Plot.

Before story events.

In 1930s Paris, young Hugo Cabret and his father repair an automaton at the museum where his father works. When Hugo's father dies in a fire, his uncle brings him to live and work at the train station maintaining the clocks. His uncle disappears, and Hugo keeps the clocks running by himself, living inside the station walls and stealing food from the shops. He rescues the automaton from the burnt museum in hopes of restoring it.

Part 1.

A few months later, Hugo is caught stealing from a toy booth and is forced to return his stolen tools and mechanisms, as well as his notebook containing his father’s drawings of the automaton. Hugo follows the shopkeeper to his house but fails to retrieve his notebook. A girl in the house named Isabelle promises Hugo she will make sure the notebook is not destroyed.  The next day, Hugo returns to the toy booth, where the shopkeeper tells him the notebook has been burnt; he encounters Isabelle, who assures him it is safe. Isabelle brings him to a bookshop to meet her friend Etienne, who sneaks them into the cinema; Papa Georges, the shopkeeper, has forbidden Isabelle from watching films.  Georges allows Hugo to work at the toy booth, with the possibility of returning the notebook; the job further delays Hugo’s clock duties. Hugo and Isabelle visit the theater but learn Etienne has been fired for sneaking children in, so Isabelle unlocks the door with a bobby pin. They are kicked out, and Hugo is almost caught by the station inspector. Isabelle asks Hugo about his life, but he runs away, fearing that sharing the truth will send him to an orphanage or prison. Isabelle chases him but trips, revealing a heart-shaped key around her neck, which Hugo realizes is the key to the automaton.  The next morning, Hugo learns that Isabelle has read his notebook. He pickpockets the key with a technique learned from Etienne and returns to his hidden room, where he is confronted by Isabelle. They use the key to activate the automaton, which produces a drawing of a rocket shooting a face in the moon.

Part 2.

The automaton signs its drawing “Georges Méliès”, who Isabelle reveals is Papa Georges. Believing Hugo has stolen the automaton, she runs home; Hugo follows, and inadvertently crushes his hand in the front door, and she brings him inside. Hugo notices a strangely locked drawer; Isabelle picks it open but drops the heavy box inside, breaking it and her leg. Georges enters and is enraged, ripping up the drawings inside the box. After Mama Jeanne forces everyone to bed, Hugo takes the key to the toy booth back to the station.  The next day, he and Isabelle collect the money from the booth and buy medicine for Georges. Hugo visits the film academy library where Etienne now works. Hugo finds a book titled "The Invention of Dreams" with a drawing of the automaton, which he learns is a scene from the first movie his father ever saw, "A Trip to the Moon", directed by Georges Méliès. Hugo invites Etienne and the book’s author, René Tabard, to Isabelle's house later, and explains Méliès’ career to Isabelle.  At the house, Tabard and Etienne screen "A Trip to the Moon", and George finally reveals his past: he was the prolific and innovative filmmaker Méliès, but after World War I, the deaths of Isabelle's parents, and the loss of most of his films in a fire, he sank into depression and burned the rest, to begin a new life at the toy booth. He also created the automaton; excited to learn it has survived, he asks Hugo to bring it to him. Hugo returns to the station, stealing breakfast from Monsieur Frick and Miss Emily as usual; overhearing that his uncle was found dead, Hugo drops the milk bottle and is discovered. He escapes and fetches the automaton, but is pursued by the station inspector. In the chase, Hugo is almost struck by a train but is pulled back by the inspector, and faints.  Hugo awakens in a cell. He reveals everything to the inspector and is released to be adopted by Georges, Mama Jean, and Isabelle. He and Méliès repair the automaton together.

Epilogue: 6 months later.

Six months later, Hugo and his new family attend a grand concert including Méliès’ surviving film scenes. Onstage, Tabard acknowledges Hugo, Isabelle, and Etienne for their help in honoring Georges. In the end, it is revealed that Hugo made his own automaton that wrote and drew the entire book of "The Invention of Hugo Cabret".

Main characters.

Hugo Cabret.

The main protagonist of the story, Hugo Cabret, who is only 12, has a great talent for working with mechanical contraptions, especially clockworks. It is mentioned in the book that he could fix almost everything. After moving to the train station after his father died, he became used to stealing food and drinks and other objects from people to survive in the walls train station, even if reluctantly. He is a smarty pants, a thief and determined, but can also be a little rude due to not having any friends for 2 years of living in the station, until meeting Isabelle. He is described to have dirty and tousled hair. It is also believed that his hair is black due to his depiction in the drawings in the book, but could also be yellow, since the drawings are illustrated in black and white. He cares deeply about his friend and family, especially his father, who has died.

Isabelle.

The second main character in the book. After her parents died in a car crash, her godfather, Georges Méliès and godmother, Jeanne Melies adopted her. Due to the risk of Isabelle knowing that he was a movie maker until he was sent into depression and began working at the toy booth, Melies banished her from permission of going to the cinema. She still is able to watch the cinema since her friend, Etienne often helps sneak her in, but still is unable to find out about who her uncle actually is, and still doesn't until meeting Hugo. She is described to have large black eyes, and to be slightly taller than Hugo.

Georges Méliès.

Georges's parents worked on making shoes and encouraged him to do the same, yet he disliked it. When he grew into a young man and the movies were invented, he asked the Lumiere brothers, one of the first directors, to sell him a camera, they refused so Melies made his own camera out of his remaining materials from his parent's shoe company. His most famous work, "A Trip to the Moon", was the first sci-fi movie ever made. He was also the director who first began using special effects in movies. Selznick made his personality to be often cold and haughty. In the drawings it is shown that by this point in the book he is in his senior years, and at the beginning of the book he is called 'the old man'.

Hugo's father.

Hugo's father worked at a museum in Paris when he found the automaton. When there was a fire in the museum, he dies. Hugo is still able to continue his father's work of fixing it with his notebook. There is no mention of a mother at all, and since Hugo left with his uncle to the station, it is assumed that his mother may have died.

Georges Méliès' automaton.

One of Selznick's inspirations to incorporate an automaton into the story was the book titled "Edison’s Eve: A Magical Quest for Mechanical Life" by Gaby Wood, which includes a chapter on Georges Méliès' collection of automata. His automata were kept in a museum in Paris but were later thrown away. Selznick's original idea was to have Hugo find an automaton in a pile of garbage and fix it. At that time, Selznick began his research on automata and the curator at the Franklin Institute allowed him to study their automaton. The history of the automaton at the Institute also had a mysterious origin that was similar to what Selznick had in mind. The automaton donated to the Institute suffered major damage from a fire. It was believed at the time of donation that it was made by a French inventor named Maelzel. However, after a member of staff fixed it and got it to work, the automaton wrote at the end of a poem in French: ""Ecrit par L'Automate de Maillardet"" — translated as ""Written by the automaton of Maillardet"", revealing its true maker to be Henri Maillardet. After many different ideas, Selznick settled on the story that Hugo's father had a connection with the automaton and died before the automaton was found in a burned-out building. The automaton illustrated in the book has many elements that resemble the automaton at the Institute.

Secondary characters.

Uncle Claude.

Hugo's uncle, who adopted and brought him to work on the clocks at the train station. He is also the reason that Hugo stopped attending school, but Hugo began school again after Georges Melies adopted him. Claude made Hugo sleep on the floor and yelled at him angrily when he made a mistake with the clocks. He smoked a lot and was an alcoholic, and died when he tripped into and drowned in a river. He was the clock timekeeper at the Paris train station, a task overtaken by Hugo after Claude's death.

Etienne.

Isabelle's friend, who often sneaks her into the cinema due to her godparent's refusal. When he gave Hugo a coin to buy the book that he used for stealing Isabelle's key, he asks Hugo to guess what was behind his eye patch. Hugo guesses an eye, but Ettienne reveals that he lost his eye as a child when he was playing with fireworks. Hugo gives up on guessing, and so Ettienne takes a coin from behind the eyepatch and gives him it to buy the book. The drawings in the book depicts a young man with smooth hair, a genuine smile and an eyepatch. He is polite, especially with children, but can also be mischievous, as shown when he is caught sneaking children into the cinema and when he was playing with fireworks. Used to work at the cinema, but then got fired and worked at the film academy library.

René Tabard.

The author of "The Invention of Dreams" and Etienne's master at the film academy. Like most characters in the book, he enjoys the movies. A huge, probably the biggest, fan of director Georges Melies and was hired as assistant director and editor of his movies.

Jeanne Méliès.

Known to Isabelle as Mama Jean, the wife of Georges Méliès was trusted by him to keep the heart-shaped key that began the automaton - until it got stolen by her goddaughter Isabelle. She, in her defense, said that she just thought it was pretty. Like Georges, she is in her elder years.

Madame Emile.

A character who only appears twice in the book, the first time being when she found out that Hugo was stealing her and Monsieur Frick's croissant, and the second time being when she was there when Hugo was in the fugitive cell, and believed that he was telling the truth to the station inspector.

Station inspector.

Hugo has been avoiding this character ever since his uncle Claude disappeared. The first sign that the station inspector noticed of irregularity was when the clocks began to be too early and too late, even if just by seconds. That was because Hugo decided to work for Georges and since his right hand's fingers were crushed. The second was when he sent a letter to Claude, asking for an interview with him, but there was no response. Finally, he decided to go see what was going on, only to have a long chase with Hugo Cabret. He is described as wearing a green uniform and smelling of vegetables.

Film adaptation.

Martin Scorsese bought the screen rights to the book in 2007, and John Logan wrote the script. Scorsese began shooting the film in London at Shepperton Studios in June 2010. It was produced in 3D, with its theatrical release on November 23, 2011, and distributed by Paramount Pictures. Asa Butterfield played the lead role of Hugo, with Ben Kingsley as Papa Georges (Méliès), Chloë Grace Moretz as Isabelle and Sacha Baron Cohen as the station inspector. Jude Law, Richard Griffiths, Ray Winstone, Christopher Lee, Frances de la Tour and Helen McCrory were also featured. The film was released to universal critical acclaim, scoring a 94% on Rotten Tomatoes, and 83 on Metacritic. In 2012, the film was nominated for 11 Academy Awards, including Best Picture, and ended up winning five (for Best Sound Editing, Best Sound Mixing, Best Art Direction, Best Cinematography and Best Visual Effects).

The Invention of Hugo Cabret is an American historical novel written and illustrated by Brian Selznick and published by Scholastic. The hardcover edition was released on January 30, 2007, and the paperback edition was released on June 2, 2008. With 284 pictures between the book's 533 pages, the book depends as much on its pictures as it does on the words. Selznick himself has described the book as "not exactly a novel, not quite a picture book, not really a graphic novel, or a flip book or a movie, but a combination of all these things". The book won the 2008 Caldecott Medal, the first novel to do so, as the Caldecott Medal is for picture books.

L'Invention de Hugo Cabret (titre original : "The Invention of Hugo Cabret") est un roman illustré pour enfant écrit et illustré par l'auteur américain Brian Selznick. Publié dans sa langue d'origine aux États-Unis le par les éditions Scholastic Press, il est traduit en français en 2008 par la traductrice Danièle Laruelle. Le roman a obtenu en 2007 la médaille Caldecott, qui distingue l'illustrateur du meilleur livre pour enfant américain de l'année.


Activation of naive helper T cells.

Following T cell development in the thymus, these cells (termed recent thymic emigrants (RTE)) egress from the thymus and home to secondary lymphoid organs (SLO; spleen and lymph nodes). Maturation of RTE in SLO results in the generation of mature naive T cells (Naïve T cells are those T cells that have never been exposed to the antigen that they are programmed to respond to), but naive T cells now lack or lowered the expression of the RTE-related surface markers, such as CD31, PTK7, Complement Receptor 1 and 2 (CR1, CR2) and the production of interleukin 8 (IL-8). Like all T cells, they express the T cell receptor-CD3 complex. The T cell receptor (TCR) consists of both constant and variable regions. The variable region determines what antigen the T cell can respond to. CD4 T cells have TCRs with an affinity for Class II MHC, and CD4 is involved in determining MHC affinity during maturation in the thymus. Class II MHC proteins are generally only found on the surface of specialised antigen-presenting cells (APCs). Specialised antigen-presenting cells are primarily dendritic cells, macrophages and B cells, although dendritic cells are the only cell group that expresses MHC Class II constitutively (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as follicular dendritic cells, but unprocessed antigens do not interact with T cells and are not involved in their activation. The antigens that bind to MHC proteins are always short peptides, 8-10 amino acids long for MHC Class I, and up to 25 or so for MHC Class II.

Recognition (signal 1).

During an immune response, professional antigen-presenting cells (APCs) endocytose foreign material (typically bacteria or viruses), which undergoes processing, then travel from the infection site to the lymph nodes. Once at the lymph nodes, the APCs begin to present antigen peptides that are bound to Class II MHC, allowing CD4 T cells that express the specific TCRs against the peptide/MHC complex to activate.  When a T cell encounters and recognises the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. These interactions bring these proteins closer together, allowing the intracellular kinases present on the TCR, CD3 and CD4 proteins to activate each other via phosphorylation. With the assistance of a phosphatase present on the intracellular section of CD45 (common leukocyte antigen), these molecules activate major T cell intracellular pathways. These active pathways are known as Signal 1 of T cell activation, as it is the first and primary pro-activation signal in a T cell. Upon subsequent encounters with a given antigen, memory T cells are re-activated using the same TCR pathways.  The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the T cell adhere during T cell activation, but the integrin protein LFA-1 on the T cell and ICAM on the APC are the primary molecules of adhesion in this cell interaction.  It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions, but CD45 has various isoforms that change in size depending on the T cell's activation and maturation status. For example, CD45 shortens in length following T activation (CD45RA to CD45RO), but whether this change in length influences activation is unknown. It has been proposed that the larger CD45RA+ may decrease the accessibility of the T cell receptor for the antigen-MHC molecule, thereby necessitating an increase in the affinity (and specificity) of the T cell for activation. However, once the activation has occurred, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.

Verification (signal 2).

Having received the first TCR/CD3 signal, the naïve T cell must activate a second independent biochemical pathway, known as Signal 2. This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming anergic (anergy is generated from the unprotected biochemical changes of Signal 1). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate throughout the body with no value until they undergo apoptosis.  The second signal involves an interaction between CD28 on the CD4 T cell and the proteins CD80 (B7.1) or CD86 (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as co-stimulatory molecules.  Although the verification stage is necessary for the activation of naïve helper T cells, the importance of this stage is best demonstrated during the similar activation mechanism of CD8 cytotoxic T cells. As naïve CD8 T cells have no true bias towards foreign sources, these T cells must rely on the activation of CD28 for confirmation that they recognise a foreign antigen (as CD80/CD86 is only expressed by active APC's). CD28 plays an important role in decreasing the risk of T cell auto-immunity against host antigens.  Once the naïve T cell has both pathways activated, the biochemical changes induced by Signal 1 are altered, allowing the cell to activate instead of undergoing anergy. The second signal is then obsolete; only the first signal is necessary for future activation. This is also true for memory T cells, which is one example of learned immunity. Faster responses occur upon reinfection because memory T cells have already undergone confirmation and can produce effector cells much sooner.

Proliferation.

Once the two-signal activation is complete the T helper cell (T) then allows itself to proliferate. It achieves this by releasing a potent T cell growth factor called interleukin 2 (IL-2) which acts upon itself in an autocrine fashion. Activated T cells also produce the alpha sub-unit of the IL-2 receptor (CD25 or IL-2R), enabling a fully functional receptor that can bind with IL-2, which in turn activates the T cell's proliferation pathways.  The autocrine or paracrine secretion of IL-2 can bind to that same T cell or neighboring T's via the IL-2R thus driving proliferation and clonal expansion. The T cells receiving both signals of activation and proliferation will then become T0 cells (T helper 0) cell that secrete IL-2, IL-4 and interferon gamma (IFN-γ). The T0 cells will then differentiate into T1 or T2 cells depending on cytokine environment. IFN-γ drives T1 cell production while IL-10 and IL-4 inhibit T1 cell production. Conversely, IL-4 drives T2 cell production and IFN-γ inhibits T2 cells. These cytokines are pleiotropic and carry out many other functions of the immune response.

Effector function.

In 1991, three groups reported discovering CD154, which is the molecular basis of T cell helper function. Seth Lederman at Columbia University generated a murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4+ T cells. Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig. Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.

Determination of the effector T cell response.

Helper T cells are capable of influencing a variety of immune cells, and the T cell response generated (including the extracellular signals such as cytokines) can be essential for a successful outcome from infection. In order to be effective, helper T cells must determine which cytokines will allow the immune system to be most useful or beneficial for the host. Understanding exactly how helper T cells respond to immune challenges is currently of major interest in immunology, because such knowledge may be very useful in the treatment of disease and in increasing the effectiveness of vaccination.

T1/T2 model.

Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as T1 and T2 cells (also known as Type 1 and Type 2 helper T cells, respectively).  T1 helper cells lead to an increased cell-mediated response, typically against intracellular bacteria and protozoa. They are triggered by the polarising cytokine IL-12 and their effector cytokines are IFN-γ and IL-2. The main effector cells of T1 immunity are macrophages as well as CD8 T cells, IgG B cells, and IFN-γ CD4 T cells. The key T1 transcription factors are STAT4 and T-bet. IFN-γ secreted by CD4 T cells can activate macrophages to phagocytose and digest intracellular bacteria and protozoa. In addition, IFN-γ can activate iNOS to produce NOx free radicals to directly kill intracellular bacteria and protozoa. T1 overactivation against autoantigens will cause Type 4 delayed-type hypersensitivity. Tuberculin reaction or Type 1 diabetes belong to this category of autoimmunity.  T2 helper cells lead to a humoral immune response, typically against extracellular parasites including helminths. They are triggered by the polarising cytokines IL-4 and IL-2, and their effector cytokines are IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25. The main effector cells are eosinophils, basophils, and mast cells as well as B cells, and IL-4/IL-5 CD4 T cells. The key T2 transcription factors are STAT6 and GATA3. IL-4 is the positive feedback cytokine for T2 cells differentiation. Besides, IL-4 stimulates B-cells to produce IgE antibodies, which in turn stimulate mast cells to release histamine, serotonin, and leukotriene to cause broncho-constriction, intestinal peristalsis, gastric fluid acidification to expel helminths. IL-5 from CD4 T cells will activate eosinophils to attack helminths. IL-10 suppresses T1 cells differentiation and function of dendritic cells. T2 overactivation against autoantigen will cause Type1 IgE-mediated allergy and hypersensitivity. Allergic rhinitis, atopic dermatitis, and asthma belong to this category of autoimmunity. In addition to expressing different cytokines, T2 cells also differ from T1 cells in their cell surface glycans (oligosaccharides), which makes them less susceptible to some inducers of cell death.  While we know about the types of cytokine patterns helper T cells tend to produce, we understand less about how the patterns themselves are decided. Various evidence suggests that the type of APC presenting the antigen to the T cell has a major influence on its profile. Other evidence suggests that the concentration of antigen presented to the T cell during primary activation influences its choice. The presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated, but our understanding is nowhere near complete.

T17 helper cells.

T17 helper cells are a subset of T helper cells developmentally distinct from T1 and T2 lineages producing interleukin 17 (IL-17). T cells produce IL-17 which is a pro inflammatory substance. This means it is especially good at fighting extracellular pathogens and fungi.

THαβ helper cells.

THαβ helper cells provide the host immunity against viruses. Their differentiation is triggered by IFN α/β or IL-10. Their key effector cytokine is IL-10. Their main effector cells are NK cells as well as CD8 T cells, IgG B cells, and IL-10 CD4 T cells. The key THαβ transcription factors are STAT1 and STAT3 as well as IRFs. IL-10 from CD4 T cells activate NK cells' ADCC to apoptose virus-infected cells and to induce host as well as viral DNA fragmentation. IFN alpha/beta can suppress transcription to avoid virus replication and transmission. Overactivation of THαβ against autoantigen will cause type 2 antibody-dependent cytotoxic hypersensitivity. Myasthenia gravis or Graves' disease belong to this category.

Limitations to the T1/T2 model.

The interactions between cytokines from the T1/T2 model can be more complicated in some animals. For example, the T2 cytokine IL-10 inhibits cytokine production of both T subsets in humans. Human IL-10 (hIL-10) suppresses the proliferation and cytokine production of all T cells and the activity of macrophages, but continues to stimulate plasma cells, ensuring that antibody production still occurs. As such, hIL-10 is not believed to truly promote the T2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of antibodies.  There are also other types of T cells that can influence the expression and activation of helper T cells, such as natural regulatory T cells, along with less common cytokine profiles such as the T3 subset of helper T cells. Terms such as "regulatory" and "suppression" have become ambiguous after the discovery that helper CD4 T cells are also capable of regulating (and suppressing) their own responses outside of dedicated regulatory T cells.  One major difference between regulatory T cells and effector T cells is that regulatory T cells typically serve to modulate and deactivate the immune response, while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle. The latter is a feature of T3 cells, which transform into a regulatory subset after its initial activation and cytokine production.  Both regulatory T cells and T3 cells produce the cytokine transforming growth factor-beta (TGF-β) and IL-10. Both cytokines are inhibitory to helper T cells; TGF-β suppresses the activity of most of the immune system. There is evidence to suggest that TGF-β may not suppress activated Th2 cells as effectively as it might suppress naive cells, but it is not typically considered a Th2 cytokine.  The characterisation of another novel T helper subtype, T helper 17 cells (T17) has cast further doubt on the basic T1/T2 model. These IL-17 producing cells were initially described as a pathogenic population implicated in autoimmunity but are now thought to have their own distinct effector and regulatory functions. Of note, recent evidence suggest that functional plasticity is an intrinsic capacity of T helper cells. Indeed, a study in mice demonstrated that T17 cells transform into T1 cells "in vivo". A subsequent study furthermore showed that extensive T helper cell plasticity is also prominent in man.  Many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details), and it is becoming clear that while the original T1/T2 model is enlightening and gives insight into the functions of helper T cells, it is far too simple to define its entire role or actions. Some immunologists question the model completely, as some "in vivo" studies suggest that individual helper T cells usually do not match the specific cytokine profiles of the T model, and many cells express cytokines from both profiles. That said, the T model has still played an important part in developing our understanding of the roles and behaviour of helper T cells and the cytokines they produce during an immune response.  Recent scientific studies by Stockinger et al. revealed that another T helper subset may exist. Th9 cells are claimed to be an IL9 (interleukin 9)–producing T cell subset focused on defending helminth infections.

Memory T cell.

Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers. Central memory T cells reside in the lymph nodes while effector memory T cells lack the C-C chemokine receptor type 7 (CCR7) and L-selectin (CD62L) receptors, which prevents them from trafficking to the lymph nodes.  Additional populations of memory T cells are now known to exist. These include tissue-resident memory T (Trm) cells and virtual memory T cells. The single unifying theme for all memory T cell subtypes is that they are long-lived and can expand quickly to large numbers of effector T cells upon encountering their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens.

Role in disease.

Considering the diverse and important role helper T cells play in the immune system, it is not surprising that these cells often influence the immune response against disease. They also appear to make occasional mistakes, or generate responses that would be politely considered non-beneficial. In the worst-case scenario, the helper T cell response could lead to a disaster and the fatality of the host. Fortunately this is a very rare occurrence.

Hypersensitivity.

The immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a hypersensitivity response occurs. Hypersensitivity is believed to be the cause of allergy and some auto-immune disease.  Hypersensitivity reactions can be divided into four types:  Other cellular hypersensitivities include cytotoxic T cell mediated auto-immune disease, and a similar phenomenon; transplant rejection. Helper T cells are required to fuel the development of these diseases. In order to create sufficient auto-reactive killer T cells, interleukin-2 must be produced, and this is supplied by CD4 T cells. CD4 T cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as interferon-gamma, encouraging these cytotoxic cells to kill host cells in certain circumstances.  The mechanism that killer T cells use during auto-immunity is almost identical to their response against viruses, and some viruses have been accused of causing auto-immune diseases such as Type 1 diabetes mellitus. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system believes, by mistake, that a host antigen is foreign. As a result, the CD8 T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.  Some of this section is a simplification. Many auto-immune diseases are more complex. A well-known example is rheumatoid arthritis, where both antibodies and immune cells are known to play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.

HIV infection.

Perhaps the best example of the importance of CD4 T cells is demonstrated with human immunodeficiency virus (HIV) infection. HIV mainly targets lymphoid CD4 T cells, but can infect other cells that express CD4 such as macrophages and dendritic cells (both groups express CD4 at low levels).  It has been proposed that during the non-symptomatic phase of HIV infection, the virus has a relatively low affinity towards T cells (and has a higher affinity for macrophages), resulting in a slow kill rate of CD4 T cells by the immune system. This is initially compensated for via the production of new helper T cells from the thymus (originally from the bone marrow). Once the virus becomes lymphotropic (or T-tropic) however, it begins to infect CD4 T cells far more efficiently (likely due to a change in the co-receptors it binds to during infection), and the immune system is overwhelmed. Of note, recent studies suggest that only ~5% of the lymphoid-derived CD4 T cells targeted by HIV are permissive and become productively infected with the virus. More than 95% of the CD4 T cells that die are resting and are unable to support productive infection. These cells undergo abortive infection with HIV. Cell death is triggered when the host cell detects HIV foreign DNA intermediates and initiates a suicidal death pathway in an attempt to protect the host, leading to caspase-1 activation in inflammasomes, thus causing pyroptosis (a highly inflammatory form of programmed cell death).  At this point chronic inflammation ensues, and functional CD4 T cell levels begin to decrease, eventually to a point where the CD4 T cell population is too small to recognize the full range of antigens that could potentially be detected. The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel progression to acquired immune deficiency syndrome (AIDS). CD4 T cell depleted to the cell count of less than 200cell/μL in blood during AIDS allows various pathogens to escape T cell recognition, thus allowing opportunistic infections that would normally elicit a helper T cell response to bypass the immune system. While these complete bypass situations only occur when the helper T cell response is absolutely necessary for infection clearance, most infections increase in severity and/or duration because the immune system's helper T cells provide less efficient immune response.  Two components of the immune system are particularly affected in AIDS, due to its CD4 T cell dependency:  If the patient does not respond to (or does not receive) HIV treatment they will succumb usually to either cancers or infections; the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease.  Inhibition of CD4 T-cell expansion during HIV infection may occur due to microbial translocation in an IL-10-dependent way. Triggering PD-1 expressed on activated monocytes by its ligand PD-L1, induces IL-10 production which inhibits CD4 T-cell function.

The T helper cells (T cells), also known as CD4 cells, are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

Les lymphocytes T auxiliaires (en anglais "T helper", Th), parfois appelés lymphocytes T CD4+, sont un type original de lymphocytes T, non cytotoxiques, au centre de la réponse immunitaire adaptative (aussi appelé réponse immunitaire acquise). Ils prolifèrent seulement lorsqu'ils reconnaissent certains antigènes pathogènes présentés par une cellule présentatrice d'antigène. Ils activent une quantité d'autres types de cellules qui agiront de manière plus directe sur la réponse, d'où leur autre nom de « lymphocytes T auxiliaires ».


Background.

Fien was born in Mount Isa, Queensland, Australia.

North Queensland.

Fien was educated at Blackheath and Thornburgh College, Charters Towers and played his junior rugby league for Brothers in Mount Isa. In 2000 he made his debut with the North Queensland Cowboys, playing against the Penrith Panthers. In 2001 his form warranted selection to the Queensland side, where he came off the bench for one State of Origin match. In the 2004 NRL season, Fien played 23 games for North Queensland as the club reached the finals for the first time in their history. They would defeat eventual premiers Canterbury in week one of the finals and go on to reach the preliminary final against the Sydney Roosters before losing 16-19 at Telstra Stadium.

New Zealand Warriors.

After playing 93 games for North Queensland, Fien signed with the New Zealand Warriors from the season 2005 onwards. He later extended his contract until the end of 2009.  In 2008 he was told that he would not be required past the 2009 season at the Warriors and that they would consider releasing him at the end of the 2008 season. Fien initially turned down this offer, hoping that his form in the World Cup could earn him a contract extension. However, after the Huddersfield Giants failed to gain a work visa for Todd Carney they approached Fien with a large offer. In January 2009 Fien requested that the Warriors release him from his final season. This request was initially turned down by the Warriors due to the earlier release of Grant Rovelli, however on 30 June 2009 it was announced that Fien would transfer to the St. George Illawarra Dragons for the remainder of the season.

St. George Illawarra.

In May 2009, after being dropped from first grade by the Warriors, Fien announced he has signed a three-year deal with the St. George Illawarra Dragons from 2010. On 30 June the Warriors agreed to release Fien from the rest of his contract, and he joined the Dragons for the second half of the 2009 season.  In the opening round of 2010 he suffered a serious ankle injury which kept him out until just before the finals. Upon his return he provided attacking options to the team and proved an invaluable player throughout the end of the regular season and finals. He was in the 2010 premiership winning St. George Illawarra team and scored the final try of the 2010 NRL Grand Final, showcasing his dummy half skills. He was re-signed until the end of 2013. He retired at the end of the 2013 season.

International career.

Born in Australia, Fien claimed eligibility to play for New Zealand through a New Zealand-born grandmother, and played in two 2006 Tri-Nations matches. After these appearances it emerged that his New Zealand born relation was, in fact, a great-grandmother. Following this discovery the International Rugby League Board declared him ineligible to play for the Kiwis, and New Zealand was stripped of its 2 championship points they got from beating Great Britain. The issue was dubbed Grannygate by the media.  In August 2008, Fien was named in the New Zealand training squad for the 2008 Rugby League World Cup - now being eligible for New Zealand due to residency qualifications via his tenure at the Auckland-based Warriors - and in October 2008 he was named in the final 24-man Kiwi squad. Fien played at halfback in the World Cup final, which was won by New Zealand.  He retired from international rugby league following the 2012 ANZAC Test.

Nathan Fien (born 1 August 1979), also known by the nickname of "Fieny", is a former New Zealand international rugby league footballer who played as a and in the 2000s and 2010s.

Nathan Fien, né le à Mount Isa, est un ancien joueur de rugby à XIII australien international néo-zélandais évoluant au poste de demi de mêlée dans les années 2000. Il a commencé sa carrière professionnelle aux North Queensland Cowboys en 2000 puis la poursuit aux New Zealand Warriors et aux St. George Illawarra Dragons. Titulaire en club, il est sélectionné en équipe de Nouvelle-Zélande pour la coupe du monde 2008 qu'il remporte et lors du Four Nations 2010, au cours duquel il inscrit l'essai de la victoire à la. Enfin, il a également pris part au State of Origin en 2001 avec les Queensland Maroons.


Character story.

While Dame Edna is a fictitious character (whose life story has been entirely created by Barry Humphries), so complete is her identity as an individual that Macmillan published "My Gorgeous Life", Edna's "autobiography" (written by Humphries but credited to Edna herself), on its non-fiction list. Humphries has also written an "Unauthorised Biography" of his life as Edna's manager: "Handling Edna", published in 2010.  According to "My Gorgeous Life", and statements Edna has made over the years, she was born Edna May Beazley in Wagga Wagga, New South Wales, with a sibling who would give birth to Barry McKenzie. Everage started her stage career in a sketch entitled "Olympic Hostess" in the revue "Return Fare" on 19 December 1955 as Mrs. Norm Everage, an "average Australian housewife" from Moonee Ponds, a suburb in Melbourne, Victoria. She spends her time visiting world leaders and jet-setting between her homes in Los Angeles, London, Sydney, Switzerland and Martha's Vineyard. She is a friend and confidante of the Queen and has advised prime ministers and presidents. Edna once took an on-air phone call from President Ronald Reagan to assure him that he was, indeed, still the president; and at stageshows she has claimed to be giving former Australian Prime Minister, Julia Gillard, elocution lessons.  The character has three adult children, Bruce, Kenny, and Valmai. Her first daughter, Lois, when still an infant, went missing and was believed to have been abducted by a "rogue koala" during a family camp-out in the outback, à la Azaria Chamberlain. In "Handling Edna, the Unauthorised Biography", Humphries absolves the koala of any role in the affair and reveals the true fate of Lois, who in fact survived abduction to become a Catholic nun. Edna's surviving daughter, Valmai, has assisted Dame Edna on her most recent programmes for ITV1, including "The Dame Edna Treatment" and has assisted on her live tour shows. Edna takes great pride in her two sons: Bruce, who works as an engineer in South Melbourne and is married to Joylene from Ivanhoe, and her youngest, Kenneth (or Kenny), who is a fashion designer in London and designs all of her frocks. Dame Edna refers often to him and his partner, Clifford Smale, both of whom Edna believes are searching for "Miss Right", although she admits they are looking "in some very strange places". Kenny appeared in Sir Les Patterson's documentary "Les Patterson and the Great Chinese Takeaway" as a boutique owner in Hong Kong.  Dame Edna's mother is incarcerated in a "maximum-security twilight home for the permanently bewildered". Valmai and Kenny are the only family members (so far) who have appeared on stage or screen with their mother. Her husband, Sir Norman Everage, died in 1988 after many years in hospital suffering from prostate problems and a "testicular murmur"; Edna founded the non-profit "Friends of the Prostate" in his honour. Dame Edna was not with Norm when he died. And due to his insistence that all his organs be donated; by the time she reached his bedside, Norm had been "globally recycled" and all that remained was "a dent in the pillow". As a result, Dame Edna almost believed that Norm's cremation was a "waste of money".  In recent years, Edna has demonstrated her social conscience and sensitivity, telling audiences of her intention to adopt an African child from "the country where Madonna shops for loved ones".  Dame Edna spent many years accompanied by her bridesmaid and constant companion Madge Allsop (played by Emily Perry), a New Zealander from Palmerston North who assisted Dame Edna with her appearances and television shows. (Perry died at the age of 100 in 2008 and now Dame Edna's daughter Valmai has replaced her on stage). Madge never spoke a public word (although she sang on Comic Relief), and while she was often the butt of Dame Edna's jokes, the two were devoted. In "Handling Edna, the Unauthorised Biography", Humphries gives Madge a voice and explains the sad loss of her own husband in New Zealand's boiling mud, whilst the couple were on their honeymoon.  On some of her shows ("The Dame Edna Experience") Dame Edna was joined on stage by 'Chuck' (Charlton Heston) where he would be mildly humiliated and mistreated.  Dame Edna is praised for her insights into her homeland. When asked why Australians are so good at sport she commented: "Good food and diet; open air life; juicy steaks; sunshine — and the total absence of any kind of intellectual distraction".  Dame Edna launched a campaign to be appointed as a BBC newsreader in 2009 after the corporation announced it wished to seek a female newsreader over 50 years old.

Honours.

On 7 March 2007, Melbourne renamed a city street in her honour: Dame Edna Place, formerly Brown Alley off Little Collins Street, was officially opened by the Lord Mayor of Melbourne, John So. Dame Edna Place is opposite Royal Arcade and The Causeway, between the major roads, Elizabeth Street and Swanston Street; it was, until its renaming, a service alley for adjoining buildings. Dame Edna was not at the renaming ceremony but was represented by ten look-alike Dames. Everage Street in suburban Moonee Ponds has also been named in her honour.  In 1982, Dame Edna's alter-ego Barry Humphries was made an Officer of the Order of Australia for "services to the theatre" and on 16 June 2007 he was made a Commander of the Order of the British Empire for services to entertainment.  In MAC Cosmetics 2008 Winter Line-Up, a Dame Edna collection of cosmetics were released including eye shadow, lipstick, powder, and nail polish.  A bronze statue was unveiled at Melbourne Docklands in January 2009. It is located by the Yarra river near Harbour Town which also includes statues of singer John Farnham, Dame Nellie Melba, and Graham Kennedy.

Invention of the character.

Barry Humphries was invited to join the fledgling Union Theatre Repertory Company early in 1955 and toured Victorian country towns performing "Twelfth Night", directed by Ray Lawler. On tour, Humphries invented Edna gradually as part of the entertainment for the actors during commutes between country towns. Humphries gradually developed a falsetto impersonation of a Melbourne housewife, imitating the Country Women's Association representatives who welcomed the troupe in each town. At Lawler's suggestion, Mrs Everage (later named Edna after Humphries' nanny) made her first appearance in a Melbourne University's UTRC revue at the end of 1955, as the city prepared for the 1956 Olympic Games. The sketch involved a houseproud "average housewife" offering her Moonee Ponds home as an Olympic billet, spruiking her home as possessing "burgundy wall-to-wall carpets, lamington cakes and reindeers frosted on glass dining-room doors".  At this time the character was billed as "Mrs Norm Everage" (Humphries describing this name as "Everage as in 'average', husband Norm as in 'normal'") and had none of the characteristic flamboyant wardrobe of later years.  His mother (whom the interviewer William Cook said "sounds like a frightful snob") was a major inspiration for Edna, although he denied it when she was alive to protect her feelings. Her first monologue in 1955 was about her "lovely home", reflecting young Barry’s own site visits accompanying his builder father. Originally she was a "mousy" character and too quiet to please the raucous crowd at The Establishment club in London.  According to John Lahr, Edna came into her own during the 1980s when the policies of Thatcherism—and what he described as the "vindictive style of the times"—allowed Dame Edna to sharpen her observations accordingly. Lahr wrote that Edna took Prime Minister Margaret Thatcher's "seemingly hypocritical motto" of "caring and compassion" for others and turned it on its head, Edna became the voice of Humphries' outrage.  In a 2011 interview with CUNY TV, actor Zoe Caldwell claimed that the character had been written with her in mind, but that she turned it down as she did not believe she could make it funny. She then suggested to Humphries that he perform the role himself.

Stage and screen performances.

1950s–1999.

Humphries played the character at comedy clubs, satirising the atmosphere of 1950s Melbourne suburbia. An interview with "Mrs Everage" was one of the programmes screened on HSV-7's first day of programming in 1956. Another revue called Rock'n'Reel followed in 1958 at the New Theatre in Melbourne. She appeared in a televised revue shown on New Year's Eve, 1958, "Wild Life and Christmas Belles".  The character's overseas debut, now as Edna Everage, was in the early 1960s at comedian Peter Cook's nightclub, The Establishment, in London's West End, where she received a poor review from Bamber Gascoigne, then the drama critic for "The Spectator". Barry Humphries cites Cook as being instrumental in launching Edna's UK career. While her first appearances at the Establishment Club were a flop, the mousy Edna being too quiet to please that raucous crowd, a 2016 interviewer William Cook saw the early failure as a blessing, so that Humphries spent the sixties as a jobbing actor rather than as a pampered star.  In 1972, the character appeared as Barry McKenzie's "Aunt Edna" in the film, "The Adventures of Barry McKenzie". In the sequel "Barry McKenzie Holds His Own", the Australian Prime Minister Gough Whitlam cameos at the close of the film to confer upon Edna the title of Dame, henceforth to be known as "Dame Edna".  Following the lukewarm reception to Edna's early appearances in Humphries' 1969 stageshow "Just a Show" and the BBC television series "The Barry Humphries Scandals", a growing awareness and appreciation among British audiences for Edna emerged and Humphries devised a stage show titled "Edna Everage Housewife Superstar" which was successfully presented in London's West End in the mid-1970s. The show featured monologues, songs and what was becoming an Edna trademark – interaction with the theatre audience.  In April 1976, Edna made an appearance in "A Poke in the Eye (with a Sharp Stick)" — the first of what became Amnesty International's Secret Policeman's Ball series of benefit shows. Edna performed a song for the show and was featured in the film of the show. She also appeared in the 1981 Amnesty show "The Secret Policeman's Other Ball". Edna made a cameo appearance in the 1978 film "Sgt. Pepper's Lonely Hearts Club Band". In 1979 she was the subject of a BBC "Arena" mockumentary: "La Dame aux Gladiolas".  Humphries debuted the character off-Broadway in New York City in the late 1970s, but the show received such a poor review from "The New York Times" that Humphries later joked that he thought, "Well, I'll go back to Broadway but I'll wait till the critic's dead — and I had to wait 25 years. I had to wait a quarter of a century for that critic to die".  Dame Edna's success grew in the UK throughout the 1980s and early 1990s with semi-regular stage and television shows. Her first TV specials were in 1978–1979 on BBC, but she became popular with broadcaster ITV after her initial performance on "An Audience With... Dame Edna Everage" in 1980, in front of an audience of invited celebrities. She went on to perform two more "An Audience With..." specials (in 1984 and 1988), the only performer ever to make three shows in the series.  In 1987, Edna starred alongside Humphries's vulgar alter-ego Les Patterson in the comedy feature "Les Patterson Saves the World". In the same year "The Dame Edna Experience", ostensibly a talk show which she described as "really a monologue interrupted by total strangers" aired, featuring high-profile "celebrity guests" such as Sean Connery, Mel Gibson, Joan Rivers, and Germaine Greer (an old friend of Humphries'), as well as Madge, her silent, sour-faced "bridesmaid and travelling companion". In 1989, the show was back for a second season, this time taking place in her "luxury penthouse suite" where her guests stayed and, in the case of Douglas Fairbanks, Jr, did her grocery shopping. Subsequently, these shows were aired in the U.S. on PBS, broadening her audience and enlarging her fame. "Dame Edna's Neighbourhood Watch" a reality/game show hybrid, aired in 1992, and saw her and Madge having a look at her "by invitation only, ladies audience" member's houses, and evaluating their housekeeping skills. U.S. television specials followed, as did an unsuccessful series which aired only one episode. She appeared as a guest of Phil Donahue on his talk show on 17 February 1993.  In 1997, she appeared in another television talk show "Dr Dame Edna Kisses It Better". Edna continued her Australian stage and television appearances including a record five appearances as guest presenter at the TV Week Logie Awards and a role as a co-narrator (along with Humphries and Les Patterson) of the ABC's Australian social history series "Barry Humphries Flashbacks" in 1999.

2000–2009.

In 2000 and 2004, Dame Edna appeared on Broadway, and toured America with both shows. These were ostensibly not "performances", but rather "appearances", with Dame Edna giving monologues and interacting with audience members. Her 2000 show, "The Royal Tour," won the Drama Desk Award for Outstanding One-Person Show, and a Tony Award.  During 2001 and 2002, Dame Edna appeared in the fifth season of the television show "Ally McBeal" playing the guest role of Claire Otoms, a client of the show's law firm who later became a secretary at the same firm. The character shared Dame Edna's voice and style and was explicitly listed in the opening credits as being played by Dame Edna Everage (although Barry Humphries received a credit in the closing credits). Claire Otoms is an anagram of "A Sitcom Role".  In the 2002 motion picture "Nicholas Nickleby" Dame Edna plays the role of Mrs. Crummles, an actress and wife of the manager of a provincial theatre company. Barry Humphries also appears in the film as Mr. Leadville.  Dame Edna appeared at the Party at the Palace in London in 2002 where she referred to the Queen as the "jubilee girl".  The nostalgic "Barry Humphries: Back to my Roots" tour featured Humphries, Edna, Sir Les and Sandy Stone around Australia in 2003.  In 2003, she had an interview punctuated with NPR Weekend Edition's host Scott Simon's table-pounding laughter.  The character celebrated her 50th "birthday" in 2005. She appeared in the 2005 Myer Christmas advert. To mark the occasion, in 2006, Australia Post featured Edna on a postage stamp and the Lord Mayor of Melbourne presented Edna with the key to the city. She toured Australia with the stageshow "Barry Humphries Back With a Vengeance" and appeared on camera "together" with Humphries for the first time in an interview by Ray Martin for Australia's 60 Minutes. She also appeared on screen at the Closing Ceremony of the 2006 Commonwealth Games in Melbourne while 1000 "Commonwealth Dames" danced around the arena wearing purple wigs, garish costumes and gladioli, singing along to her song, "We've Made The Most of Melbourne" : "It's not as small as Adelaide, Compared to Canberra, it's bliss, And if you've been to Melbourne, You can give Sydney a miss."  On 20 May 2006 she appeared on ITV's coverage of The Prince's Trust 30th Birthday Concert. During the telethon-style segments of the event, she took part in a game of "Blind Date" picking former "X Factor" contestant Chico Slimani over actors Roger Moore and Richard E Grant.  In the summer of 2006, Dame Edna appeared on "The Tonight Show with Jay Leno" alongside Billy Crystal. On 23 September 2006, during an interview on "Parkinson", she revealed that she would be returning to ITV in 2007 with a new chat show called "The Dame Edna Treatment". The show began on Saturday 17 March 2007, with the set-up being that Edna runs a health spa where various famous guests come for treatment.  On 17 December 2006, Dame Edna appeared as a guest panellist on the ABC TV Show "Spicks and Specks" where she sang with presenter Adam Hills. On 16 December 2007 she appeared as the last guest on the final episode of the "Parkinson" UK talk show. On 29 May 2008 she appeared on "The Graham Norton Show" alongside Ray Mears and Alanis Morissette. On 8 August 2008 she appeared on "Loose Women" on the final show of that year's series. On 12 September and 15 December 2008, and also on 27 May 2009, she made guest appearances on "The Tonight Show with Jay Leno".  Accompanied by her daughter Valmai in America and Sir Les Patterson in the UK, Dame Edna again toured with what was declared "My First Last Tour". On television in early 2009, she appeared in adverts to publicise the insurance company Norwich Union's change of name to Aviva, quoting her change of name from Mrs Everage. On 9 June 2009, she appeared as a guest on "The Late Late Show" with Craig Ferguson. On 17 July 2009, she appeared as a guest on "Friday Night with Jonathan Ross". On an episode of "The One Show" in September 2009 a piece of graffiti on Sunderland's Penshaw Monument read "Edna Woz Ere 09" and a pair of Everage's signature glasses were drawn next to it. Dame Edna performed the "Last Night of the Poms" at the Royal Albert Hall accompanying the Royal Philharmonic Orchestra on 15 September 2009 and on 21 September, she appeared as a guest on Channel 4's "The Paul O'Grady Show".

2010–present.

In 2010, Dame Edna collaborated with cabaret pianist and singer Michael Feinstein for a two-person revue in the United States, titled "All About Me", based on the premise that the pair were rivals who were forced to work together for the show's sake. The show opened as the second production for the newly refurbished Henry Miller's Theatre and was planned to run from 18 March through 18 July 2010 (with previews beginning on 22 February), but lukewarm reviews and low ticket sales led to the limited engagement being cut short and closing on 4 April 2010, after 27 previews and 20 regular performances. On 25 March 2010, she appeared on the television talk show "The View" as a guest host to promote the production.  On 29 April 2011 she appeared on the BBC-1 broadcast "William and Kate: The Royal Wedding", with Karl Stefanovic and Lisa Wilkinson, covering the wedding of Prince William and Catherine Middleton at Buckingham Palace, along with Tracy Grimshaw and Kathy Lette at Westminster Abbey.  On 18 March 2012, Humphries announced he would "retire" the Dame Edna character because he was "beginning to feel a bit senior".  On 15 March 2013, Dame Edna Everage appeared on "Red Nose Day 2013" as a guest star and judge for the "Comic Relief Does MasterChef" competition between Jack Whitehall and Micky Flanagan.  In June 2013, Dame Edna returned in a Sydney Opera House production of "Peter and the Wolf".  In 2013, Dame Edna announced her final tour of the United Kingdom. The show opened in November 2013 at the London Palladium before beginning a UK tour in January 2014.  On 11 February 2015 she appeared on "The Great Comic Relief Bake Off" in aid of Comic Relief.  "Dame Edna's Glorious Goodbye – The Farewell Tour" – began in Seattle, Washington at The Moore Theatre (15–18 January 2015) and continued on to The Ahmanson Theatre in Los Angeles (24 January 2015 through 15 March 2015) next traveling to San Francisco's Orpheum Theater (17–22 March 2015) then on to the McCallum Theatre in Palm Desert, California (30 March 2015 – 4 April 2015) then Toronto, Ontario, Canada's Princess of Wales Theatre (9–19 April 2015) and concluding in Washington, DC at the National Theatre (21–26 April 2015.)  Dame Edna was a guest on "Michael McIntyre's Big Christmas Show", broadcast by BBC1 on Christmas Day 2015.  Dame Edna appeared briefly in "" (2016) in a non-speaking cameo, one of two characters played by Humphries in the film.  On Thursday 19 September 2019, Dame Edna appeared on the Today programme with John Humphreys. This was John Humphreys final programme as presenter.  Dame Edna returned to the BBC for a one-off special where she (belatedly) publicly acknowledged the death of Madge in her 2019 TV special "Dame Edna Rules The Waves", first broadcast on BBC1, 31 December 2019. During the show, Dame Edna attempts to dispose of Madge's ashes from the porthole of her luxury yacht, "The Ocean Widow", but is prevented from doing so to protect the environment. Madge's last will and testament insisted that Dame Edna took on the care of her sister Mabel, who has now become Dame Edna's silent sidekick, sticking labels on her celebrity guests. Mabel is portrayed by British actress Anne Rason.

Discography.

In 1997 Naxos released a CD in the Children's Classics series (catalogue number 8.554170)

Satirical advice column.

In 2003, "Vanity Fair" magazine invited Dame Edna to write a satirical advice column. She created controversy with a piece published in the February 2003 issue. Replying to a reader who asked if she should learn Spanish, she wrote:  Some members of the Hispanic community read this reply as a racist remark and complaints flooded in to the magazine. Actress Salma Hayek responded angrily, penning a furious letter in which she denounced Dame Edna. After "Vanity Fair" received death threats, the magazine published a full-page apology to the Hispanic community.  Humphries commented later: "If you have to explain satire to someone, you might as well give up". When Dame Edna was questioned about the controversy on the eve of her 2003 Australian tour, she retorted that Hayek's denunciation was due to "professional jealousy", and that Hayek was envious because the role of painter Frida Kahlo, for which Hayek received an Oscar nomination, had originally been offered to Edna:  When I was offered the part of Frida I turned it down, and she was the second choice. I said 'I'm not playing the role of a woman with a moustache and a monobrow, and I'm not having same-sex relations on the screen'... I'm not racist. I love all races, particularly white people. You know, I even like Roman Catholics.

Dame Edna Everage, often known simply as Dame Edna, is a character created and performed by Australian comedian Barry Humphries, known for her lilac-coloured or "wisteria hue" hair and cat eye glasses or "face furniture", her favourite flower, the gladiolus ("gladdies") and her boisterous greeting: "Hello, Possums!" As Dame Edna, Humphries has written several books including an autobiography, "My Gorgeous Life", appeared in several films and hosted several television shows (on which Humphries has also appeared as himself and other alter-egos).

Dame Edna Everage est un personnage imaginaire incarné par l'humoriste australien Barry Humphries. Elle est facilement reconnaissable à ses cheveux couleur lilas (couleur qu'elle affirme être naturelle) et à ses lunettes.


2008 United States House of Representatives elections in Illinois

Élections législatives américaines de 2008 dans l'Illinois

District 1.

This district includes part of Cook County. Democratic incumbent Bobby Rush, who has held the seat since 1993, ran against Republican nominee Antoine Members. CQ Politics forecast the race as 'Safe Democrat'.

District 2.

This district includes parts of Cook and Will counties. Democratic nominee Jesse Jackson, Jr., who has held the seat winning a special election in December 1995, ran against Republican nominee Anthony Williams. CQ Politics forecast the race as 'Safe Democrat'.

District 3.

This district includes part of Cook County. Democratic incumbent Dan Lipinski, who has held the seat since 2005, ran against Republican nominee Michael Hawkins and Green Party nominee Jerome Pohlen. CQ Politics forecast the race as 'Safe Democrat'.  Perennial candidate and alleged white supremacist Richard Mayers had attempted to run in the Green Party primary.

District 4.

This district includes part of Cook County. Democratic incumbent Luis Gutierrez, who has held the seat since January 1993, ran against Republican nominee Daniel Cunninghan and Green Party nominee Omar López. CQ Politics forecast the race as 'Safe Democrat'.  Earlier in 2007, Cook County Commissioner Roberto Maldonado and Chicago aldermen Manny Flores, Ricardo Muñoz, and George Cardenas had announced their intentions to run for the seat in 2008, as Gutierrez had said he planned to retire. However, Gutierrez later changed his mind and announced he would seek re-election in 2008.

District 5.

This district includes part of Cook County. Democratic incumbent Rahm Emanuel, who has held the seat since 2003, ran against Republican nominee Tom Hanson and Green Party nominee Alan Augustson. CQ Politics forecast the race as 'Safe Democrat'.

District 6.

This district includes parts of DuPage and Cook counties. Freshman Republican incumbent Peter Roskam, who won the then-open seat in a close election in 2006, ran against Democratic nominee Jill Morgenthaler, an Iraq War veteran. CQ Politics forecast the race as 'Republican Favored'.

District 7.

This district lies entirely within Cook County. Democratic incumbent Danny K. Davis, who has held the seat since 1997, ran against Republican nominee Steve Miller, a United States Navy veteran. CQ Politics forecast the race as 'Safe Democrat'.

District 8.

This district includes parts of Lake, McHenry and Cook counties. Democratic incumbent Melissa Bean, who has held the seat since 2005, ran against Republican nominee Steve Greenberg. CQ Politics forecast the race as 'Democrat Favored'.

District 9.

This district includes all of Evanston, Skokie, Niles, Morton Grove, Park Ridge and Norridge, parts of Wilmette, Northfield, Glenview, Golf, Rosemont and Des Plaines, and much of the North Side of Chicago. Democratic incumbent Jan Schakowsky, who has held the seat since 1999, ran against Republican nominee Michael B. Younan and Green Party nominee Morris Shanfield. CQ Politics forecast the race as 'Safe Democrat'.

District 10.

This district includes parts of Lake and Cook counties. Republican incumbent Mark Kirk, who has held the seat since 2001, ran against Democratic nominee Dan Seals, who also ran against Kirk in the 2006 election. CQ Politics forecast the race as 'No Clear Favorite'.

District 11.

This district includes the towns of Joliet, Kankakee, LaSalle, Ottawa and Streator, and all or parts of Will, Kankakee, Grundy, LaSalle, Bureau, Woodford and McLean counties. An open seat, Democratic State Senate Majority Leader Debbie Halvorson ran against Republican nominee Marty Ozinga, a local businessman, and Green Party nominee Jason Wallace. CQ Politics forecast the race as 'Democrat Favored'.  Republican incumbent Jerry Weller, who had held the seat since 1995, decided not to seek re-election, leaving this an open seat. Tim Baldermann, mayor of New Lenox and police chief of Chicago Ridge, won the Republican nomination but withdrew on February 23. Martin Ozinga was chosen to replace Baldermann on April 30.

District 12.

This district is in the southwest part of the state and includes the cities of Alton, Carbondale and East St. Louis. Democratic incumbent Jerry Costello, who has held the seat since August 1988, ran against Republican nominee Tim Richardson and Chairman of the Metro East Green Party Rodger Jennings. CQ Politics forecast the race as 'Safe Democrat'.

District 13.

This district includes parts of the Cook, DuPage and Will counties. Republican incumbent Judy Biggert, who has held the seat since January 1999, ran against Democratic nominee Scott Harper and Green Party nominee Steve Alesch. CQ Politics initially forecast the race as 'Safe Republican', but changed the forecast to 'Republican Favored' after Harper had raised more money than the 2006 Democratic nominee for this seat by mid-July.

District 14.

This district includes the cities of Aurora, Elgin, DeKalb and Dixon, and parts of Henry, Whiteside, Lee, DeKalb, Kane, Kendall, and DuPage counties. Democratic nominee Bill Foster, who had held the seat since March 2008, won against Republican nominee Jim Oberweis, who also lost to Foster in the special election. CQ Politics forecast the race as 'Leans Democratic'.  The district was previously represented by former Speaker of the House Dennis Hastert from 1987 to 2007. He resigned in November 2007, and Bill Foster won the special election held on March 8, 2008.

District 15.

This district includes the cities of Charleston, Urbana, Danville and Champaign, and all or parts of Livingston, Iroquois, Ford, McLean, DeWitt, Champaign, Vermillion, Macon, Piatt, Douglas, Edgar, Moultrie, Coles, Cumberland, Clark, Crawford, Lawrence, Wabash, Edwards, White, Saline and Gallatin counties. Republican incumbent Timothy V. Johnson, who has held the seat since January 2001, won against Democratic nominee Steve Cox. CQ Politics forecast the race as 'Safe Republican'.

District 16.

This district includes the cities of Rockford, Crystal Lake, Machesney Park, Belvidere, Freeport and Galena, and all or parts of Jo Daviess, Stephenson, Winnebago, Boone, McHenry, Carroll, Ogle, DeKalb and Whiteside counties. Republican incumbent Donald A. Manzullo, who has held the seat since 1993, won against Democratic nominee Robert G. Abboud and Green Party nominee Scott K. Summers. CQ Politics forecast the race as 'Safe Republican'.

District 17.

This district includes the cities of Sterling, Rock Island, Moline, Kewanee, Galesburg, Canton, Macomb, Quincy, Springfield and Decatur, and includes all or parts of Henry, Whiteside, Rock Island, Mercer, Knox, Warren, Henderson, Fulton, McDonough, Hancock, Adams, Pike, Calhoun, Greene, Jersey, Macoupin, Madison, Montgomery, Christian, Sangamon, Macon, Shelby, and Fayette counties. Democratic incumbent Phil Hare, who has held the seat since January 2007, ran unopposed. CQ Politics forecast the race as 'Safe Democrat'.

District 18.

This district in the central and western part of the state includes the cities of Jacksonville, Peoria and Springfield. Republican nominee Aaron Schock won against Democratic nominee Colleen Callahan and Green nominee Sheldon Schafer. CQ Politics forecast the race as 'Republican Favored'.  Republican incumbent Ray LaHood, who had held the seat since 1995, decided to retire, leaving this an open seat.

District 19.

This district in the central part of Southern Illinois includes part of Springfield and the outer St. Louis suburbs. Republican incumbent John Shimkus, who has held the seat since 1997, won against Democratic nominee Daniel Davis and Green Party nominee Troy Dennis. CQ Politics forecast the race as 'Safe Republican'.

See also.

United States House of Representatives elections, 2008

The 2008 congressional elections in Illinois were held on November 4, 2008 to determine who would represent the state of Illinois in the United States House of Representatives, coinciding with the presidential and senatorial elections. Representatives are elected for two-year terms; those elected served in the 111th Congress from January 3, 2009 until January 3, 2011.

En 2008, les élections à la Chambre des représentants des États-Unis ont eu lieu le 4 novembre. 435 sièges devaient être renouvelés. Le mandat des représentants étant de deux ans, ceux qui ont été élus à l'occasion de cette élection siègeront dans le Congrès du 3 janvier 2009 au 3 janvier 2011.


In Bacteria.

Bacterial RNase P has two components: an RNA chain, called M1 RNA, and a polypeptide chain, or protein, called C5 protein. "In vivo", both components are necessary for the ribozyme to function properly, but "in vitro", the M1 RNA can act alone as a catalyst. The primary role of the C5 protein is to enhance the substrate binding affinity and the catalytic rate of the M1 RNA enzyme probably by increasing the metal ion affinity in the active site. The crystal structure of a bacterial RNase P holoenzyme with tRNA has been recently resolved, showing how the large, coaxially stacked helical domains of the RNase P RNA engage in shape selective recognition of the pre-tRNA target. This crystal structure confirms earlier models of substrate recognition and catalysis, identifies the location of the active site, and shows how the protein component increases RNase P functionality.

Bacterial RNase P class A and B.

Ribonuclease P (RNase P) is a ubiquitous endoribonuclease, found in archaea, bacteria and eukarya as well as chloroplasts and mitochondria. Its best characterised activity is the generation of mature 5'-ends of tRNAs by cleaving the 5'-leader elements of precursor-tRNAs. Cellular RNase Ps are ribonucleoproteins (RNP). RNA from bacterial RNase Ps retains its catalytic activity in the absence of the protein subunit, i.e. it is a ribozyme. Isolated eukaryotic and archaeal RNase P RNA has not been shown to retain its catalytic function, but is still essential for the catalytic activity of the holoenzyme. Although the archaeal and eukaryotic holoenzymes have a much greater protein content than the eubacterial ones, the RNA cores from all the three lineages are homologous—helices corresponding to P1, P2, P3, P4, and P10/11 are common to all cellular RNase P RNAs. Yet, there is considerable sequence variation, particularly among the eukaryotic RNAs.

In Archaea.

In archaea, RNase P ribonucleoproteins consist of 4-5 protein subunits that are associated with RNA. As revealed by "in vitro" reconstitution experiments these protein subunits are individually dispensable for tRNA processing that is essentially mediated by the RNA component. The structures of protein subunits of archaeal RNase P have been resolved by x-ray crystallography and NMR, thus revealing new protein domains and folding fundamental for function.  Using comparative genomics and improved computational methods, a radically minimized form of the RNase P RNA, dubbed "Type T", has been found in all complete genomes in the crenarchaeal phylogenetic family Thermoproteaceae, including species in the genera Pyrobaculum, Caldivirga and Vulcanisaeta. All retain a conventional catalytic domain, but lack a recognizable specificity domain. 5′ tRNA processing activity of the RNA alone was experimentally confirmed. The Pyrobaculum and Caldivirga RNase P RNAs are the smallest naturally occurring form yet discovered to function as trans-acting ribozymes. Loss of the specificity domain in these RNAs suggests potential altered substrate specificity.  It has recently been argued that the archaebacteriium "Nanoarchaeum equitans" does not possess RNase P. Computational and experimental studies failed to find evidence for its existence. In this organism the tRNA promoter is close to the tRNA gene and it is thought that transcription starts at the first base of the tRNA thus removing the requirement for RNase P.

In eukaryotes.

In eukaryotes, such as humans and yeast, most RNase P consists of an RNA chain that is structurally similar to that found in bacteria as well as nine to ten associated proteins (as opposed to the single bacterial RNase P protein, C5). Five of these protein subunits exhibit homology to archaeal counterparts. These protein subunits of RNase P are shared with RNase MRP, a catalytic ribonucleoprotein involved in processing of ribosomal RNA in the nucleolus. RNase P from eukaryotes was only recently demonstrated to be a ribozyme. Accordingly, the numerous protein subunits of eucaryal RNase P have a minor contribution to tRNA processing per se, while they seem to be essential for the function of RNase P and RNase MRP in other biological settings, such as gene transcription and the cell cycle. Despite the bacterial origins of mitochondria and chloroplasts, plastids from higher animals and plants do not appear to contain an RNA-based RNase P. It has been shown that human mitochondrial RNase P is a protein and does not contain RNA. Spinach chloroplast RNase P has also been shown to function without an RNA subunit.

Therapies using RNase P.

RNase P is now being studied as a potential therapy for diseases such as herpes simplex virus, cytomegalovirus, influenza and other respiratory infections, HIV-1 and cancer caused by fusion gene BCR-ABL. External guide sequences (EGSs) are formed with complementarity to viral or oncogenic mRNA and structures that mimic the T loop and acceptor stem of tRNA. These structures allow RNase P to recognize the EGS and cleave the target mRNA. EGS therapies have shown to be effective in culture and in live mice.

Ribonuclease P (, "RNase P") is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein-based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA molecules. Further, RNase P is one of two known multiple turnover ribozymes in nature (the other being the ribosome), the discovery of which earned Sidney Altman and Thomas Cech the Nobel Prize in Chemistry in 1989: in the 1970s, Altman discovered the existence of precursor tRNA with flanking sequences and was the first to characterize RNase P and its activity in processing of the 5' leader sequence of precursor tRNA. Recent findings also reveal that RNase P has a new function. It has been shown that human nuclear RNase P is required for the normal and efficient transcription of various small noncoding RNAs, such as tRNA, 5S rRNA, SRP RNA and U6 snRNA genes, which are transcribed by RNA polymerase III, one of three major nuclear RNA polymerases in human cells.

La ribonucléase P ou RNase P est une endoribonucléase présente dans toutes les cellules vivantes et dont la fonction est la maturation des ARN de transfert (ARNt). La ribonucléase P clive les précurseurs des ARNt du côté 5' libérant l'extension 5' (5' leader) et l'ARNt maturé en 5' (monophosphate en 5' des ARNt matures).


Biography.

Early years.

Zeoli was born in Canarsie, Brooklyn on October 12, 1949, to an Austrian/Dutch Jewish mother and Italian father. She and her half-brothers and sisters were raised by her stepfather and mother, and alternately attended the Dutch Reform Church and the Catholic church. The family moved to Hialeah, Florida when she was 14. Her stepfather was an alcoholic and physically abusive towards the children, and Zeoli tried unsuccessfully to run away at age 17. After high school, she married Jim Perry and gave birth to her first son, Ben. The marriage ended in divorce and she moved to a farm outside Asheville, North Carolina with Pat Mulloy. They married and she had another son, Christopher. Zeoli adopted her daughter, Atira, years later in 1988.  Based on a series of instructive dreams since she was 19, Zeoli began a meditation practice, later identified as chod by HH Penor Rinpoche, culminating in a spiritual experience at age 30. She studied with a New Age teacher named Jim Gore and led classes at the Black Mountain Light Center in North Carolina. In 1980, she met Michael Burroughs, a graduate student in religions at the University of Virginia and separated from Malloy in 1981.  Zeoli moved with Burroughs and her son Christopher to Kensington, Maryland. She married Burroughs in 1983 and changed her name to Catharine. Together they formed the Center For Discovery and New Life beginning with former members from the Black Mountain Light Center. She gave channeled teachings, specifically a three-year cycle of teachings called the Santu Series Her group quickly expanded, with the students practicing the meditation techniques Zeoli herself practiced from her dreams, a Light Expansion Prayer, and taking vows of compassion that Zeoli composed. The group began a 24-hour prayer vigil in the basement of their Kensington home in April, 1985 inspired by her experiences when she searched for a place to pray and found locked doors.

Meeting her root guru.

In 1984, Zeoli's growing group of students met a Tibetan man named Kunzang, Penor Rinpoche's main lay attendant, who was selling rugs to support Namdroling Monastery. The students sponsored seventy Namdroling monks. A few months later, Penor Rinpoche stayed with the Burroughs on his first visit to the US. During that week, he interviewed most of Jetsunma's students, as well as Jetsunma herself, about what was being taught and what they were practicing. The students asked him what their missions were to help the world. He concluded that Zeoli had been teaching Mahayana Buddhism without any formal instruction and attributed it to a very high level of practice accomplished in previous lifetimes. Penor Rinpoche then gave Jetsunma's students the traditional refuge and bodhisattva vows, which constitute formal entry into the Hinayana and Mahayana Buddhist paths, respectively. Rinpoche visited the meditation and prayer center operated by the Burroughs, which at the time was nonsectarian rather than Buddhist.  Thereafter Zeoli continued the channeled teachings, but they took on a more Buddhist flavor as the center hosted Khenpo Palden Sherab and Khenpo Tsewang Dongyal and she and her students began traditional Buddhist preliminary practice, ngöndro. Beset by health problems, she made a trip in 1986 to Ashland, Oregon to visit Gyatrul Rinpoche, one of Penor Rinpoche's other hosts on his American tour the previous year. She formed a strong and immediate connection with Gyatrul Rinpoche, himself recognized as an incarnation of Palyul Monastery's founder, Rigdzin Kunzang Sherab (1636-1699). Gyatrul Rinpoche echoed the sentiment that the practices and teachings that naturally arose in Zeoli's mind were due to many past lifetimes as a lama, and encouraged her to visit Penor Rinpoche in India to investigate the matter further.

Transmissions.

At the age of 37, Jetsunma began the sequence of Buddhist practices that most tulkus begin very young. She was given the Nam Cho Ngöndro by Gyaltrul Rinpoche in 1986, accumulating prostrations alongside her students. A year later, she was given the Three Roots from Penor Rinpoche at Namdroling monastery in India.  She received the Rinchen Terzod, Nam Cho Tsa Lung, Nyingthik Yabshi, Ratna Lingpa, Dudjom Tersar, Yeshe Lama, and Nam Cho cycle of empowerments, which were hosted at Kunzang Palyul Choling from 1988 through 1996. She received the Kama transmission at Tashi Choling in Ashland, Oregon, in 1988, and the Nam Cho a second time from Karma Kuchen in McDonough, New York, in 2018.

Expansion.

In 1985, the Center for Discovery and New Life formed a corporation and purchased an antebellum style mansion in Poolesville, Maryland where the Kunzang Palyul Choling temple was established. They also purchased numerous large crystals weighing hundreds of pounds and held a three-day retreat to instate the 24-hour prayer vigil at the new location.  Participants have maintained two-hour prayer shifts. The vigil is dedicated to the end of suffering and has remained unbroken, In 1999, Kunzang Palyul Choling (KPC) began another 24-hour prayer vigil shortly after Alyce established the Sedona, Arizona location.  The temple has been partially closed to indoor activities since 2013, awaiting necessary renovations to comply with Montgomery County's Building Use and Occupancy Code. The prayer room, which is separate from the main building, remains open and houses all teachings and activities, and the prayer vigil remains undaunted. The organization raised $1 million for the building of the new temple as of February 18, 2019.  The temple built a 36' stupa in 1988 which was consecrated by H.H. Penor Rinpoche during the Rinchen Terzod. A circle of eight small stupas encircling an 18' stupa were built in 1991 and consecrated by Khenchen Tsewang Gyatso. H.H. Penor Rinpoche gave Jetsunma a relic from Tulku Migyur Dorje to be housed in the Migyur Dorje Stupa, which was built and consecrated in 1996.  In 1996, in addition to the temple, prayer vigil, teachings and stupas, Jetsunma's vision for Kunzang Palyul Choling included a place for pilgrimage with a hospice, school for children, a monastery and an institute for higher education in the Buddha's teachings. The school, called Pema Choling, ran from 1992 to 1997, and the Migyur Dorje Institute continued from 1996 through 2001.

Buddhist recognitions.

The Third Drubwang Padma Norbu ("Penor") Rinpoche, 11th Throneholder of Palyul Monastery, former Supreme Head of the Nyingma tradition, officially recognized Ahkon Lhamo in 1987 as the tulku of Genyenma Ahkon Lhamo during her visit to his Namdroling Monastery in Bylakuppe, Karnataka, India. As is customary, Penor Rinpoche sought confirmation of his recognition before announcing it. He received it from both Dilgo Khyentse Rinpoche (1910–91), the then Supreme Head of the Nyingma tradition who was on a teaching visit to Namdroling at the time, and the most senior Palyul tulku, the Second Dzongnang Jampal Lodro Rinpoche (d. 8/87).  "The Buddha From Brooklyn" asserts that the students determine what title they will use for their own teacher and that Zeoli's ex-husband, Michael Burroughs, selected the title 'Jetsunma' for her. This is a title rarely given to even the most revered Tibetan Buddhist women teachers.

Predecessor.

The first Genyenma Ahkon Lhamo, a meditator recognized as a primordial wisdom dakini was one of the main disciples of Namchö Mingyur Dorje (1645–67) and sister of Rigdzin Kunzang Sherab, Migyur Dorje's Dharma heir and the First Throneholder of Palyul Monastery (founded 1665).[8] She is remembered both as being instrumental in the founding of Palyul (now one of the Nyingma's six main or "mother" monasteries) and for leaving an extraordinary relic. During the cremation of her body, her "kapala" (top half of the skull) is said to have flown three kilometers and come to rest at the foot of the teaching throne of her brother. Found to be miraculously embossed with the sacred syllable AH, the kapala became one of the most treasured relics at Palyul monastery. Penor Rinpoche has recounted how, as a young tulku in Tibet (he was recognized and brought to Palyul Monastery in 1936, at the age of four), inspired by seeing the skull relic, he made prayers to find Ahkon Lhamo's incarnation. Though most of the kapala relic was pulverized into dust during the Cultural Revolution, one Tibetan man managed to save the silver dollar-size piece on which the syllable "AH" appears. Penor Rinpoche acquired it from him on a return trip to Tibet in 1987. He had it preserved in a crystal lotus and presented it to Jetsunma just prior to the occasion of her enthronement ceremony at Kunzang Palyul Choling (KPC) in 1988. The relic remains at KPC and is displayed on auspicious days.

Rinchen Terdzod ceremony.

From June to September 1988, Penor Rinpoche was in residence at KPC in Poolesville to transmit all of the teachings contained in the Rinchen Terdzod ("Treasury of Precious Termas"), Jamgon Kongtrul Lodro Thaye’s massive 19th-century compilation of all of the extant revelations of Guru Padmasambhava’s teaching cycles known as terma. This was the first time that these teachings had ever been conferred in a Western country., According to Penor Rinpoche’s explanation at the time there is a point toward the end of the Rinchen Terdzod transmissions, during the conferral of the Vajrapani empowerment from Rigdzin Godem’s Jangter ("Northern Treasures") cycle, where it is customary to perform enthronement of tulkus. Thus, on September 24, 1988, Penor Rinpoche conducted this ceremony for Jetsunma as the tulku of Genyenma Ahkon Lhamo. Jetsunma considers Penor Rinpoche to be her root guru, along with Ven. Gyatrul Rinpoche, Spiritual Director of Yeshe Nyingpo based in Ashland, Oregon, who is recognized as an incarnation of the first Ahkon Lhamo's brother, Rigdzin Kunzang Sherab.

Mandarava emanation.

In 1994, Terton Orgyen Kusum Lingpa indicated in a long life prayer he composed that Jetsunma was an emanation of Lhacham Mandarava, the Indian princess of Zahor and one of the consorts of Padmasambhava, a tantric master who helped establish the Buddha's teaching in Tibet. In 1996, she traveled to India and visited many of the places where Mandarava was known to have practiced. Inspired by these events, several of Jetsunma's students sought out and found a copy of Mandarava's middle-length spiritual biography, revealed as a terma in the 17th century by Samten Lingpa, at the U.S. Library of Congress. They then sponsored the first English translation of the text, published as "The Lives and Liberation of Princess Mandarava" in 1998.

Activities.

24-hour prayer vigils.

Jetsunma believes strongly in the transformative power of prayer. She initiated a 24-hour Prayer Vigil for World Peace in her Kensington, Maryland shrine room on April 18, 1985. It relocated later that year to the newly purchased World Prayer Center (now Kunzang Palyul Choling). Students engage in traditional Buddhist practices in the Nyingma tradition. In addition for the ongoing prayers for peace, members and individuals not associated with KPC request prayers be dedicated to loved ones, pets, the recently deceased, or those hit by natural disasters. Occasionally Jetsunma asks that the vigil be dedicated to specific situations. For example, the members dedicated eight months of prayer for Asia Claus, a three-year-old daughter of temple members who was suffering from her second bout of cancer. The effort concluded when doctors could find no trace of the cancer, sparking renewed media attention.  The Maryland vigil continues unbroken to the present day. A simultaneous 24-hour Prayer Vigil was conducted by KPC students in Sedona, AZ from October 31, 1999 to August 31, 2008.

Stupa construction.

Like many Buddhist Lamas, Jetsunma has long extolled the benefits of building stupas, Buddhist reliquaries said to represent the mind of enlightenment in architectural form. Her students built one of the first large stupas in America, the 36’ Enlightenment Stupa, as an offering to Penor Rinpoche on the occasion of his conferral of the Rinchen Terdzod empowerments in 1988. Other stupas built by Jetsunma's students include:

Community of monks and nuns.

In September, 1988, toward the end of Penor Rinpoche’s conferral of the Rinchen Terdzod, 25 of Jetsunma's students underwent the traditional ordination ceremony to become monks and nuns, instantly creating one of the largest communities of ordained Westerners in the Tibetan Buddhist tradition in North America. Though some have since left their ordination or died, others have joined, and by 2008 the number of KPC's ordained had grown to 40.

Mongolian Buddhism Revival Project.

Growing out of a friendship with then Mongolian Ambassador Choinkhor and his wife, Jetsunma asked her students in 2004 to create the Mongolian Buddhism Revival Project (MBRP) to help with Mongolia's post-Communist revival of its Buddhist culture, especially the Nyingma lineage. Permanent staff was sent to Mongolia's capital, Ulaanbaatar, in early 2005. In June, 2009, at Jetsunma's direction, staff was removed from Mongolia.

Migyur Dorje Institute.

From 1996–2001, Jetsunma hosted the Migyur Dorje Institute of Higher Buddhist Studies (MDI). Under this program, taught by Khenchen Tsewang Gyatso, students received complete commentary teachings on classic Buddhist texts by Shantideva, Chandrakirti, Asanga, Ngari Panchen, and Mipham Rinpoche. This curriculum was supplemented by annual 30-day retreats teaching the traditional Nyingmapa sequence of the inner tantra: Ngondro, Tsa Lung, Trekchod, and Togyal. With Penor Rinpoche’s development of a similar program at the Palyul Retreat Center in McDonough, NY, the MDI program has been discontinued.

Animal Rescue and Shelter.

Following Hurricane Katrina, in 2005 Zeoli led a group of students to New Orleans to rescue animals left behind. She founded a No Kill animal shelter, Tara's Babies, in order to continue to rescue animals. The target group was dogs on death row, so Tara's Babies mainly rescued dogs from shelters, specializing in fearful and other dogs other shelters rejected. Initially caring for 130 dogs, the sanctuary was set in of former ranch land nestled in the three-million acre (12,000 km2) Tonto National Forest near Payson, Arizona. After finding homes for the dogs, closed in 2011 due to volunteer staffing challenges and lack of funding.

Jetsunma Ahkon Lhamo (born October 12, 1949; born Alyce Louise Zeoli) is an enthroned tulku within the Palyul lineage of the Nyingma tradition of Tibetan Buddhism. In the late 1980s, she gained international attention as the first Western woman to be named a reincarnated lama. She continues to serve as Spiritual Director for Kunzang Odsal Palyul Changchub Choling, a Buddhist center in Poolesville, Maryland, which includes one of the largest communities of Western monks and nuns in North America. She went on to found a center in Sedona, Arizona, U.S.A. Jetsunma has been described by her own teachers, as well as many other Tibetan Buddhist lamas who have visited her temple, as a dakini or female wisdom being.

Jetsunma Ahkon Lhamo est la première occidentale à avoir été reconnue comme réincarnation (tulku). Alyce Louise Zeoli est née le d'une mère juive et d'un père italien. Mariée et mère de famille, elle développa un intérêt pour le bouddhisme initialement du fait de rêves, puis en soutenant un monastère tibétain de Penor Rinpoché, qui la reconnut comme la réincarnation de Genyenma Ahkön Lhamo, Mandarava.


University of Queensland experiment.

The best known version of the experiment was started in 1927 by Professor Thomas Parnell of the University of Queensland in Brisbane, Australia, to demonstrate to students that some substances which appear solid are actually highly viscous fluids. Parnell poured a heated sample of pitch into a sealed funnel and allowed it to settle for three years. In 1930, the seal at the neck of the funnel was cut, allowing the pitch to start flowing. A glass dome covers the funnel and it is placed on display outside a lecture theatre. Large droplets form and fall over a period of about a decade.  The eighth drop fell on 28 November 2000, allowing experimenters to calculate the pitch as having a viscosity of approximately 230 billion (2.3) times that of water.  This experiment is recorded in Guinness World Records as the 'world's longest continuously running laboratory experiment', and it is expected there is enough pitch in the funnel to allow it to continue for at least another hundred years. This experiment is predated by two other (still-active) scientific devices; the Oxford Electric Bell (1840) and the Beverly Clock (1864), but each of these has experienced brief interruptions since 1937.  The experiment was not originally carried out under any special controlled atmospheric conditions, meaning the viscosity could vary throughout the year with fluctuations in temperature. Some time after the seventh drop fell (1988), air conditioning was added to the location where the experiment takes place. The lower average temperature has lengthened each drop's stretch before it separates from the rest of the pitch in the funnel.  In October 2005, John Mainstone and the late Thomas Parnell were awarded the Ig Nobel Prize in physics, a parody of the Nobel Prize, for the pitch drop experiment.  Professor Mainstone subsequently commented:  The experiment is monitored by a webcam but technical problems prevented the November 2000 drop from being recorded. The pitch drop experiment is on public display on Level 2 of Parnell building in the School of Mathematics and Physics at the St Lucia campus of the University of Queensland. Hundreds of thousands of Internet users check the live stream each year.  Professor John Mainstone died on 23 August 2013, aged 78, following a stroke. Custodianship then passed to Professor Andrew White.  The ninth drop touched the eighth drop on 17 April 2014. However, it was still attached to the funnel. On 24 April 2014, Professor White decided to replace the beaker holding the previous eight drops before the ninth drop fused to them. While the bell jar was being lifted, the wooden base wobbled and the ninth drop snapped away from the funnel.  Since mid-March 2018, the live feed was interrupted due to technical problems in the experiment's webpage.

Timeline.

Timeline for the University of Queensland experiment:

Trinity College Dublin experiment.

The pitch drop experiment at Trinity College Dublin in Ireland was started in October 1944 by an unknown colleague of the Nobel Prize winner Ernest Walton while he was in the physics department of Trinity College. This experiment, like the one at Queensland University, was set up to demonstrate the high viscosity of pitch. This physics experiment sat on a shelf in a lecture hall at Trinity College unmonitored for decades as it dripped a number of times from the funnel to the receiving jar below, also gathering layers of dust.  In April 2013, about a decade after the previous pitch drop, physicists at Trinity College noticed that another drip was forming. They moved the experiment to a table to monitor and record the falling drip with a webcam, allowing all present to watch. The pitch dripped around 5:00pm on 11 July 2013, marking the first time that a pitch drop was successfully recorded on camera.  Based on the results from this experiment, the Trinity College physicists estimated that the viscosity of the pitch is about two million times that of honey, or about 20 billion times the viscosity of water.

Experiment at Aberystwyth University in Wales.

It is reported that a pitch drop experiment has been recently rediscovered at Aberystwyth University in Wales. Dating from 1914, it predates the Queensland experiment by 13 years. But as the pitch is more viscous (or the average temperature lower) this experiment has not yet produced its first drop.

Demonstrations of Lord Kelvin.

In the Hunterian Museum at the University of Glasgow are two pitch-demonstrations by Lord Kelvin from the 19th century. Kelvin placed some bullets on top of a dish of pitch, and corks at the bottom: over time, the bullets sank and the corks floated.  Lord Kelvin also showed that the pitch flows like glaciers, with a mahogany ramp that allowed it to slide slowly downward and form similar shapes and patterns to rivers of ice in the Alps.

The pitch drop experiment is a long-term experiment which measures the flow of a piece of pitch over many years. 'Pitch' is the name for any of a number of highly viscous liquids which appear solid; most commonly bitumen. At room temperature, tar pitch flows at a very low rate, taking several years to form a single drop.

L'expérience de la goutte de poix est une expérience de longue durée destinée à mesurer l'écoulement d'un fragment de poix sur de nombreuses années. Le nom de « poix » est donné à n'importe quel liquide très visqueux, qui semble solide, le plus souvent, du bitume. Ainsi, le goudron forme un écoulement à température ambiante et forme une goutte, bien que très lentement.