of virus infection with a constitutively activated form of IRF-3. Substitution of the C-terminal Ser-Thr phosphorylation sites with the phosphomimetic Asp in the region ISNSHPLSLTSDQ between amino acids 395 and 407 [IRF-3(5D)], but not the adjacent S385 and S386 residues, generates a constitutively activated DNA binding form of IRF-3. In contrast, substitution of S385 and S386 with either Ala or Asp inhibits both DNA binding and transactivation activities of the IRF-3(5D) protein. These studies thus define the transactivation domain of IRF-3, two domains that participate in the autoinhibition of IRF-3 activity, and the regulatory phosphorylation sites controlling IRF-3 dimer formation, DNA binding activity, and association with the CBP/p300 coactivator.
Related Articles
Synoviocyte innate responses: II. Pivotal role of interferon regulatory factor 3
Sweeney, Susan E.
Kimbler, Trevor B.
Firestein, Gary S.
Journal of immunology (Baltimore, Md. : 1950)
Innate immune responses likely contribute to synovial inflammation in rheumatoid arthritis (RA). Of the innate receptors implicated in RA, TLR3 activates several signaling cascades, including -interferon regulatory factors 3 and 7 (IRF), resulting in production of viral-stress IFN-inducible genes. The present study was designed to investigate the contributions of IRF3 and IRF7 to the type I IFN response as well as the expression of other cytokines, chemokines, and degradative enzymes in synoviocytes.
Fibroblast-like synoviocytes (FLS) were stimulated with poly (I-C) after transfection with IRF3 or IRF7 siRNA to knockdown transcription factor expression. Western blots, luciferase assay after transfection with reporter constructs, Q-PCR, and AP-1 DNA binding ELISA was performed to evaluate the role of IRF3 and IRF7 in poly (I-C)-induced signaling and synoviocyte gene expression.
IRF3 and IRF7 knockdown showed that IRF3 regulates IFN-stimulated response element (ISRE) promoter activity as well as IFNβ, IRF5, IRF7, RANTES, IP-10, MCP-1, and MIP1α gene expression in response to poly (I-C). IRF7 knockdown modestly decreased a subset of genes and ISRE activity, although the results were not significant. Surprisingly, IRF3 knockdown almost completely blocked expression of additional genes in which the ISRE is not traditionally considered a dominant promoter site in FLS, including MMP3, MMP9, IL-6 and IL-8. We then investigated a possible role for IRF3 in c-Jun activation and AP-1 binding because its promoter site is present in all four of the non-IFN regulated genes. IRF3 deficiency significantly decreased AP-1 binding of activated c-Jun compared with control.
In contrast to immune cells, IRF3 rather than IRF7 regulates TLR3-mediated type I IFN responses in human synoviocytes. IRF3 activates IFN-response gene expression by increasing ISRE promoter activity. In addition, IRF3 regulates other cytokines, chemokines, and MMPs through a novel mechanism that involves c-Jun and the AP-1 promoter site. Because the signaling pathway modulated by IRF3 plays a crucial role in synoviocytes, targeting IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses.
Rheumatoid arthritis; signal transduction; transcription factors; interferon
Related Articles
Phosphorylation of IRF-3 on Ser 339 Generates a Hyperactive Form of IRF-3 through Regulation of Dimerization and CBP Association▿
Clément, Jean-François
Bibeau-Poirier, Annie
Gravel, Simon-Pierre
Grandvaux, Nathalie
Bonneil, Éric
Thibault, Pierre
Meloche, Sylvain
Servant, Marc J.
Journal of Virology
The IκB kinase-related kinases, TBK1 and IKKi, were recently shown to be responsible for the C-terminal phosphorylation of IRF-3. However, the identity of the phosphoacceptor site(s) targeted by these two kinases remains unclear. Using a biological assay based on the IRF-3-mediated production of antiviral cytokines, we demonstrate here that all Ser/Thr clusters of IRF-3 are required for its optimal transactivation capacity. In vitro kinase assays using full-length His-IRF-3 as a substrate combined with mass spectrometry analysis revealed that serine 402 and serine 396 are directly targeted by TBK1. Analysis of Ser/Thr-to-Ala mutants revealed that the S396A mutation, located in cluster II, abolished IRF-3 homodimerization, CBP association, and nuclear accumulation. However, production of antiviral cytokines was still present in IRF-3 S396A-expressing cells. Interestingly, mutation of serine 339, which is involved in IRF-3 stability, also abrogated CBP association and dimerization without affecting gene transactivation as long as serine 396 remained available for phosphorylation. Complementation of IRF-3-knockout mouse embryonic fibroblasts also revealed a compensatory mechanism of serine 339 and serine 396 in the ability of IRF-3 to induce expression of the interferon-stimulated genes ISG56 and ISG54. These data lead us to reconsider the current model of IRF-3 activation. We propose that conventional biochemical assays used to measure IRF-3 activation are not sensitive enough to detect the small fraction of IRF-3 needed to elicit a biological response. Importantly, our study establishes a molecular link between the role of serine 339 in IRF-3 homodimerization, CBP association, and its destabilization.
Related Articles
TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1▿
Ning, Shunbin
Campos, Alex D.
Darnay, Bryant G.
Bentz, Gretchen L.
Pagano, Joseph S.
Molecular and Cellular Biology
We have recently shown that interferon regulatory factor 7 (IRF7) is activated by Epstein-Barr virus latent membrane protein 1 (LMP1), a member of the tumor necrosis factor receptor (TNFR) superfamily, through receptor-interacting protein-dependent K63-linked ubiquitination (L. E. Huye, S. Ning, M. Kelliher, and J. S. Pagano, Mol. Cell. Biol. 27:2910-2918, 2007). In this study, with the use of small interfering RNA and TNFR-associated factor 6 (TRAF6) knockout cells, we first show that TRAF6 and its E3 ligase activity are required for LMP1-stimulated IRF7 ubiquitination. In Raji cells which are latently infected and express high levels of LMP1 and IRF7 endogenously, expression of a TRAF6 small hairpin RNA construct reduces endogenous ubiquitination and endogenous activity of IRF7. In TRAF6−/− mouse embryonic fibroblasts, reconstitution with TRAF6 expression, but not with TRAF6(C70A), which lacks the E3 ligase activity, recovers LMP1's ability to stimulate K63-linked ubiquitination of IRF7. Further, we identify IRF7 as a substrate for TRAF6 E3 ligase and show that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo. Most important, we determine that the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 variant A are essential for activation of IRF7; these are the first such sites identified. A ubiquitination-deficient mutant of IRF7 with these sites mutated to arginines completely loses transactivational ability in response not only to LMP1 but also to the IRF7 kinase IκB kinase ɛ. In addition, we find that K63-linked ubiquitination of IRF7 occurs independently of its C-terminal functional phosphorylation sites. These data support our hypothesis that regulatory ubiquitination of IRF7 is a prerequisite for its phosphorylation. This is the first evidence to imply that ubiquitination is required for phosphorylation and activation of a transcription factor.
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Great hotel and greate view from 18 floor, never forgot Amsterdam Arena at night.
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This hotel is awesome. Decorated by ikea with very funky furniture. Very clean, service is excellent and the beds very comfortable.
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Cd :What a difference a day makes? After a 8 hour bus trip we find our hotel the Mercure yep the wrong Mercure. Our hotel was outside the city but an easy train ride to the city centre. The best way to get around was a 3 day transit pass great value at 17e. After a short walk around the city we head off to find the Van Gough Museum however the fast …
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After another uneventful train ride, except for the trains in Berlin! Thought I'd had sussed the way into the city I went horribly wrong, thinking I would miss my train to Amsterdam. Well I am here, it is very pretty, will get to see more of it tomorrow, But tonight I went through part restaurant, part cannabis shops and then the sex shops, shows …
Kings Day
Kings Day in Amsterdam was amazing! It started unofficially last night and continued on the public holiday today. The inner city was closed to cars and trams so that the people could walk freely. The streets and canals were lined with flea markets and stalls of food/drink and orange clothing/accessories. Parks were filled with children (and their parents) ...


text: Republican presidential candidate Donald Trump speaks at a rally in Las Vegas. A Hispanic coalition is condemning NBC's Saturday Night Live for inviting Trump to host the show. John Locher/AP hide caption toggle caption John Locher/AP Code Switch Would 'SNL' Have Donald Trump As Host If It Had Latino Cast Members? October 25, 2015 NPR's TV critic Eric Deggans says a more diverse cast might have made the show think twice about a hosting gig for the presidential candidate after his comments about Mexican immigrants.


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30 Reviews
Our local super had a sale on red cabbage and I decided to try this recipe last night. I can highly recommend it, and this will be added to my recipe list. Very flavorful combination including the chicken stock, wine, and brown sugar. Since I'm a garlic lover, I added a couple extra cloves of garlic. Easy, flavorful side dish. Thanks, Lennie!
This is a great recipe - only change I made was adding a couple of pieces of crumbled bacon - my sister-in-law used to make it many years ago and she used bacon with a little pit of bacon grease (today that's probably not a good idea)! Oh, and try adding balsemic vinegar in place of the red wine - gives it a better sweet/sour taste. Anyway, my husband loved it - we ate all of it in one sitting!!!!
Loved this recipe. I cut the recipe ingredients but half to match the 4 cups of chopped cabbage I had on hand. I used green cabbage and I added 1 large carrot, shreaded to the dish along with the onion. I found that the cook time, as listed, was way too long as mine was done in under 20 minutes.
Nice and simple and very healthy! Not too sweet. Next time I might try it with a tad more brown sugar and vinegar. Thanks Lennie
Pretty darn good I used Splenda and bacon fat. Next time try a bit of soy sauce. That livens it up a bit and enhances the cabbage flavor
I made this recipe as posted, and found it to be a bit bland for my family. I searched my fridge and found some cranberry salsa, added another apple, a bit more splenda , and voila a delicious dish Thanks so much for the basic recipe.We will be enjoying this dish for a longtime to come. With the cranberries it could make it to the Thanksgiving table.
This was really good and easy. I had it as a side dish to the Chipotle Pork Roast. It was a tasty combination. It would be good with any pork roast. I will definately keep this one.
This was simply fabulous! My husband and I are on the South Beach Diet (Phase one) and I made this for super tonight. I omitted the fruit since we are not allowed to have any yet and replaced the sugar with Splenda. Super Yummy! Definately a keeper! Can't wait to try this with apples!
We really enjoyed this-- and so healthy too. We were in the middle of a snow storm so didn't have apples so I used dried cranberries and dried prunes diced up. Came out well. I will make this again. Thank you.
Hello everyone ,would just like to add a variation to the Braised Red Cabbage recipe, I do not add garlic but I add to your taste peeled and diced green apple and the same with cranberry jam the amount varies with your taste ,if its too tarte add some sugar ,braise all the ingredients in a heavy based saucepan this includes the shredded red cabbage -diced green apples-cranberry jam -spanish onion,braise till all is tender if there is a little too much liquid I thicken with a small amount of cornflour ,give it a try and you will be amazed with the result I've used this in my chef kitchen for years ,ps season as required thanks ---Nev D.


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The energy and enthusiasm of this dance troupe was amazing! They genuinely seemed pleased to be sharing their talents and heritage with the audience. We saw them on our first night in Budapest and it was the perfect way to begin our visit. Don't miss this one!
One of the most outstanding and memorable excursion on our vacation in Europe! The show was a class act and inspiring followed by a dinner that was top notch with incredible views from the cruise ship!
What a wonderful show ! I would highly recommend this to anyone in Budapest. Outstanding performance.
Great music, high energy performance.
The show was great and the Danube cruise dinner too. I booked this for a family of 5. All enjoyed it. Food was great and included open buffet with music band.
We loved the music and and cruise. It was affordable and enjoyable for everyone in my group. The only problem was we were unable to ever reach this company by telephone to find out the location....the hall. There are 2 different halls and we kept calling for 2 days. Either the telephone number is wrong on the sheet we printed or no one was ever available. Think the number was wrong. Our hotel manager finally contacted the telephone company and got another number that finally worked.
This Folklore Show was amazing! I highly recommend it! We booked this tour with the driver to and from our hotel. The only complaint is the smoking on board the ship on the outside decks. IT says in designated areas only, but it was everywhere. Otherwise, the food was great and the service staff very helpful.
Muy buen show y la calidad excelente de la comida.
Wonderful show - so much talent! My wife and I enjoyed the dinner cruise very much - very romantic with spectacular illuminated night views of the city and excellent live music!
It was fantastic.the folk show gives you a very lovely cultural evening you see the group dancing and the music . It is a must do attraction if it is your first visit to this part of the world
very good show
Artur Ribeiro Brazil
Fantástico show. O Duna Palota é uma excelente casa de espetáculos e o espetáculo em sim é perfeito. Excelente banda ou orquestra e grupo de bailarinos. Ótimo show!
It was a wonderful evening. It did not start on time, nor did the cruise, but it was wonderful all the same. I would recommend it to those that enjoy classical music. The location was not that easy to find. Walked in circles a bit, but once there the performance was great. The food on the Cruise was plentiful and delicious.
Wow! Hungarians really know how to party! The cruise was dreamy and the food was some of the best I had during my entire holiday. Truly a night to remember. Thanks Budapest
Excellent, will be using your services again !!
Thank you, we really enjoyed the folklore show however we found the dinner was way too late for us. The music on the cruise was great! The meal was also delicious. We would recommend it to anyone, especially if they don't mind eating a hearty meal at 10.00pm. Thank you again. Keep the Hungarian folklore alive!!
This performance was excellent and worth seeing while in Budapest. It was the highlight of the trip. Strongly recommend this offer to all visitors.
Loved it!
A must do if you go to Budapest. The performances were amazing, the dancers were really a joy to watch and the Danube palace is just a beautiful piece of history and art. The dinner cruise after was also an experience not to miss. Budapest at night is spectacular and the food really was delicious.
Steven G United States of ...
Excellent show, followed by a dinner / evening on the Danube. Professional dancing and orchestra playing Hungarian music. It was a very enjoyable evening and comes highly recommended!
Fabulous !
This is a great gem. The dancing is fantastic and the musicians are awesome
Loved being introduced to the culture. Talented crew.
We did this our first night here and it really set the mood. The dances and music were the perfect start and it was fun to see that the dancers and musicians were having fun while performing. Budapest at night on the river is specatular! The dinner on the cruise was fantastic. A must do in my opinion!
This tour was amazing!
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What would happen if you discovered that your family was one of the most powerful in human history? What if you were told that the source of the family's power was hidden around the world, in the form of 39 Clues? What if you were given a choice - take a million dollars and walk away...or get the first Clue? If you're Amy and Dan Cahill, you take the Clue - and begin a very dangerous race.
Follow the clues! Listen to more mysteries in the 39 Clues series.
Please note: When you purchase this title, you will be emailed a unique ID that provides access to accompanying online material.
©2008 Rick Riordan; (P)2008 Scholastic Inc.
"Its cool im deadpool"
I like the percy jackson books more i think you should make more of those
I LOVED IT !! It was narrated perfectly !😀👍🏻👍🏻👍🏻👍🏻, but what I loved the most was the way it switched between the two characters . I HIGHLY RECOMMEND IT TO ANYONE THAT WANTS TO BE ABLE TO GET THE SAME EXPERIENCE OF AWESOMENESS!!
"loving audio"
I have the book series but hearing the story brought to life was just awesome!
"We were in Boston and started this on a trip"
Even my eight year old liked it! Made the trip to Legoland so much better and traffic was tolerable with a fun book to listen to! Riordan makes great characters and writes much like James Patterson in that the action is fast-paced and hooks you!
"Amy and Dan are the coolest"
Amy and Dan are admirable, yet believable.
I liked book 1 and I will probably add the rest to my wish list. Though, If they are only going to solve 1 clue per book, I don't know if I will have the patience to listen to all of them. Amy and Dan need to learn not to talk so loudly, they also need to stop letting their relatives sneak up on them so easily.
"Great for kids and grownups alike"
very well
Won't say, don't like spoiler alerts.
After a suggestion from a friend, I got the first two books for my grandchildren. Then I decided to listen so I could discuss it with them and I really enjoyed the story.
"Great listen!"
Enjoyed this first book very much! Although Rick Riordan writes for a younger audience, I was drawn into the story! Looking forward to continuing this story line!
"Very suspenseful for my 8 year old"
Yes, there is a lot of history to learn as well as follow the mystery in finding the clues
When the mansion was burnt
this was our first
Dan makes us laugh
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Rent Reflexology for Back Pain 1st edition today, or search our site for other textbooks by Ann Gillanders. Every textbook comes with a 21-day "Any Reason" guarantee. Published by Barron's Educational Series, Incorporated.
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Overland Expo is produced and solely owned by Roseann & Jonathan Hanson
through Overland Expo LLC. A portion of proceeds from the show supports ConserVentures Charitable Organization, an Arizona-based non-profit whose mission is promoting exploration of our planet and conservation of its cultural and natural heritage. www.ConserVentures.org
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Email Roseann [before emailing, please see note below]
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FOR general attendance, registration or cancelation information,
Please email US HERE or fill out the form below.
**** OVerland Expo Team communication schedule:
Please note that after Saturday, May 14th, the ENTIRE Overland Expo Team will be on-site preparing for the WEST event. This is no small feat, which also means we will have limited time to respond to emails and phone calls. Please help us out and look for answers on the website or read the FAQ first before contacting us. Thank you for understanding and we'll see you soon!
General Questions? Check out our FAQ.
Still need answers? Fill out the form below and one of us will be happy to respond as soon as possible.
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Hartford – Gov. Dannel P. Malloy today announced an additional $500,000 in funding has been placed on the State Bond Commission agenda to aid the Mystic Seaport in costs associated with the ongoing restoration of the whaling ship Charles W. Morgan.
The Seaport will hold a ceremony at 2 p.m. Sunday for the relaunch of the Morgan, which has been undergoing a $7 million restoration since 2008. The ship is the world's last surviving wooden whaling ship, the oldest American commercial vessel still in existence and a National Historic Landmark.
"Last year, we launched Still Revolutionary to spark visitor interest in our state by highlighting our rich history and deep roots in the founding of this country – to date, the campaign has boosted attendance at our major attractions by 7 percent and increased awareness in Connecticut as a tourist destination by nearly 20 percent," Malloy said in a statement.
"Our investment in this historic treasure represents our commitment to preserving our maritime heritage and is a small part of a much larger investment to continue to bring more people, business and economic development to our state," he said.
State Sen. Andrew Maynard, D-Stonington, said the money is expected to be approved in a July 26 meeting. It supplements $500,000 in similar funding approved by the Commission in 2012.
"Over 20 million people have explored the decks of the Morgan since her arrival at the Seaport, and after a comprehensive restoration we can expect her to draw millions more to the region," Maynard said in a statement. "I'm very pleased that the Governor is continuing to invest in the local economy and in the future of Connecticut's tourism industry, keeping our rich maritime tradition alive and providing an invaluable educational resource for students and tourists alike."
Malloy had previously joined Maynard and Stephen White, president of the Mystic Seaport Museum, in announcing that the 2013-14 academic year will be dedicated to the Morgan. Beginning in September 2013, Connecticut students will learn more about the state's unique maritime tradition and its historic relationship with the whaling industry.
Built and launched in New Bedford in 1841, the Morgan sailed on 37 voyages around the globe over an 80-year whaling career.
State approves funds for Morgan restoration and Coast Guard Museum
Cutting hair, chatting up customers for more than 50 years in New London
The Yankees honoring Ortiz? Mikey D. just doesn't understand
U.S. Supreme Court to hear sovereign immunity case involving Mohegan limo driver
East Lyme first selectman recommends independent police force


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Santa Barbara Bowl
1122 North Milpas St.
Santa Barbara, CA
United States
Phone Number:
805 568 2695
MidFlorida Credit Union Amphitheatre, Tampa, Fla.
John Davisson
August 6, 2016 |
Van Andel Arena, Grand Rapids, Mich.
Jim Hill
August 13, 2016 |
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This pie chart and accompanying supercut really say it all.
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The Mountain from 'Game of Thrones' smashes Viking weightlifting record
A thousand years ago, when Iceland probably had a lot in common with Westeros, a Viking named Orm Storolfson picked up a log weighing 1,433 pounds and dragged it three steps. On the third step, his back broke. Ouch. Nevertheless, Storolfson made it into Icelandic lore as a legendary strongman.
The first season 5 'Game of Thrones' trailer just leaked
Last night, I was one of the lucky Game of Thrones fans who caught an IMAX screening of the two most recent episodes, "The Watchers on the Wall" and "The Children." After the episodes aired, we were shown an exclusive trailer for season 5. And of course, it was leaked online within minutes.


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Welcome to Glock Talk
Why should YOU join our Glock forum?
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If you consider yourself a beginner or an avid shooter, the Glock Talk community is your place to discuss self defense, concealed carry, reloading, target shooting, and all things Glock.
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Discussion in 'Reloading' started by FLSlim, May 5, 2010.


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Welcome to the MA ClubHelping people with long-term mental illness find and secure employment, housing, and education, services and support in the community through a physical activity and natural approach.
We can help a lot to you.
To work with others towards helping to make the community more accessible and user friendly to people with disabilities.
For some bizarre reason, that we can't quite fathom, it seems that some people don't believe that women need protein in their diet as much as men do.
Why this would be, we are not quite sure, but make no mistake, the female of the species needs proteins just as much as the males do. After all, we are mammals too!
One thing a lot of women looking to lose weight fast may forget, is just how important protein – including of course whey protein – is to ensure adequate nutrition.
Yoyo dieting can wreak havoc on the body and its ability to regulate its weight. But did you know that when the body starts to burn muscle, this is a bad thing for your diet. Quite apart from the fact that you don't want your muscles to waste away (do you?) muscles are where the fat burning occurs.
So, you want to keep your muscles, even if you are not into body building and of course this goes double or even treble for anyone who is looking to tone up as well as slim down.
In order to maintain or increase your muscles, you therefore need to ensure an adequate supply of protein. Naturally, it is best if you can meet your protein needs from your diet. This would usually be from red meat, fish and eggs and the like. But if, like many people, your diet may suffer from one or two gaps, you may be considering a protein supplement.
Whey protein would therefore be a good place to start.
The proven health benefits are manifold. It may help boost your immune system, for example, which is always good news. It does this by increasing the levels of glutathione, which aids your body in its own personal detox.
More good news comes in the form of osteoporosis or rather the lack of it – hopefully! This is because whey protein is derived from milk and milk contains calcium, something which women can sometimes be deficient in, leading to the danger from osteoporosis – amongst other things.
Another thing that might prove to be an unexpected bonus, when using whey powder supplements, particularly through drinks, is that it has been proven to help beat those hunger pangs that are the curse of so many a diet.
Of course, there are calories within the supplements themselves, which is to be expected and this should always be worked into any calorie plan that you have, but the good news is that these supplements have been shown to limit the amount of ghrelin, a hormone that puts our brains on hunger alert!
So the next time you were thinking of snacking on a cupcake or some chocolate, consider instead a whey protein bar or shake – not only will it help tone you up, which will lead to increased fat burning in the long run, but it could also help you when reaching for the next cookie and the next…
Creatine Supplement
The first thing you want to know is what is creatine and why do we need it.
Creatine is the second most important protein that your body needs, after whey protein, to help the development of all essential muscles.
But this is not all. As well as the beneficial effects of growing your muscles, it also helps you power through the most high-intensity work out sessions, in a breeze.
The human body generates this at about a gram or two a day, but it does not hang about in your system for long and you may want to give it a little helping hand.
However, like all things in life, knowing how to and how much to and when to, are the key points to successfully boost the creatine in your body.
Put simply, there's no need to overdo it. Sometimes less can be more when it comes to creatine. Here we have put together a simple guide to creatine as part of your workout schedule.
Anyone who is doing high intense gym workouts might consider taking creatine as a supplement to their diet. However, if you are a long distance runner, or doing prep for a marathon then maybe this is not the product for you, as it does not show any really beneficial effects on long, slow types of exercise.
Also, if your diet is already high in creatine, then you may simply not need this and since there is no evidence taking more than required (i.e. loading up) actually works on the human body any better than simply taking the amount advised.
Studies have shown that people who eat a diet that is high in red meat have naturally higher creatine levels than those that don't. In other words, if you are a vegetarian this is a supplement that you may need particularly in your diet.
If you have decided that creatine is for you, the next question will naturally be, how should I take this supplement? The short answer is, in a drink.
As previously stated, more could be less in the case of creatine or at the very least, there isn't really any point in taking any more than the stated dose as it would just be a waste of money.
The good news is that you don't actually need to take very much of this supplement and it can be quite easily added to your daily protein shake.
5 grams is the recommended dosage, in monohydrate form, taken with 400 mls of water (or your shake),
Other forms of creatine are available, for example liquid form or nitrate, but the general advice is that the monohydrate is the most efficient form.
It doesn't mix in particularly well, so be patient and wait for all the lumps to dissolve properly before drinking, it will work better if you do!
The best time to take creatine is after a workout, and not before it. This is because it can cause water to be drawn into your gastrointestinal tract, which could possibly result in bloating and cramping – not something you want before you hit the gym!
Maybe you are new to the world of protein shakes and supplements and the whole thing is confusing you a bit. You may have heard about this and its use as a muscle developing tool, but not be exactly sure about what it is and how to use creatine safely and effectively.
The good news here is that it is very safe to add as a supplement to your diet and any negative side effects are fairly unlikely or not very serious.
Any side effects should be limited to, at worst, perhaps some mild bloating and cramping. Even then, these aren't completely proven.
Because creatine is already produced by the human body, it is a natural protein, however, it is not produced in very high amounts. By taking a supplement you can increase the quantity produced, but why might you want to do this?
Well, if you are a gym buff you may have heard about its potential to build muscles, giving you the toned, ripped physique you are after.
And it is true that the use of this protein could lead to a weight gain – this is an effect that could be good or bad, depending on what it is that you want to achieve,
In the short term, any weight gain may only be down to an increase in water retention, but, with long term use it can provide the bulking up in muscle that you desire.
However, getting more buff in the muscle department is not the only beneficial effect of this protein. People also love it for the feeling of strength and the amounts of energy associated with it.
Before we get too carried away with the idea, it is important to note that this is only when it is used correctly and in accordance with the instructions on the packaging.
There is nothing to be gained by taking more than the stated dose, here. Also, in about 20-30% of the population, there will be no effects at all of taking creatine supplements, as some people seem to be naturally immune to it!
So back to the thorny question of how to use creatine? Despite there being some alternative ways to get this essential protein into your system, the best way, think the experts is the creatine monohydrate. This is to be taken, 5 mls dissolved into 400 mls of water.
Some people favor adding it to green tea, others add it to their daily protein shake.
Timing, as with so many things in life, is crucial though. You particularly do not want to go taking this just before you go and hit the gym…remember the potential bloating side effects.
Generally afterwards is the best time to take creatine. One note of caution here, it is not the most soluble thing in the world ever and will take some time to mix in properly, so make sure you give it a good stir.
Despite one or two minor downsides, this is a safe and easy to use supplement that should see you powering through your exercise program in no time


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HP CEO Léo Apotheker unveils IT leadership plan
Hewlett-Packard (HP) chief executive officer Léo Apotheker has announced plans to take a leading role in defining the future of information technology.
This Article Covers
Hewlett-Packard (HP) chief executive officer Léo Apotheker has announced plans to take a leading role in defining the future of information technology.
Your exclusive guide to CIO trends
A collection of our most popular articles for IT leaders from the first few months of 2016, including: - Corporate giants recruit digitally-minded outsiders to drive transformation - Analytics platforms to drive strategy in 2016 - Next generation: The changing role of IT leaders.
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Speaking about his strategy for the first time since his appointment last October, Léo Apotheker said HP was well-positioned for the role, through a combination of financial strength, scale, global reach and position in the consumer and enterprise markets.
Apotheker is departing from the approach of his predecessor Mark Hurd by concentrating on revenue growth, rather than cost-cutting.
Cloud computing is changing the way IT is delivered, he said, but HP believes a hybrid environment, that combines the best of traditional environments with private and public clouds, will be the prevailing model for large enterprises for a long time.
Apotheker committed to continue enhancing HP's offerings across its hardware, software and services portfolio.
He said HP will also develop the cloud- and connectivity-based solutions of the future to meet the needs of consumers, small and mid-size companies and large enterprises.
This includes becoming a leading provider of cloud-based platform services, Apotheker said.
"We see clearly a world in which the impact of cloud and connectivity is changing not only the user experience, but how individuals, small businesses and enterprises will consume, deploy and leverage information technology. HP is well-positioned to be the trusted leader in addressing this opportunity," he said.
Apotheker outlined a four-point strategy to extend HP's leadership in; managing and optimising traditional environments; to build and manage next-generation cloud-based architectures; to enable a seamless transition to hybrid computing models; and to define and deliver the connected world from the consumer to the enterprise.
"Everything we do in the future will be delivered as a service," Apotheker said. "It's the first time HP is trying to put all of the elements of what it's doing together."
To achieve these goals, HP plans to develop a portfolio of cloud services from infrastructure to platform services, and to develop and run the industry's first open cloud marketplace for consumer and enterprise services and applications.
Apotheker said HP will build and acquire the software it needs to help companies write and run applications using its cloud service.
HP also plans to build webOS into a leading connectivity platform by putting the software onto a broader range of products and potentially delivering up to 100 million webOS-enabled devices a year.
Enjoy the benefits of CW+ membership, learn more and join.


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Photo needs the "A" Team :))
Started Oct 8, 2012 | Discussions thread
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Gradybaby OP • Contributing Member • Posts: 664
Re: Photo needs the "A" Team :))
In reply to Daviskw • Oct 9, 2012
These are all fantastic thanks for all your help.
Gradybaby's gear list:Gradybaby's gear list
Fujifilm X-T1 Nikon D750 Fujifilm XF 56mm F1.2 R
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