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Key Features
Massive cutting area after opening
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Delivering a massive cutting area, the all-new Swhacker Broadhead will leave you with better blood trails, reduced search time, and easier harvest recovery. The high-carbon steel tip enters the animal well before the blades impact, eliminating deflections as the blades penetrate. Wing blades efficiently cut through the hide and ribs. The two main blades remain unopened on initial penetration, keeping the edge intact for cutting internal organs. Stainless steel .032" blades. Package of 3 broadheads.


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"They're Jewish Too"
Alyssa Appelman I've always hated that "Wherever You Go" song. You know, the one about how Jews are everywhere and some wear sombreros while others eat hamburger buns? It's a catchy enough tune and all, but the lyrics have always bothered me: "Wherever you go, there's always someone Jewish. You're never alone when you say you're a Jew. So when you're not home and you're somewhere kind of "newish" The odds are, don't look far, 'cause they're Jewish too." It's always sounded like some type of reverse anti-Semitism: that you don't have to worry about actually interacting with people who are different than you because there'll always be ex-USYers and Ramahniks wherever your travels lead you. I've always heard an anti-people-who-aren't-Jewish sentiment in the song. But as I was thinking about this month's theme, "Jewish Pluralism," I began to wonder if perhaps I had been too quick to judge. The song highlights the Jewish community's diversity. And maybe we don't think about that enough. At least for me, Judaism has always had a sort of a narrow connotation. It's not that I don't know a lot of Jewish people; I just don't really feel that I've been exposed to that much diversity within the community. Outside of the Reform and Conservative branches of American Jewry, I don't know much about the diversity within the Jewish faith. I've been to a few shuls in Israel and Western Europe, but that's really the extent of my experiences. I know very little about diversity within Judaism. And if that's the case, how much can I really know about diversity outside of Judaism? We can see Judaism, not as a private world unto itself, but as a diverse section of an even more diverse society. Understanding the pluralistic nature of the Jewish people can give us a clearer picture of other types of diversity as well. Focusing our attention inwards, therefore, doesn't necessarily mean ignoring everyone else. On the contrary, appreciating the pluralism within the Jewish faith can actually help us. Taking time to understand the diversity within Judaism can give us a better sense of our role in the greater community. Perhaps it was just my cynical side forcing me to see a Jewish-people-are-the-only-ones-worth-talking-to message instead of recognizing the song's illustration of Jewish pluralism. When you look at it from that point of view, it's a pretty interesting concept. Although I'm not yet sure about the word "newish" – give me a little more time to get used to it. [Posted 05/18/07] |


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Originally Posted by rogerd It is the light in the sunlight that is converted to electricity. When the light hits the panels it is converted to tiny amounts of electricity. So, even if you have cold but sunny days you can get really hot water. That's not how mine works, but the last sentence is true. I get 170° water on 30° days.
Solar Energy is a sunlight that converts in electricity. But we have check whether volt is high while using the solar energy. In winter day how we get a hot water.
Solar Hot Water
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Announce your availability and submit your resume to hundreds of Employers that visit this site. Employers can contact you directly as soon as a suitable position becomes available. Post your Resume to Fontbonne University Career Opportunities!
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Speech-Language Pathologist Opportunities in School ProgramsPosted by: Invo HealthCare AssociatesPosted date: 2013-Jun-10
Location: Greater St. Louis Metro Area Invo HealthCare Associates is looking for licensed Speech and Language Pathologists to join our nationwide group of therapists. We need SLPs to fill positions in various education settings including Early Intervention (0-3), Preschool (3-5), and School Based Programs (K-12). Pathologists would work directly with students to evaluate and treat speech, language, cognitive-communication, and swallowing disorders. Because we work with schools across the country, there are opportunities available nationwide. Please apply today to see if there are open opportunities in your area. |


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Location: Berea, OH
The Marketing Team at Equity Trust is looking for someone to join us as the Marketing Supervisor/Project Manager. The Marketing Supervisor leads a team of support personnel (copywriter, graphic designer, data analyst, etc), who are responsible for providing marketing support to our various Marketing Managers on their respective initiatives/projects. Additionally, the Supervisor will lead the support personnel as they accomplishing projects which they are solely responsible for delivering (Testimonials, Videos, Social Media Campaigns, Collateral Creation, etc.) As a supervisor, the incumbent is responsible for the performance and development of the team members. He/she will host coaching sessions, complete scorecards, establish goals, remove obstacles, etc. He/she will proactively identify his/her team needs from a staffing and workload standpoint. He/she will conduct interviews for new employees, contract out work as necessary, and establish contingency game plans when needed. Project Management is an essential component of this position. The incumbent is responsible for managing a large number of marketing projects to ensure they are completed with good quality, on time, and in budget. As the supervisor, the incumbent is responsible for setting the tone in the department - creating a fun, upbeat, creative, engaging, and productive environment. He/she shall lead by example - as a creative and innovative marketing professional and should encourage that from all team members. We have a fast paced environment with lots of cutting edge marketing initiatives. We are seeking someone with 5 -10 years of previous marketing experience. Leadership and Project Management experience is a definite plus. We require a Bachelor's Degree in Marketing, Communications, Business, or other related field.
Type: | Permanent | ||
Location: | Berea, OH | ||
Country: | United States of America | ||
Contact: | HR | ||
Advertiser: | Equity Trust Company | ||
Reference: | JSCBSRC-470 |


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Quick Facts
- NAME: Lyndon B. Johnson
- OCCUPATION: U.S. President, U.S. Vice President
- BIRTH DATE: August 27, 1908
- DEATH DATE: January 22, 1973
- EDUCATION: Southwest Texas State Teachers College (Texas State University), Johnson City High School
- PLACE OF BIRTH: Stonewall, Texas
- PLACE OF DEATH: Stonewall, Texas
- Full Name: Lyndon Baines Johnson
- AKA: Lyndon Johnson
- Nickname: "Bull Johnson"
- Nickname: "Landslide Lyndon"
- Nickname: "Light Bulb Lyndon"
- AKA: Lyndon B. Johnson
Best Known For
Lyndon B. Johnson was elected vice president of the U.S. in 1960 and became the 36th president in 1963, following the assassination of President John F. Kennedy.
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Bloody Sunday (4:04)
Lyndon B. Johnson - Before the War on Poverty
After spending time teaching impoverished Mexican-American immigrants on the border of Texas and Mexico, Lyndon B. Johnson was inspired to bring an end to poverty.
Thurgood Marshall - The Solicitor General
In 1965 President Lyndon B. Johnson appointed Thurgood Marshall to the post of Solicitor General, forging a strong relationship between Marshall and the President.
Thurgood Marshall - Appointed to the Supreme Court
In 1967, President Lyndon B. Johnson appointed Thurgood Marshall to the Supreme Court.
Bloody Sunday
On March 7, 1965 around 600 people crossed the Edmund Pettus Bridge in an attempt to begin the Selma to Montgomery march. State troopers violently attacked the peaceful demonstrators in an attempt to stop the march for voting rights.
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Play NowLyndon B. Johnson. (2014). The Biography Channel website. Retrieved 06:26, Mar 10, 2014, from http://www.biography.com/people/lyndon-b-johnson-9356122.
Lyndon B. Johnson. [Internet]. 2014. The Biography Channel website. Available from: http://www.biography.com/people/lyndon-b-johnson-9356122 [Accessed 10 Mar 2014].
"Lyndon B. Johnson." 2014. The Biography Channel website. Mar 10 2014, 06:26 http://www.biography.com/people/lyndon-b-johnson-9356122.
"Lyndon B. Johnson," The Biography Channel website, 2014, http://www.biography.com/people/lyndon-b-johnson-9356122 [accessed Mar 10, 2014].
"Lyndon B. Johnson," The Biography Channel website, http://www.biography.com/people/lyndon-b-johnson-9356122 (accessed Mar 10, 2014).
Lyndon B. Johnson [Internet]. The Biography Channel website; 2014 [cited 2014 Mar 10] Available from: http://www.biography.com/people/lyndon-b-johnson-9356122.
Lyndon B. Johnson, http://www.biography.com/people/lyndon-b-johnson-9356122 (last visited Mar 10, 2014).
Lyndon B. Johnson. The Biography Channel website. 2014. Available at: http://www.biography.com/people/lyndon-b-johnson-9356122. Accessed Mar 10, 2014.
Lyndon B. Johnson, the 36th president of the United States, was born in Texas on August 27, 1908. He was elected vice president of the United States in 1960, and became the 36th president in 1963, after President John F. Kennedy was assassinated. During his administration, Johnson initiated the "Great Society" social service programs, signed the Civil Rights Act into law,
"There are no problems we cannot solve together, and very few that we can solve by ourselves."
"Poverty must not be a bar to learning and learning must offer an escape from poverty."
"I will do my best. That is all I can do. I ask for your help—and God's."
"Being president is like being a jackass in a hailstorm. There's nothing to do but to stand there and take it."
and bore the brunt of national opposition to his vast expansion of American involvement in the Vietnam War. Johnson died in Texas on January 22, 1973.
Younger Years
Born in Stonewall, Texas, on August 27, 1908, Lyndon Baines Johnson's family had settled in Texas before the Civil War. His parents, Samuel Ealy Johnson Jr. and Rebekah Baines Johnson, had three girls and two boys. Lyndon was the oldest, born August 27, 1908. The nearby town of Johnson City was named after the Johnson family, known for farming and ranching. Lyndon's father was a rancher and part-time politician, but did not inherit the family's ranching talent and ran into financial difficulty, losing the family farm when Lyndon was in his early teens.
Lyndon B. Johnson struggled in school, but managed to graduate from Johnson City High School in 1924. He enrolled at Southwest Texas State Teachers College (now Texas State University) and participated in debates and campus politics. After graduating in 1930, he briefly taught school, but his political ambitions had already taken shape: In 1931, Johnson won an appointment as legislative secretary to Texas Democratic Congressman Richard M. Kleberg, and relocated to Washington, D.C. He quickly built a network of congressmen, newspapermen, lobbyists and friends, including aides to President Franklin D. Roosevelt.
In 1934, Lyndon B. Johnson met Claudia Alta Taylor, known to her friends as "Lady Bird." Claudia soon became Johnson's top aide. She used a modest inherence to bankroll his 1937 run for Congress, and ran his office for several years. She later bought a radio station and then a television station, which made the Johnsons wealthy.
Early Political Career
After the Japanese bombing of Pearl Harbor in December 1941, President Roosevelt helped Lyndon B. Johnson win a commission in the U.S. Naval Reserve as a lieutenant commander. Johnson served on a tour of the South Pacific and flew one combat mission. Not long into the mission, Johnson's plane was forced to turn back due to mechanical difficulty, but he managed to receive a Silver Star medal for his participation. Soon after, he returned to his legislative duties in Washington, D.C.
In a close and controversial election, Lyndon B. Johnson was elected as a senator for Texas in 1948. He advanced quickly and, with is connections, became the youngest minority leader in Senate history in 1953. Democrats won control of the Senate the following year, and Johnson was elected majority leader.
Johnson had an uncanny ability to gather information on his fellow legislators, and knew where each of his colleagues stood on political issues.
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The first U.S. president, former military leader George Washington, took his oath of office on April 30, 1789, on the balcony of Federal Hall. From that moment onward, the United States' highest office has been filled regularly by elected officials who aim to serve the people under the guidance of the U.S. Constitution. Learn more about the 43 men who have served as America's chief executive.
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Copyright © 2008 Elsevier Inc. All rights reserved.
Immunity, Volume 28, Issue 2, 197-205, 15 February 2008
Add/View Comments (0)Apoptosis Regulators Fas and Bim Cooperate in Shutdown of Chronic Immune Responses and Prevention of Autoimmunity
Peter D. Hughes1, 2, Gabrielle T. Belz1, Karen A. Fortner3, Ralph C. Budd3, Andreas Strasser1, 4, , and Philippe Bouillet1, 4, ,
1 Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Australia
2 Department of Medical Biology, The University of Melbourne, Melbourne 3010, Australia
3 Immunobiology Program, The University of Vermont College of Medicine, Burlington, VT 05405-0068, USA
Corresponding author
4 These authors contributed equally to this work.
- Apoptotic death of T lymphocytes is critical for shutdown of immune responses and hemopoietic cell homeostasis. Both death receptor (Fas) activation and mitochondrial apoptosis triggered by the BH3-only protein Bim have been implicated in the killing of antigen-stimulated T cells. We examined mice lacking the gene encoding Bim (Bcl2l11) and with the inactivating lpr mutation in the gene encoding Fas (Fas), designated Bcl2l11−/−Faslpr/lpr mice. Shutdown of an acute T cell response to herpes simplex virus involved only Bim with no contribution by Fas, whereas both pathways synergized in killing antigen-stimulated T cells in chronic infection with murine γ-herpesvirus. Bcl2l11−/−Faslpr/lpr mice developed remarkably enhanced and accelerated fatal lymphadenopathy and autoimmunity compared to mice lacking only one of these apoptosis inducers. These results identify critical overlapping roles for Fas and Bim in T cell death in immune response shutdown and prevention of immunopathology and thereby resolve a long-standing controversy.
In response to infection or immunization, T cells that express antigen-specific T cell receptors (TCR) become activated and proliferate, and some differentiate into effector cells (Sprent and Tough, 2001). Activated T cells then produce cytokines that help coordinate the immune response aimed at eliminating the pathogen. Clearance of the antigen is accompanied by the shutdown of T cell immune responses and involves apoptosis of a large fraction of antigen-activated T cells. This prevents accumulation of no-longer-needed and potentially dangerous effector cells and thereby precludes immunopathology. Two distinct but ultimately converging pathways control apoptosis initiation in mammalian cells (Strasser et al., 1995). Ligation of "death receptors," members of the tumor necrosis factor receptor (TNF-R) family with an intracellular "death domain" (e.g., Fas or the tumor necrosis factor receptor 1 [TNF-R1]) triggers formation of the "death-inducing signaling complex" (DISC), which promotes cell demolition through activation of caspase-8 (Ashkenazi and Dixit, 1998,Krammer, 2000,Wallach et al., 1998). Conversely, the "mitochondrial" (also called "intrinsic" or "B cell lymphoma [Bcl-2]-regulated") apoptotic pathway, activated by developmental cues or cytotoxic stimuli, such as cytokine deprivation, is independent of caspase-8 and Fas-associated death domain protein (FADD), but instead involves mitochondrial release of cytochrome c, which promotes Apaf-1-mediated activation of caspase-9 (Green and Kroemer, 2004,Wang, 2001). This pathway is controlled by the Bcl-2 protein family, which consists of three subgroups: the Bcl-2-like prosurvival proteins essential for cell survival; the Bax and Bak-like proteins required for mitochondrial outer membrane disruption, release of apoptogenic proteins (e.g., cytochrome c), and activation of the caspase cascade (Green and Kroemer, 2004,Wang, 2001); and the proteins containing only the Bcl-2 homology domain 3 (BH3-only proteins, e.g., Bim), which are activated by distinct death stimuli and are essential for initiation of apoptosis signaling (Huang and Strasser, 2000).
Both death receptor signaling and the mitochondrial apoptotic pathway have been shown to be critical for lymphocyte homeostasis (Krammer, 2000,Sprent and Tough, 2001). Mice (Watanabe-Fukunaga et al., 1992) or humans (ALPS, autoimmune lymphoproliferation syndrome patients) (Rieux-Laucat et al., 1995) defective for Fas (Faslpr/lpr mice) or its ligand, FasL (Faslgld/gld mice), develop progressive lymphadenopathy and splenomegaly resulting from accumulation of excess mature T and B cells as well as "unusual" αβTCR+CD4−CD8−B220+ T cells. Bcl-2-deficient mice (Veis et al., 1993) and mice lacking myeloid cell leukemia 1 (Mcl-1) in the hematopoietic system (Opferman et al., 2005) exhibit profound lymphopenia, whereas mice overexpressing a Bcl-2 transgene throughout the hematopoietic compartment show marked lymphadenopathy (Ogilvy et al., 1999). Mice lacking the BH3-only protein Bim also accumulate excess lymphocytes and myeloid cells and these cells are abnormally resistant to cytokine deprivation, deregulated calcium flux, and ER stress (Bouillet et al., 1999,Puthalakath et al., 2007). Moreover, Bim is critical for apoptosis during negative selection of autoreactive thymocytes (Bouillet et al., 2002), mature T cells (Davey et al., 2002), and B cells (Enders et al., 2003).
The relative contributions of the two distinct apoptotic pathways in the termination of T cell immune responses has been a matter of controversy for a long time. FasL and Fas have been implicated because activation-induced cell death (AICD), an in vitro model in which mitogen-activated T cell blasts are killed by TCR restimulation, which causes FasL upregulation, is inhibited by FasL or Fas inactivation (Brunner et al., 1995,Dhein et al., 1995,Russell et al., 1993). Moreover, clearance of Staphylococcus Enterotoxin B (SEB)-activated TCR Vβ8+ T cells was reported to depend partially on Fas (Mogil et al., 1995,Van Parijs et al., 1996). The mitochondrial pathway has been implicated in immune response shutdown, because Bcl-2 overexpression (Strasser et al., 1991), loss of Bim (Hildeman et al., 2002,Pellegrini et al., 2003), or Bax and Bak deficiency (Rathmell et al., 2002) inhibited death of T cells stimulated in vitro or in vivo by a single dose of SEB or in vivo after infection with human herpes simplex virus (HSV-1). It is conceivable that Fas and Bim may have overlapping roles in T cell killing, with their relative contribution determined by the nature of the immune response (acute versus chronic). In acute immune responses, apoptosis is triggered by the drop in cytokine amounts, after clearance of the pathogen or injected immunogen (Hildeman et al., 2002,Krammer, 2000,Sprent and Tough, 2001). A single administration of SEB, which is known to be eliminated quickly from the body (Vabulas et al., 1996), would therefore mimic an acute infection. In contrast, TCR restimulation of activated T cells in vitro (AICD) or repeated administration of SEB to mice is more likely to imitate the repeated TCR activation that is thought to occur during chronic immune responses, such as persistent infections or stimulation with self-antigens (Krammer, 2000,Sprent and Tough, 2001).
The removal of effector T lymphocytes prevents immunopathology, but the mechanisms for apoptosis induction remain contentious (Krammer, 2000,Sprent and Tough, 2001). In the present study, we have generated mice lacking Bim and harboring the inactivating lpr mutation in the Fas gene, and we used acute and chronic viral infection models to decipher the individual and combined roles of Fas and Bim in the shutdown of T cell immune responses and in immunopathology.
Bcl2l11−/−Faslpr/lpr Lymphoid Cells Are Resistant to Both Fas-Transduced as well as Bim-Dependent Apoptotic Stimuli
To investigate the functional interaction of Bim and Fas in the control of lymphocyte homeostasis, we generated mice lacking both of these apoptosis inducers (with both parental strains backcrossed to C57BL/6 >20 generations prior to intercrossing). Bim is required for the killing of lymphocytes induced by growth factor withdrawal, deregulated calcium flux, DNA damage, or treatment with dexamethasone (Bouillet et al., 1999). Bcl2l11−/− thymocytes are, however, normally sensitive to treatment with phorbol myristyl acetate (PMA, a death stimulus that can be countered by Bcl-2 overexpression) or FasL, which triggers the death receptor pathway (Bouillet et al., 1999). To determine the consequences of the combined mutations on cell survival, we sorted several lymphocyte populations and subjected them in culture to cytokine deprivation, treatment with FasL, the calcium ionophore ionomycin, PMA, or the DNA damage-inducing drug etoposide. CD4+CD8+ thymocytes (Figure 1A) as well as mature B cells (see Figures S1 E–S1G available online) and T cells (CD4+, CD8+, and αβTCR+CD4−CD8−B220+; Figures 1B and 1C; Figure S1 ) from Bcl2l11−/−Faslpr/lpr mice were resistant to both FasL as well as Bim-dependent apoptotic stimuli, such as growth factor withdrawal or treatment with ionomycin. Thymocytes remained, however, normally sensitive to PMA (Figure 1), which was shown to require the BH3-only protein Puma for cell killing (Villunger et al., 2003). These results demonstrate that Fas signaling and Bim exert nonredundant roles in the apoptosis of hemopoietic cells.
Clearance of HSV-Specific CD8+ T Cells in Acute Infection Requires the BH3-Only Protein Bim but Is Fas Independent
Although the importance of Fas and Bim in lymphocyte homeostasis is widely accepted, their respective roles in immune response shutdown remain controversial (Hildeman et al., 2002,Krammer, 2000,Sprent and Tough, 2001). We addressed the existing controversy by measuring the numbers of antigen-stimulated CD8+ T cells in spleen and lymph nodes during acute and chronic immune responses in Bcl2l11−/−Faslpr/lpr as well as Bcl2l11+/−Faslpr/lpr, Faslpr/lpr, Bcl2l11−/−, and WT mice (Figures 2A–2D and 3A–3D). Consistent with the acute nature of an HSV-1 (HSV1 KOS) infection and the ensuing immune response (Pellegrini et al., 2003), all mice were able to clear the virus rapidly (not shown). Previous studies have shown that the number of HSV-specific CD8+ T cells in the spleen of WT and Faslpr/lpr mice peaks at day 7, after which the majority of these effectors are eliminated by cell death (Pellegrini et al., 2003). Consistent with this, flow cytometric analysis showed that the spleens of WT and Faslpr/lpr mice contained only low numbers (<106) of HSV-specific CD8+ T cells on days 17 and 35 after HSV infection (Figures 2A and 2B). In contrast, in Bcl2l11−/− mice, the numbers of HSV-specific CD8+ T cells in the spleen did not fall substantially after pathogen clearance (Figure 2E). Notably, the additional loss of Fas (in Bcl2l11−/−Faslpr/lpr mice) did not further increase the accumulation of viral antigen-stimulated CD8+ T cells (Figure 2E). HSV-specific CD8+ cell numbers were also similar in nonlymphoid tissues (lungs and liver) of Bcl2l11−/− and Bcl2l11−/−Faslpr/lpr mice 17 and 35 days after infection with HSV-1 (Figure S2 ). These results demonstrate that Fas activation, which requires repeated TCR stimulation to upregulate FasL in T cells, is not involved in the shutdown of acute immune responses; instead, this death is mediated predominantly by Bim.
Bim and Fas Cooperate to Eliminate MHV-OVA-Specific T Cells in Chronic Infection
Both mitochondrial as well as Fas-mediated apoptosis have been hypothesized to mediate the death of CD4+ as well as CD8+ T cells during chronic antigenic stimulation (Krammer, 2000,Sprent and Tough, 2001). We therefore examined the individual and combined roles of Bim and Fas in the T cell immune response to mouse γ-herpes virus (MHV) transgenically expresssing ovalbumin (MHV 68-OVA) (Figure 3). This virus causes a chronic infection predominantly in the lung and B cells, with persistent antigen presentation in the lung (Figure S3 ; Rajcani and Kudelova, 2005). Total numbers of leukocytes as well as CD8+ T cells were determined 14, 40, and 60 days after infection (Figures 3A–3D). Surface staining for viral antigen (ovalbumin)-specific TCR (Figures 3E and 3F) or intracellular staining for IFN-γ production after brief antigenic (ovalbumin) stimulation in culture (Figures 3G and 3H) demonstrated that in spleens and draining lymph nodes of WT mice, MHV-OVA-specific CD8+ T cells (undetectable prior to infection) were greatly expanded on days 14 and 40 after infection, followed by a loss of nearly 50% of these cells by day 60. Loss of Bim resulted in a significant (p < 0.05), albeit relatively small, increase in MHV-OVA-specific CD8+ T cells on days 40 and 60, which was particularly prominent in the spleen (Figures 3E and 3G). Fas-deficient mice contained similarly increased numbers of these cells (Figures 3E and 3G; p < 0.05). Remarkably, the combined absence of both apoptosis inducers had dramatic effects, causing a 43- or 63-fold increase of MHV-OVA-specific CD8+ T cells in the spleen compared to WT mice on days 40 and 60, respectively. The increase of MHV-OVA-specific CD8+ T cells in the mediastinal lymph nodes was even more spectacular, with an 83- or 845-fold difference compared to WT mice observed on days 40 and 60, respectively (Figures 3F and 3H). This preferential increase of antigen-specific CD8+ T cells in the draining lymph nodes might be a consequence of the ongoing antigen release from the lungs resulting in lymphocyte homing to this site. These results demonstrate that Fas-mediated death receptor signaling and the Bim-mediated mitochondrial apoptotic pathway cooperate to prevent deregulated expansion of activated T cells during chronic antigenic stimulation.
Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr Mice Develop Extreme Lymphadenopathy
Loss of either Bim or Fas both lead to marked lymphadenopathy. Whereas Bcl2l11−/− mice show an increase in most lymphoid and myeloid cell populations in the periphery (Bouillet et al., 1999), lymphadenopathy in Faslpr/lpr mice is due in large part to the accumulation of unusual αβTCR+CD4−CD8−B220+ T cells (Watanabe-Fukunaga et al., 1992). These unusual T cells are not found in WT or Bcl2l11−/− mice. Bcl2l11−/−Faslpr/lpr and even Bcl2l11+/−Faslpr/lpr mice developed lymphadenopathy and splenomegaly at a dramatically increased magnitude and rate compared to mice lacking either apoptosis initiator alone (Figure 4; Figure S5 ). In particular, the αβTCR+CD4−CD8−B220+ T cell population was increased 4–5 times in the spleen of Bcl2l11−/−Faslpr/lpr mice compared to Faslpr/lpr mice. Precise quantification in the lymph nodes was made impossible by huge variations between individual mice (one particular Bcl2l11−/−Faslpr/lpr mouse was found to have 12.7 g of lymph nodes; Figure S6 ), but very large lymph nodes were a hallmark of all Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice (Figures S5 A and S5B). Conventional CD4+ and CD8+ T cells, B cells, and, unexpectedly, granulocytes were also markedly increased in spleens and lymph nodes of Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice compared to WT mice or animals lacking only one of these apoptosis inducers (Figure 4). This shows that the Fas-activated death receptor and the Bim-mediated mitochondrial apoptotic pathways act synergistically to control homeostasis of all mature lymphocyte subpopulations and granulocyte turnover.
The thymi of Bcl2l11−/−Faslpr/lpr, Bcl2l11+/−Faslpr/lpr, Bcl2l11−/−, Faslpr/lpr, and WT mice were all similar in size and cellularity. The distribution of the four major cellular subsets (defined by the expression of CD4 and CD8) within the thymus of Bcl2l11−/−Faslpr/lpr mice was comparable to that of Bcl2l11−/− mice (Bouillet et al., 1999), with a reduction in CD4+CD8+ cells and a 2- to 3-fold increase in CD4−CD8− as well as mature (CD4+CD8− and CD4−CD8+) T cells (Figure S4 ). Thus, loss of Bim and Fas do not cooperate to cause abnormalities in the thymus, demonstrating that the enhanced lymphadenopathy and splenomegaly seen in Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice are a consequence of defects in peripheral lymphoid organs.
Lymphadenopathy in Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr Mice Is Not Associated with Lymphoid Malignancy
Deregulation of apoptosis is thought to contribute to the development of many, perhaps all, types of cancer (Hanahan and Weinberg, 2000). We have previously shown that loss of Bim accelerates lymphoma development in mice expressing a Myc transgene in their B cell compartment (Egle et al., 2004). Because the dramatic expansion of the lymphocyte compartment in Bcl2l11−/−Faslpr/lpr and even the Bcl2l11+/−Faslpr/lpr mice was due to the disruption of apoptotic pathways, we examined whether the T cells accumulating in these animals were monoclonal and hence most likely lymphomatous. However, immunofluorescent staining with a panel of monoclonal antibodies to different TCR-Vβ subtypes demonstrated that T cells from multiple lymph nodes of different Bcl2l11−/−Faslpr/lpr mice had a normal polyclonal repertoire of TCR specificities (Figure 5; Figure S7 ). To confirm the absence of hematological (or other) malignancy in Bcl2l11−/−Faslpr/lpr mice, we verified that C57BL/6 mice injected with 2 × 106 lymph node cells from several Bcl2l11−/−Faslpr/lpranimals did not develop tumors over a 12 month observation period (data not shown). These results show that the extreme lymphadenopathy and splenomegaly in Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice are caused by the polyclonal expansion of nontransformed lymphocytes.
Autoimmune Pathology in Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr Mice
Bim (Davey et al., 2002) as well as Fas (Van Parijs et al., 1998) have been implicated in the killing of T cells chronically activated by self-antigens, so it appears predictable that loss of both may synergize to cause severe immunopathology. Although Faslpr/lpr (Watanabe-Fukunaga et al., 1992) as well as Bcl2l11−/− (Bouillet et al., 1999) mice generally produce autoantibodies, they develop immune-complex deposits and fatal SLE-like autoimmune disease only on particular genetic backgrounds (e.g., MRL for lpr mice or mixed C57BL/6x129SV for Bcl2l11−/− mice). On the C57BL/6 background, Bcl2l11−/− mice develop lymphocyte infiltrates in lung, liver, and kidneys around 1 year of age, but these have no discernible consequences for their health. All Faslpr/lpr and Bcl2l11−/− mice examined between 16 and 42 weeks were healthy, and histological examination did not show any signs of severe autoimmunity. In contrast, all Bcl2l11−/−Faslpr/lpr and even the Bcl2l11+/−Faslpr/lpr mice had become moribund by 250 days of age, with a median survival of 114.5 days for Bcl2l11−/−Faslpr/lpr mice and 159 days for Bcl2l11+/−Faslpr/lpr mice (Figure 6). Almost all of these animals had to be sacrificed because they presented with labored breathing resulting from filling of the chest cavity by large lymph nodes. Histological examination revealed the presence of massive lymphocyte infiltrates in the lungs, kidneys, and liver of Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice (Figure 6A). All moribund mice also tested positive for the presence of anti-DNA autoantibodies (not shown). 20%–30% of the Bcl2l11−/−Faslpr/lpr and ∼10% of the Bcl2l11+/−Faslpr/lpr mice also presented with urticarial rash between the ears and in the neck area. In contrast, all Faslpr/lpr, Bcl2l11−/−, and WT mice survived well beyond 250 days without symptoms. These observations demonstrate that Bim-dependent mitochondrial apoptosis and Fas death receptor signaling cooperate in hematopoietic cell homeostasis and prevention of immunopathology.
Immune responses to an infectious pathogen or injection of a foreign substance result in the clonal expansion of antigen-specific T cells and, upon pathogen or antigen clearance, this is followed by contraction of this T cell population (Sprent and Tough, 2001). The shutdown of T cell immune responses is mediated by their programmed death (Kawabe and Ochi, 1991), but the mechanisms for apoptosis induction remain controversial (Hildeman et al., 2002,Krammer, 2000). This is (at least in part) due to the use of different model systems. Culturing antigen- or mitogen-activated T cells with IL-2 and restimulating them through the TCR or with PMA plus ionomycin has long been used as the standard in vitro model to mimic the removal of activated T cells in vivo (Krammer, 2000). Experiments with blocking antibodies or FasL- or Fas-deficient mutant mice demonstrated that in this setting, TCR restimulation causes the expression of FasL, which induces autocrine and/or paracrine killing of Fas-expressing T cells (Brunner et al., 1995,Dhein et al., 1995,Russell et al., 1993). This led to the conclusion that FasL-Fas signaling is responsible for the shutdown of T cell immune responses. Some studies showed that deletion of SEB-activated T cells in mice was in part FasL-Fas dependent (Mogil et al., 1995,Renno et al., 1996), whereas others found that Fas deficiency (in Faslpr/lpr mutant mice) had no impact but that loss of Bim provided profound protection (Hildeman et al., 2002). These discrepancies might be due to differences in the regimes of SEB injection. This is supported by the finding that effects of Fas deficiency on deletion of activated T cells in vivo were observed most consistently when mice were administered several doses of SEB (Strasser et al., 1995). Interestingly, the death of antigen-activated CD8+ T cells during shutdown of and acute immune response to a viral (HSV-1) infection was substantially inhibited by loss of Bim but was not affected by Fas deficiency (Pellegrini et al., 2003). We therefore reasoned that depending on the nature of an immune response—acute versus chronic—Fas-mediated death receptor signaling and Bim-dependent mitochondrial apoptosis might contribute to different extents to the killing of activated T cells (Strasser and Pellegrini, 2004). Accordingly, a single low-dose challenge with SEB would mimic a response to an acute infection, whereas high-dose and/or repeated challenge with this superantigen would be expected to resemble the response to a chronic infection.
Our analysis of Bcl2l11−/−Faslpr/lpr mice demonstrates that killing of activated T cells during termination of a response to acute infection relies predominantly on Bim with no apparent contribution by Fas death receptor signaling. In contrast, these two pathways synergize in the killing of T cells during shutdown of an immune response to chronic infection, and they also cooperate to maintain homeostasis of T cells, B cells, as well as granulocytes, and to prevent autoimmune pathology. These results help reconcile current controversies regarding the relative contributions of the death receptor versus the mitochondrial apoptotic pathway to the shutdown of T cell immune responses. They are consistent with the notion that during shutdown of an acute immune response, killing of activated T cells is not elicited by repeated TCR ligation, which would have been required for activation of the Fas pathway (Hildeman et al., 2002,Pellegrini et al., 2003). Instead, apoptosis requires the BH3-only protein Bim, which is thought to be activated by the drop in cytokine levels that occurs after pathogen clearance (Strasser and Pellegrini, 2004). This fits with the observations that Bim is critical for cytokine deprivation-induced apoptosis (Bouillet et al., 1999) and transcriptionally (Dijkers et al., 2000) as well as post-translationally (reviewed in Ley et al., 2005) activated by this death stimulus. It is possible that a drop in the levels of prosurvival Bcl-2 family members, particularly Bcl-2 (Hildeman et al., 2002), and/or the induction of the BH3-only protein Puma (encoded by the Bbc3 gene), which is also involved in growth factor withdrawal-induced apoptosis of hemopoietic cells (Jeffers et al., 2003,Villunger et al., 2003), are also involved in the killing of antigen-activated T cells during shutdown of an acute immune response. Indeed, Bim and Puma doubly deficient T cells survive better in culture in the absence of cytokines than those lacking only Bim or Puma (Erlacher et al., 2006). Analysis of HSV-1-infected Bcl2l11−/−Puma−/− mice could help determine whether these two BH3-only proteins have overlapping functions in the shutdown of acute T cell immune responses.
The finding that Fas-mediated death receptor signaling and the Bim-dependent mitochondrial apoptosis both contribute to shutdown of chronic immune responses is consistent with the observations that loss of Bim (Grayson et al., 2006), Bcl-2 overexpression (Strasser et al., 1995), or loss of Fas (Kawabe and Ochi, 1991), each on their own, enhanced (to a relatively small extent) survival of T cells chronically stimulated by repeated SEB injection or LCMV infection. These results are consistent with the notion that the death receptor and the mitochondrial apoptotic pathways are distinct and that they can cooperate in the removal of a cell population (Strasser et al., 1995). Our results are reminiscent of the effects observed upon the overexpression of Bcl-2 in Faslpr/lpr mice. It is highly probable that Bcl-2 might have countered Bim function in these mice. The importance of the genetic background on the severity of the Faslpr/lpr and Bcl2l11−/− phenotypes is well established. Direct comparison of the Bcl2-tg Faslpr/lpr mice and our present study is limited by the fact that the mice used in the former study were on the C3H/HeJ background, whereas the Bcl2l11−/−Faslpr/lpr mice are on the C57BL/6 background. It is, however, possible that other BH3-only proteins may be involved in the killing of chronically activated T cells, and lymphadenopathy and splenomegaly may therefore be even more severe in Bcl2-tg Faslpr/lpr mice than in Bcl2l11−/−Faslpr/lpr mice.
It appears likely that repeated TCR stimulation causes activation of the FasL-Fas signaling pathway in T cells during chronic infection (Brunner et al., 1995,Dhein et al., 1995), but how Bim is induced in this setting is less clear. This might be a consequence of a drop in the amounts of cytokines, similar to shutdown of acute immune responses. Alternatively, the calcium flux elicited by repeated TCR ligation might activate Bim (Bouillet et al., 2002), and, pertinently, Bim is essential for deregulated calcium flux-induced apoptosis (Bouillet et al., 1999).
Combined loss of Fas and Bim also synergized in causing lymphadenopathy, demonstrating that these two pathways cooperate not only in the killing of T cells chronically activated by pathogen-borne antigens but also those stimulated by self-antigens. The unusual αβTCR+CD4−CD8−B220+ T lymphoid cells are seen only in Faslpr/lpr but not in Bcl2l11−/− mice, consistent with the view that they are descendants of chronically activated "conventional" T cells, which previously expressed CD4 or CD8 (Renno et al., 1996) and would normally be killed by FasL-Fas signaling (Brunner et al., 1995,Dhein et al., 1995). These unusual T cells are as sensitive as conventional T cells to cytokine deprivation but can be protected by loss of Bim, providing a likely explanation as to why their numbers are greatly increased in Bcl2l11−/−Faslpr/lpr and even Bcl2l11+/−Faslpr/lpr mice compared to animals lacking only Fas. Although loss of either Fas or Bim causes fatal autoimmune disease on certain genetic backgrounds (e.g., MRL for Faslpr/lpr [Watanabe-Fukunaga et al., 1992] or mixed C57BL/6x129SV for Bcl2l11−/− [Bouillet et al., 1999]), such pathology is not apparent for either mutation on an inbred C57BL/6 background. The immunopathology seen in Bcl2l11−/−Faslpr/lpr and Bcl2l11+/−Faslpr/lpr mice on this background therefore demonstrates that these two apoptotic pathways have overlapping functions in the prevention of autoimmune disease.
These findings have implications for clinical medicine. For example, abnormally increased levels of Bim and enhanced sensitivity to FasL (Gougeon, 2003) have been detected in leukocytes from patients infected with human immunodeficiency virus (HIV) or other pathogens. Thus, Bim- and Fas-mediated apoptosis may cooperate to cause the excessive killing of antigen-specific T cells that is thought to impair clearance of the infectious microbes in these settings. Conversely, the inability to kill T cells that are chronically stimulated by self-antigens might underlie some autoimmune conditions. For example, because loss of one allele of Bim synergizes with Fas deficiency to cause immunopathology, it is possible that combinations of mutant alleles of Bim and Fas, which by themselves do not cause readily identifiable abnormalities, may underlie certain autoimmune diseases in humans.
In summary, two major pathways regulate the life and death of lymphocytes. The death receptor pathway involves membrane receptors of the TNFR1 family, whereas the mitochondrial pathway is regulated by proteins of the Bcl-2 family. Here, we show that both pathways synergize to kill activated T cells in chronic immune responses, whereas death of activated T cells in acute immune responses relies only on the mitochondrial pathway.
Experimental Procedures
All animal experiments were performed in accordance with the guidelines of the Melbourne Directorate Animal Ethics Committee. Bcl2l11−/− and Faslpr/lpr mice had been backcrossed onto a C57BL/6 genetic background for >20 generations prior to intercrossing and were housed in specific pathogen-free (SPF) conditions prior to infectious challenge.
Immunofluorescent Staining, FACS Analysis, Cell Sorting, Tissue Culture, and Cell-Survival Assays
Single-cell suspensions were prepared from thymus, spleen, and lymph nodes (axillary, brachial, and inguinal) of 6- to 10-week-old mice and total leukocyte numbers counted. Leukocyte subpopulations were identified by immunofluorescent staining with surface marker-specific mAbs coupled to FITC, R-PE, APC, Cy5, or biotin (the latter revealed by staining with streptavidin coupled to R-PE or Tricolor; Caltag) followed by flow cytometric analysis in a FACScan (Becton Dickinson) or sorting in a FACS DIVA (Becton Dickinson) or MoFlo (Cytomation). Sorted cells were resuspended in DMEM supplemented with 10% FCS, 50 μM 2-mercaptoethanol (2-ME), and 100 μM asparagine and cultured at 37°C in 96-well flat-bottom plates. Cells were incubated in medium alone (no treatment, i.e., cytokine deprivation) or treated with FLAG-tagged human recombinant FasL 10 ng/mL (Alexis) crosslinked with 1 μg/mL M2 FLAG monoclonal antibody (Sigma), ionomycin (1 μg/mL), PMA (10 ng/mL), etoposide 1 μg/mL, or γ-irradiated (1.25 Gy). Cell survival was quantified daily by staining with propidium iodide (PI; 2 μg/mL) and FACS analysis.
HSV Infection and Quantification of HSV Antigen-Specific CD8+ T Cells
Mice were injected subcutaneously (s.c.) in each hind foot with 4 × 105 plaque-forming units (PFU) of HSV-1 KOS strain under general anesthesia. After 17 and 35 days, mice were killed, and popliteal lymph nodes, spleen, liver, lungs, and feet were removed. Single-cell suspensions were prepared from these tissues, and those from the lymph nodes of mice of the same genotypes were pooled. Lymphocytes were purified from liver and lung on Percoll density gradients. To measure the percentages of viral antigen-specific T cells, single-cell suspensions from spleen and lymph nodes were first enriched for CD8+ T cells with magnetic bead depletion by staining with M1/70 (anti-Mac-1), F4/80 (macrophage marker), Ter 119 (erythroid marker), RB6-8C5 (anti-Gr-1), M5/114 (anti-class II MHC), and GK 1.5 (anti-CD4) antibodies followed by incubation with goat anti-rat IgG antibody-coupled magnetic beads (Dynal, Oslo and QIAGEN). Enriched CD8+ cells were washed and stained for 45 min at room temperature with PE-streptavidin-conjugated Kb-gB tetramers containing the immuno-dominant HSV gB498-505 peptide. Cells were then stained for 30 min on ice with APC-conjugated CD8 mAb (53-6.7) in balanced salt solution containing 2% FBS. PI staining was used to exclude dead cells and data were acquired on at least 104 viable cells with a FACSCalibre flow cytometer and analyzed with CellQuest Pro (BD Biosciences).
MHV Infection and Quantification of Viral Antigen-Specific CD8+ T Cells by Staining with PE-Streptavidin-Conjugated Kb-OVA Tetramers
Mice were infected under brief general anesthesia intranasally with 3 × 104 PFU of recombinant murine γ-herpesvirus that coexpressed ovalbumin (OVA) from an intergenic expression cassette driven by an ectopic MHV-68 lytic promoter (MHV 68-OVA). Infected mice were killed after 14, 40, or 60 days, and lungs, mediastinal lymph nodes, and spleen were collected. Single-cell suspensions were prepared and leukocytes within the lymph nodes and spleen were counted. Cells collected from the lymph nodes from mice of the same genotype were pooled. Total numbers of CD4+ and CD8+ T cells were measured by staining cells for 30 min on ice with PE-coupled anti-CD4 mAb (CT-CD4) and FITC-coupled anti-CD8 mAb (CT-CD8), and analysis was performed as described above. To enumerate viral antigen-specific T cells, suspensions from lymph nodes and spleen were enriched for CD8+ T cells as described above, labeled for 30 min on ice with FITC-coupled anti-CD8 mAb, washed, stained for 45 min at RT with PE-coupled streptavidin conjugated to Kb class I MHC tetramers loaded with SIINFEKL peptide, and then analyzed as described above.
Intracellular FACS Analysis of Cytokine Production
Approximately 1 × 106 cells from lymph nodes or spleen of Bcl2l11−/−Faslpr/lpr, Bcl2l11+/−Faslpr/lpr, Faslpr/lpr, Bcl2l11−/−, and WT mice were incubated for 5 hr at 37°C in RPMI 1640 supplemented with 50 μM 2-ME, 10% FBS, 5 μg/mL brefeldin A (which was also provided in all subsequent washes and incubations), and 10 U/mL recombinant mouse IL-2 plus either 1 μM HSV gB498-505 peptide for mice infected with HSV or 1 μM Ovalbumin257-265 (SIINFEKL) peptide for mice infected with MHV-OVA or, as a control, with no peptide. Cells were harvested, washed, stained for 30 min on ice with FITC-coupled anti-CD8 mAb, washed again, fixed for 15 min at 4°C with 1% formalin, permeabilized for 10 min at RT in PBS containing 0.5% saponin and 1% BSA, stained for 30 min on ice with PE-coupled rat anti-IFN-γ mAb (C1 XMG1.2), washed, and analyzed on a LSR or FACSCalibre flow cytometer. The frequency of virus-specific CD8+ T cells was calculated by subtracting the frequency of CD8+ IFN-γ+ T cells in samples stimulated with no peptide from the frequency of CD8+ IFN-γ+ T cells in samples with the antigenic peptide.
MHV-OVA Viral Titer Assays
Titers of infectious MHV-OVA virus were determined by plaque assay. In brief, 10-fold dilutions of (virus containing) spleen cell suspensions from infected mice were incubated for 2 hr on BHK-21 cell monolayers. The inoculum was then removed and the monolayers overlaid with Dulbecco's modified Eagle medium containing 0.3% carboxymethylcellulose. After 5 days, the monolayers were fixed in 10% formaldehyde and stained with 10% Giemsa (Merck) for 30 min before rinsing with water. Monolayers were dried at room temperature overnight before plaques were counted with a plate microscope.
Analysis of Persisting Antigen Presentation during MHV-OVA Infection
Persistent antigen presentation was evaluated by analyzing the induction of proliferation of CFSE-labeled OVA-specific CD8+ T cells (from OT-I TCR transgenic mice) after injection into mice that had been infected with MHV-OVA for various lengths of time. In brief, lymphocyte suspension from lymph nodes (inguinal, axillary, sacral, cervical, and mesenteric) of OT-I TCR transgenic mice were enriched for CD8+ T cells by incubation with antibodies specific for Mac-1 (M1/70), Mac-3 (F4/80), erythrocytes (Ter-119), B220 (RA3-6B2), MHC class II (M5/114), and CD4 (GK1.5). Antibody-coated cells were removed with goat anti-rat IgG antibody-coated magnetic beads (QIAGEN). Purity was verified by FACS analysis and was routinely found to be ∼95%. Enriched CD8+ T cell preparations were resuspended at 107 cells/mL in PBS containing 0.1% BSA and incubated for 10 min at 37°C with 5 μM CFSE stock solution (5 mM in DMSO, Molecular Probes). 1 × 106 CFSE-labeled OT-I TCR transgenic T cells were injected into naive or MHV-OVA-infected mice, and proliferation was analyzed by FACS analysis after 3 days to determine the reduction in CFSE staining intensity.
TCR-Vβ Expression Analysis
TCR-Vβ expression was analyzed by preparing cell suspensions from multiple separate lymph nodes from Bcl2l11−/−Faslpr/lpr with massive lymphadenopathy (aged approximately 12 weeks). Cells were stained with FITC-coupled Thy-1 mAb (T24.31.2) and biotinylated mAbs specific for TCR Vβ3, 4, 5, 6, 7, 8, or 10 (BD PharMingen), followed by R-phycoerythrin (PE)-streptavidin. PI was used to exclude dead cells and cells were analyzed in a FACScan.
We are grateful to J. Adams, S. Cory, A. Harris, and D. Vaux for advice and discussions. We thank J. Coughlin, G. Siciliano, J. Allen, and S. Shehata for expert animal care; B. Helbert and C. Young for genotyping; M. Robati for technical assistance; F. Battye, V. Lapatis, and C. Tarlinton for cell sorting; and S. Mihajlovic, E. Tsui, and A. Hasanein for histology. This work was supported by fellowships and grants from the National Health and Medical Research Council (Australia; #257502, #461263, and #356214), the Charles and Sylvia Viertel Foundation, the Leukemia and Lymphoma Society (New York; SCOR grant #7015), the Wellcome Trust (UK), the Howard Hughes Medical Institute, and the National Cancer Institute (NIH, US; CA 80188 and CA 43540).
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Puthalakath et al., 2007 (2007). ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129, 1337–1349. Abstract | Full Text | PDF (1477 kb) | CrossRef | PubMed
Rajcani and Kudelova, 2005 (2005). Murine herpesvirus pathogenesis: a model for the analysis of molecular mechanisms of human gamma herpesvirus infections. Acta Microbiol. Immunol. Hung. 52, 41–71. CrossRef | PubMed
Rathmell et al., 2002 (2002). Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat. Immunol. 3, 932–939. CrossRef | PubMed
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Publication Information
Received: October 24, 2007
Revised: December 9, 2007
Accepted: December 10, 2007
Published online: February 14, 2008


text:
SKU: 439531 Weight: 0.63
In stock
List Price:$13.88 Your Price:$5.22 You Save: $8.66 (62%) International customers, please view our shipping page for information on additional shipping fees. CLICK HERE
WE R MEMORY KEEPERS-Photo Sleeve Protectors. This package contains ten acid free; PVC free 12x12 photo protectors: each protector is divided into eight 3x3in and one 6x12in sleeves. These protectors are three-hole-punched so they fit standard 12x12in ring albums. Imported.


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Kirt Page describes extreme weather devastation
The angry funnel that tore into Henryville, Indiana, destroying so much, also hit home for Takoma Park resident Kirt Page. He grew up there.
His wife called him at work here when the deadly tornado struck. He said he dropped everything and came home. He spent the rest of the night calling friends and family.
His parents and siblings were all ok - their homes spared, too. But everyone knows a story of tragedy in Henryville.
Childhood buddy Rodney Hunter lost his father. Wayne Hunter died when his house collapsed. And Page's high school prom date, Shelly Lovins is good friends with Stephanie Decker, who lost both legs while shielding her two young children from the twister.
Page's high school is in ruins - he used to ride this bus, number 211, he says - now smashed into a diner.
He's collected some donations from neighbors and describes a Henryville church spearheading one relief effort.
To help, send donations to the following:
Henryville Community Church
payable to: "HCC Recovery"
P.O. Box 214
Henryville, IN 47126
Henryville High School Relief Fund
c/o New Washington State Bank
P.O. Box 243
Henryville, IN 47126
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Magic Wands: Lockout Day 41
Hardwood Classic Today: Golden State Warriors vs. Los Angeles Lakers, 1991 Western Conference Semifinals Game 2
Time/TV: 9 p.m./NBATV
Video Vault:
1) Free agent forward Earl Clark has signed a one-year deal to play in China. He will have no opt-out clause for when the lockout ends. Zach McCann of the Orlando Sentinel reports Clark has been in negotiations with Zhejiang of the Chinese Basketball Association but that nothing has been signed officially. #FreeEarlClark.
2) WDBO's Scott Anez caught up with NBA Champion Darrell Armstrong.
3) Nate Drexler of MagicBasketball.net remembers Game One of the 2009 Eastern Conference Finals. Good memories.
4) Feeling a basketball jones during the lockout? A poster at RealGM provided a link to every NBA Finals game since 1980 available for download (hat tip to follower Chase, aka @cb1115).
5) Who is the Orlando Magic's biggest rival? Dan Favale of Bleacher/Report (I feel so dirty, but nothing else is going on, I swear) says it is the Boston Celtics (I say it is Miami for a variety of reasons). The Magic are the Hawks and Bobcats' biggest rival, at least.
6) Stan Van Gundy with some inspirational words for the campers at Magic Basketball Camp last week.
7) Zach McCann of the Orlando Sentinel invites you to play find Stan Van Gundy with actual photographic proof Stan Van Gundy once played basketball.


text:
By V. Phani Kumar, Colin Ng and Leslie Shaffer
HONG KONG (MarketWatch) -- Most major Asian markets declined Tuesday, with Chinese and Hong Kong stocks weighed by fears Beijing may launch more measures to cool property prices, while upbeat forecasts from Fanuc and IHI Corp. helped Japanese stocks erase early losses.
Japan's Nikkei Stock Average of 225 Companies ended 0.4% higher and Australia's S&P/ASX 200 ended flat as trading resumed after Monday's holiday.
South Korea's Kospi slipped 0.2%, Hong Kong's Hang Seng Index shed 1.5%, China's Shanghai Composite lost 2.1% and Taiwan's Taiex slid 0.1%.
In afternoon trading, India's Sensex dropped 0.3% and Singapore's Straits Times gave up 0.6%. Dow Jones Industrial Average /quotes/zigman/627449/realtime DJIA -0.21% futures were 1 point lower in screen trade.
"Clearly, it's a bit more challenging right now given the uncertainty about policy tightening and a variety of global factors," said DBS Asia strategist Joanne Goh in Singapore, noting China's property-sector tightening measures, the Goldman Sachs probe and U.S. financial-sector reform proposals.
"The pressure from this round of tightening measures is weighing heavily on sentiment, and there is little on the news front to boost appetite," said Amy Lin at Capital Securities in China.
"If the property tax is introduced, investment activities should be severely hit," UOB KayHian said in a report.
Among mainland developers, Hong Kong-listed Sino-Ocean Land Holdings /quotes/zigman/39922/realtime HK:3377 +0.25% /quotes/zigman/544635/delayed/quotes/nls/sioly SIOLY -2.05% fell 2.2%, while China Vanke /quotes/zigman/1859106/realtime CN:000002 +0.10% dropped 1.3% in Shenzhen.
Hong Kong's Henderson Land /quotes/zigman/153948/delayed/quotes/nls/hldcy HLDCY -1.97% /quotes/zigman/14039/realtime HK:12 +0.47% dropped 3% and Hang Lung Properties /quotes/zigman/13902/realtime HK:101 +0.72% /quotes/zigman/297601/delayed/quotes/nls/hlppy HLPPY -1.40% shed 2.7%.
Japanese shares reversed early losses in afternoon trading, as industrial-robot maker Fanuc /quotes/zigman/527618/delayed/quotes/nls/fanuy FANUY -1.75% /quotes/zigman/192770/realtime JP:6954 +1.99% surged 11.5% and IHI /quotes/zigman/193838/delayed/quotes/nls/ihicf IHICF +9.24% /quotes/zigman/193828/realtime JP:7013 0.00% spiked 9.3% in strong volume on their respective positive earnings outlooks.
Australian shares gave up early gains to end flat on caution ahead of the release of banks' earnings and the Henry Tax Review due Sunday, which could propose tax reforms for the resources and financial-services sectors.
"Certainly we've been dragged down a bit by Asian stocks and although it rose on Friday, we had a pretty lackluster performance from Wall Street overnight," said Macquarie Private Wealth Client Advisor Helen Spencer.
Dragging the market, biotechnology company CSL /quotes/zigman/528121/delayed/quotes/nls/cmxhy CMXHY +0.46% /quotes/zigman/138901/realtime AU:CSL -0.22% dropped 4.2% after it announced late Friday that it has halted distribution of its pediatric influenza vaccine after Australian authorities linked influenza injections to severe adverse reactions in infants.
Banks retraced early gains, with Commonwealth Bank of Australia /quotes/zigman/181773/realtime AU:CBA +0.66% /quotes/zigman/181772/delayed/quotes/nls/cbauf CBAUF +0.97% down 0.1%, Westpac Banking Corp. /quotes/zigman/181294/realtime AU:WBC +1.54% /quotes/zigman/1470693/delayed/quotes/nls/wbk WBK -0.62% declining 0.4% and Australia & New Zealand Banking Group /quotes/zigman/180795/realtime AU:ANZ +0.09% /quotes/zigman/180802/delayed/quotes/nls/anzby ANZBY -1.12% falling 0.1% despite expectations they will report strong earnings this week, as they mirrored falls in their U.S. peers on Monday.
South Korean shares also erased early gains although first-quarter gross domestic product growth topped expectations.
"Korea's GDP data came out better than expected, but investors seem to have shifted their focus to the domestic leading indicator (due Friday), from the past (backward-looking) data. Investors are also cautious after the Kospi climbed for 11 consecutive weeks," said Kyobo Securities' Hwang Bin-ah.


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Curvy Kate Moonlight Fold Over Swim Brief CS8025This product is no longer available. Please consider one of the Customer-Recommended Replacements above, or try a new search.
A sassy bow trims the back waist of this adjustable folded waist swim bottom. Side seams are ruched and elasticized. Made of nylon/spandex.
Try these keyword searches with similar features:


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Womens | Color: White/Blue | Style Number: B4260-8
Total Number of Reviews
50% say this shoe fits True to Width
Review By: lucille vero beach fl 7/16/2012
Overall Rating:
half size small fits narrow
Shoe was to tight. wasn''t true to size.
Review By: Sylvia WPB Florida 7/3/2012
half size small true to width
To add a review, please click here.
Your Color:
Your Size/Width:
In Stock. Ships out in 1-2 business days.
A sleek-looking bowling shoe with bright, metallic detailing.
Customers who bought this also viewed:
Dexter Accessories - Insoles - Small
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text:
Quote:I think there must be about 6 inch difference in the distance where my Barcon reaches focus and where my 2.6X Glaspath reaches focus, the Barcon being the longer. This is in my 4inch apo...point is, I think you are too long. I think a 1.2X or 1.5X Glaspath would be best with your scope.
Quote:Look again TanveerI see none of what u speak
Whenever I have come into large sums of money in my life, I always put half of it aside to spend on fast cars and the pursuit of loose women.
I put aside the other half to spend frivolously.
Takahashi FS128, TSA 102, FSQ106N, Losmandy GM-8, Baader Mark V, Leica ASPH, Takahashi, Ethos and Panoptic eyepieces.
Quote:Tanveer or Eddgie,As Celestron lists the design backfocus distance of the 8" edge at 133mm and the 11" edge as 146mm could one of you try an experiment for me? Attach the MarkV's (without any GPC ) directly to the back of the scope without using any diagonal, in the case of the 8" a 2" to T-thread adapter should provide about the perfect distance ( i.e. MarkV = 123mm + T adapter = 10mm? = total of 133 distance), in the case of the 11" (MarkV = 123mm + 2" nosepiece = 20mm? total = about 145mm ). I surmise that the corrector lens in the Edge should work the same as the GPC or recommended barlow to help narrow the image and the resultant views should be about as good as possible with the widest views possible. Either of you care to try? ( I am considering getting an Edge 8" for use with MarkV's and this information would help me make a decision). ThanksRex
Quote:I have of course not used the Ziess one, but the Baader appears to perform about as good as I think a diagonal can perform.When used in my 6" APO, I could fine no difference between it and a Telvue Dielectric. Views were identical.It is not at all difficult to make a diagonal to prism to an excellent standard of quality, and the coatings on the Baader look quite excellent to me.I have no reservations at all about giving a 100$ recommendation to the standard T2. I personally believe that any difference between it and the Ziess prism will be to small to be seen at the eyepecie in any way, shape or form.That is of course only an opinion, but the unit appears to be flawless as compared to very fine, high reflectivilty mirrors.


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Moving Comfort Response: A couple of things could cause the bounce issue. 1.The band not being snug enough and/or the straps not being tightened enough. 2. Even though this bra goes through a DD cup size the issue could be that it isn't for your specific breast tissue/body type. One style I would recommend trying is the Juno, which is a racer back bra. This bra is touted for it's 'no bounce properties' (keeps your breasts snugged down)! Barb from Crownsville, MD
Options for Moving Comfort Fiona Sports Bra 350003 »
Other Moving Comfort Searches:


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My friend, Greg Balanko-Dickson, has decided to jump off the risk cliff out of his comfort zone and you all get the benefit. You may be familiar with Greg as he is an occasional guest blogger on this blog. He's brought you the wonderful articles such as Business Blogging Strategy: Build Trust and Rapport, Relationship […]
Helping you learn more about blogging and WordPress every day with help, tips, advice, and techniques for blogging and using WordPress and WordPress.com. The blogging help you need. Now.
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Thrashing Spammers Daily


text:
- The definition of a priest is someone who performs religious rituals and rites for a church or other religious organization.
An example of a priest is the person in charge of an Episcopal church.
priest definition by Webster's New World
- a person whose function is to make sacrificial offerings and perform other religious rites as an intermediary between deity and worshipers
- in the early Christian church, a presbyter, or elder
- in hierarchical Christian churches, a clergyman ranking next below a bishop and authorized to administer the sacraments
- any clergyman
Origin: Middle English prest ; from Old English preost (? with -o- by associated, association with profost, provost) ; from Ecclesiastical Late Latin presbyter, an elder ; from Classical Greek presbyteros, elder, comparative of presbys, old, old man (in Ecclesiastical Late Greek an elder) ; from Indo-European an unverified form pres-, ahead ; from base an unverified form per- (see per, pre-) plush an unverified form gwou-, cow, ox (hence, origin, originally , lead-ox)
Related Forms:
- priesthood noun
priest definition by American Heritage Dictionary
- In many Christian churches, a member of the second grade of clergy ranking below a bishop but above a deacon and having authority to administer the sacraments.
- A person having the authority to perform and administer religious rites.
Origin: Middle English preost, from Old English prēost, perhaps from Vulgar Latin *prester (from Late Latin presbyter; see presbyter) or from West Germanic *prēvost (from Latin praepositus, superintendent; see provost).
priest - Cultural Definition
One who is designated an authority on religious matters. In some churches, especially the Anglican Communion, Eastern Orthodox Church, and Roman Catholic Church, the ordained church leader who serves a congregation of believers is called a priest. The priests in these churches administer the sacraments, preach, and care for the needs of their congregations. (See also minister and pastor.)


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This was a Valentine I designed for personal use. Subsequently I re-purposed it as a piece of Facebook Flair which was downloaded thousands of times. …I guess folks respond to it on some level.
love, zombie, heart, valentine, skulls, hearts, zug, valentines day, true love
Michael Zug: Artist – Mad Man – Imagination Junkie.
View Full ProfileAwesome!
– ZugArt
nice one! its great when people work out shapes from objects – this is great :)
Thank you very much.
– ZugArt
Timeless design. I especially love the spiral patterning.
Thanks for this delicious brain juice
Thanks. I really appreciate it. There are a few elements to this design that I am beginning to appreciate more. Thanks again!
– ZugArt
I have a photo and t-shirt that I did several months ago that is the same exact idea. My photo and t-shirt is called "Forvever" http://ih1.redbubble.net/work.4000992.5.flat,55...
I just commented on your own design – great minds think alike I guess.
– ZugArt
great design x) love it
Thanks Kelly, I really appreciate it.
– ZugArt
This absolutely rocks. Excellent work, Zugart.
Thank you. I appreciate the comment.
– ZugArt
cool design!
I love it especially in light pink!
Cute cute cute! Well done :)
Thanks so much - I appreciate you taking the time to comment.
– ZugArt
love it
i love how this design bothers me so much. i cant stop looking at it.
Ok – you can stop now. Or at least get a sandwich or something.
– ZugArt


text:
7 U.S. Code § 8740 - Adjustments of loans
prev | next
Adjustment authority
Subject to subsection (e), the Secretary may make appropriate adjustments in the loan rates for any loan commodity (other than cotton) for differences in grade, type, quality, location, and other factors.
Manner of adjustment
The adjustments under subsection (a) shall, to the maximum extent practicable, be made in such a manner that the average loan level for the commodity will, on the basis of the anticipated incidence of the factors, be equal to the level of support determined in accordance with this subtitle and subtitles B through E.
Adjustment on county basis
Adjustment in loan rate for cotton
In general
The Secretary may make appropriate adjustments in the loan rate for cotton for differences in quality factors.
Revisions to quality adjustments for upland cotton
In general
Not later than 180 days after the date of enactment of this Act, the Secretary shall implement revisions in the administration of the marketing assistance loan program for upland cotton to more accurately and efficiently reflect market values for upland cotton.
Mandatory revisions
Revisions under subparagraph (A) shall include—
the establishment of differentials for the various quality factors and staple lengths of cotton based on a 3-year, weighted moving average of the weighted designated spot market regions, as determined by regional production;
Discretionary revisions
Revisions under subparagraph (A) may include—
the use of non-spot market price data, in addition to spot market price data, that would enhance the accuracy of the price information used in determining quality adjustments under this subsection;
Consultation with private sector
The Secretary shall not make adjustments in the loan rates for long grain rice and medium grain rice, except for differences in grade and quality (including milling yields).
[1] See References in Text note below.
(Pub. L. 110–234, title I, § 1210,May 22, 2008, 122 Stat. 965; Pub. L. 110–246, § 4(a), title I, § 1210,June 18, 2008, 122 Stat. 1664, 1693.)
References in Text
This subtitle and subtitles B through E, referred to in subsec. (b), probably means subtitle B (§ 1201 et seq.) and subtitles C (§ 1301 et seq.), D (§ 1401 et seq.), and E (§ 1501 et seq.) of title I of Pub. L. 110–246, June 18, 2008, 122 Stat. 1681. Subtitles B and C are classified generally to this subchapter and subchapter III (§ 8751 et seq.), respectively, of this chapter. Subtitle D enacted sections
1359ll, and
7287 of this title, amended sections
1359aa to
7272, and
7971 of this title, repealed former section
1359kk of this title, and enacted provisions set out as notes under sections
3602 and
7272 of this title. Subtitle E enacted subchapter IV (§ 8771 et seq.) of this chapter and amended sections
4504, and
4531 of this title and section
713a–14 of Title
15, Commerce and Trade. For complete classification of subtitles B to E to the Code, see Tables.
The date of enactment of this Act, referred to in subsec. (d)(2)(A), is the date of enactment of Pub. L. 110–246, which was approved June 18, 2008.
The Federal Advisory Committee Act, referred to in subsec. (d)(3)(B), is Pub. L. 92–463, Oct. 6, 1972, 86 Stat. 770, which is set out in the Appendix to Title 5, Government Organization and Employees.
Pub. L. 110–234and Pub. L. 110–246enacted identical sections. Pub. L. 110–234was repealed by section 4(a) ofPub. L. 110–246.
The table below lists the classification updates, since Jan. 3, 2012, for this section. Updates to a broader range of sections may be found at the update page for containing chapter, title, etc.
The most recent Classification Table update that we have noticed was Tuesday, August 13, 2013
An empty table indicates that we see no relevant changes listed in the classification tables. If you suspect that our system may be missing something, please double-check with the Office of the Law Revision Counsel.
7 USC | Description of Change | Session Year | Public Law | Statutes at Large |
LII has no control over and does not endorse any external Internet site that contains links to or references LII.


text:
Winter Weather In St. Louis:
Forecast | Watches & Warnings | Maps | Traffic
we are young
fun. Discuss Their GRAMMY Nomination And Getting Over Stage Fright
The past 12 months have been a whirlwind for fun. Nominated for six GRAMMY Awards, MIX 104.1/Boston sat down with the guys and discussed all things GRAMMYs. "It's been crazy. We had never really done television […]


text:
Written for intermediate- to expert-level Microsoft Word users, this book demonstrates frequently missed tools and the proper way to use new and existing tools. Word's settings, toolbars, and menus are reviewed, as are topics such as the importance of installing safe fonts, setting tabs correctly, and using styles for maximum effect. Also offered is advice on topics pertaining to work groups, such as sharing templates, styles, and toolbars and creating paper and paperless forms. New concepts such as using tables to set up forms, recording macros to cut down on repetition, automatically updating cross-references, and minimizing file sizes are covered. Instructions on keeping a hard drive clean, which can minimize general PC problems, are also provided.
Title: | Dreamboat on Word | Publisher: | Holy Macro! Books |
Author: | Anne Troy |
Edition: | Ebook , PDF |
Language: | English |
* The book summary and image may be of a different edition or binding of the same title.
* Book reviews are added by registered customers. They need not necessarily buy book. * These books are NOT available for reading online or for free download in PDF or ebook format. * Price can change due to reprinting, price change by publisher or sourcing cost change for imported books. www.infibeam.com/Books is the biggest online bookstore in India for sale of books at best price - fiction, literature, audiobooks, study guides, novels, story books, rare books, textbooks and books by popular authors. These are available in various editions and bindings e.g. paperback and at best discount. |


text:
Product Pathways - Protein Stability
TIMP3 (D74B10) Rabbit mAb #5673
PhosphoSitePlus® protein, site, and accession data: TIMP3
No. | Size | Price | ||
5673S | 100 µl (10 western blots) | --- | In Stock | --- |
5673 | carrier free and custom formulation / quantity | email request |
Already purchased this product? Write a Review.
Application | Dilution | Species-Reactivity | Sensitivity | MW (kDa) | Isotype |
W | 1:1000 | Human, Mouse, Rat, Monkey | Endogenous | 20, 25 | Rabbit IgG |
Species cross-reactivity is determined by western blot.
Applications Key: W=Western Blotting
- 5673:
- Western Blotting
Specificity / Sensitivity
TIMP3 (D74B10) Rabbit mAb detects endogenous levels of total TIMP3 protein.
Source / Purification
Monoclonal antibody is produced by immunizing animals with a synthetic peptide corresponding residues surrounding Lys53 of human TIMP3.
TIMPs are members of the family of tissue inhibitor of matrix metalloproteinases (MMPs) that includes TIMP1, TIMP2, TIMP3, and TIMP4. The main function of TIMPs is their inhibitory effect on MMPs. TIMPs irreversibly inactivate MMPs by direct binding to their catalytic zinc cofactor and resultant inhibition of proteinase function (1,2). In addition to MMP inhibition, TIMPs have also been shown to interact with various membrane receptors on the cell surface. Some of these interactions include: TIMP1 with CD63, TIMP2 with α3β1 integrin, and TIMP3 with VEGFR2, all of which result in distinct cellular effects (3). TIMPs are involved in a wide variety of biological functions, such as tumor angiogenesis and progression (4,5), wound healing, and vascular remodeling (6,7). Mutations in TIMP3 are associated with Sorsby's fundus dystrophy (8,9).
- Nagase, H. et al. (2006) Cardiovasc Res 69, 562-73.
- Visse, R. and Nagase, H. (2003) Circ Res 92, 827-39.
- Stetler-Stevenson, W.G. (2008) Sci Signal 1, re6.
- Noel, A. et al. (2004) J Clin Pathol 57, 577-84.
- Hojilla, C.V. et al. (2003) Br J Cancer 89, 1817-21.
- Gill, S.E. and Parks, W.C. (2008) Int J Biochem Cell Biol 40, 1334-47.
- Raffetto, J.D. and Khalil, R.A. (2008) Biochem Pharmacol 75, 346-59.
- Weber, B.H. et al. (1994) Nat Genet 8, 352-6.
- Yeow, K.M. et al. (2002) Matrix Biol 21, 75-88.
Application References
Have you published research involving the use of our products? If so we'd love to hear about it. Please let us know!
Companion Products
For Research Use Only. Not For Use In Diagnostic Procedures.
Cell Signaling Technology® is a trademark of Cell Signaling Technology, Inc.


text:
Throughout the pantheon of human history, governments have done more damage to the people they govern than all the invading armies put together.....................sooner or later, there will be those in power who refuse to leave government when told to do so by the electorate. When that happens, sooner or later it will, the citizens will have to march armed, to throw those in power out. Click Here if you Like this Comment
Democrats hate individual freedom.Democrats hate people of faith.Democrats hate our Constitution.Democrats hate our Bill of Rights.Democrats hate America. Click Here if you Like this Comment
God bless him!This veteran fought for us on foreign soil. Now, he´s fighting the ignorance and/or evil intentions within our country too. This is what it´s going to take from everyone who understands our Founding Documents.I´m reminded of Deuteronomy 6:3,6-93 "Hear therefore, O Israel, and observe to do it; that it may be well with thee, and that ye may increase mightily, as the Lord God of thy fathers hath promised thee, in the land that floweth with milk and honey".6 "And these words which I command you today shall be in your heart. 7 You shall teach them diligently to your children, and shall talk of them when you sit in your house, when you walk by the way, when you lie down, and when you rise up. 8 You shall bind them as a sign on your hand, and they shall be as frontlets between your eyes. 9 You shall write them on the doorposts of your house and on your gates.Too few people know the Bible and our Founding Documents. Enough of us must know both to survive as a free Republic.Hosea 4:6"My people are destroyed for lack of knowledge: because thou hast rejected knowledge, I will also reject thee" Click Here if you Like this Comment 1 person like this.
i thought chicago was already a gun-free zone? why are they holding an anti-gun forum? is it because too many of their honest, hard-working citizens are getting murdered with unregistered (illegal) guns in muggings and break-ins? way to go, idiots. take away the only sensible form of self defense from your taxpayers and leave them helpless. Click Here if you Like this Comment
Aand THAT my friends was a United States Air Force Security Policeman - an NCO I would have proudly served with during my time in blue and one I am proud of today. Click Here if you Like this Comment
#4--New Trier is a township suburban area on Chicago´s North Shore--very so-called toney--and also the name of a very snobby high school which once was I believe awarded with the HS in America having the most suicides....Think ´Ordinary People´ movie.Many D´s with $$ on the North Shore filling the pockets of all political D´s in the Chicago Metro area. Think investment bankers, lawyers, and traders.I lived amongst them, and married one of them. They wouldn´t know the business end of any weapon, or a hammer.Me, me, me...I, I, I. Click Here if you Like this Comment
It does not to any good to waste energy arguing with liberal Democrat gun grabbers. Click Here if you Like this Comment


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Product Number: | TC7015 |
Item Price: | $6.49 |
Availability: | In Stock |
Shipping Weight: | 0.01 lb. |
This is a lightweight capper with seven protruding fingers that hold caps for quick accessibility and a handy storage compartment in back for extra caps.
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text: Aliens select Earth as their next target for invasion. Assuming human form, they randomly abduct four people. What the aliens don't count on is the resourcefulness of their prisoners. Human will, determination and ingenuity are soon put to the ultimate test as the group desperately fights for their survival...and the survival of their planet.


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The Tuberous Sclerosis Alliance (TS Alliance) endeavors to stimulate, support and coordinate research that will lead to a cure for tuberous sclerosis complex (TSC), while improving the lives of those affected. A recent white paper describes the impressive scientific progress in the field and highlights key TSC research needs for the future.
The TS Alliance has funded more than $17.4 million in research on TSC since 1984. The TS Alliance Grants Program funds research focused on TSC with priorities set by the researchers together with the TS Alliance. Collaborations between basic and clinical researchers are encouraged and fostered, and the TS Alliance works constantly to increase funding for research on TSC. Download an analysis of the impact of the TS Alliance Grants Program from 1984-2010 demonstrating that principal investigators who received a total of $8.7 million from the TS Alliance garnered an additional $60 million from the NIH for TSC-related research and $6.9 million from the Department of Defense's Congressionally Directed Medical Research Program.
Rothberg Courage Award in Research
The purpose of this joint request for proposals between the TS Alliance and the Rothberg Institute for Childhood Diseases is to identify and fund research opportunities that will directly enable or lead to a clinical trial for a new approach to treat TSC manifestations resulting from abnormal cell growth. These manifestations include lymphangioleiomyomatosis (LAM), renal angiomyolipomas, facial angiofibromas or other skin growths, and subependymal giant cell astrocytomas (SEGA). Successful proposals will be those that involve collaboration between researchers at the same or different institutions with the expertise and passion to address one or more of the following:
TS Alliance 2013 Research Grants
The TS Alliance Research Grants Program supports basic research by postdoctoral scientists and studies that accelerate the translation of basic research findings into improvements in quality of life for those affected by TSC. Successful proposals will be those that address one or more of the following:
Next Anticipated Grant Cycle
The TS Alliance anticipates releasing the next request for Letters of Intent for the Research Grant Program in spring of 2014.
Related TS Alliance Resources
For Related Inquiries, Contact:
Steve Roberds, PhD Chief Scientific Officer Tuberous Sclerosis Alliance 801 Roeder Road, Suite 750 Silver Spring, MD 20910 Telephone: 1-800-225-6872 or 301-562-9890 ext. 225 E-mail: email@example.com
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