Walter and Eliza Hall Institute scientists have revealed new details about how cell signalling is controlled in the immune system, identifying in the process potential new therapeutic targets for treating severe blood disorders. Dr Jeff Babon and Professor Nick Nicola, from the institute's Structural Biology and Cancer and Haematology divisions respectively, study interactions between internal cell signalling proteins called JAKs (Janus kinases) and SOCS (Suppressors of Cytokine Signalling).
Dr Babon said the proteins were essential for blood system maintenance and immune responses.
"JAK proteins are activated in response to blood cell hormones called cytokines and instruct immune cells to respond to infection and inflammation," Dr Babon said. "SOCS proteins were discovered at the institute in the early 2000s, and provide a necessary 'negative feedback' response that stops JAKs becoming overactive, which can lead to disease."
Dr Babon said mutations in one particular protein, JAK2, are strongly associated with the development of myeloproliferative diseases.
"When JAK2 is mutated, it tells cells to continually multiply. An excessive amount of blood cells of one type are produced, and the bone marrow is overrun, leading to problems with production of other cell types, and eventually bone marrow failure," Dr Babon said.
Myeloproliferative diseases, such as polycythemia vera and essential thrombocytopenia, are serious blood disorders in which an excessive number of blood cells accumulate in the bone marrow. They can be very severe and sometimes fatal, and may progress to acute leukemias.
In a study published February 17 in the journal Immunity, Dr Babon and Professor Nicola, with colleagues Dr James Murphy and Dr Nadia Kershaw, report on a key discovery about how the proteins JAK2 and SOCS3 interact. They hope the discovery will lead to new strategies for treating myeloproliferative diseases.
"SOCS3 is a key inhibitor of JAK2 proteins in blood and immune cells, but we didn't know exactly how the two proteins interacted to suppress JAK2 function," Dr Babon said. "We wanted to identify which site the SOCS3 protein bound to on the JAK2 protein to inhibit its action, and were surprised to find that SOCS3 binds to a unique site on JAK2 and directly inhibits the protein, rather than outcompeting other molecules."
*Source: Walter and Eliza Hall Institute
20 February 2012
Nasty 'superbug' is being studied by UB researchers
University at Buffalo researchers are expressing concern about a new, under-recognized, much more potent variant of a common bacterium that has surfaced in the U.S. "Historically, in Western countries, classical strains of Klebsiella pneumoniae have caused infections mostly in sick, hospitalized patients whose host defense systems are compromised," says Thomas Russo, MD, professor in the Department of Medicine at the UB School of Medicine and Biomedical Sciences and head of its Infectious Disease Division.
"But in the last 10 to 15 years, a new variant of it has begun causing community-acquired infection in young, healthy individuals," he says. "This variant causes serious, life-threatening, invasive infections and is able to spread to other organs from the initial site of infection."
Perhaps most important, says Russo, these hypervirulent strains of Klebsiella pneumoniae have the potential to become highly resistant to antibiotics, similar to Escherichia coli and classical Klebsiella pneumoniae.
"These hypervirulent strains are the next 'superbugs' -in-waiting," he says. "If they become resistant to antibiotics, they will become difficult, if not impossible to treat."
With recent funding from the National Institutes of Health under a program to fund high-risk, high-reward research, Russo and his UB colleagues are studying the microbiology of the new variant of Klebsiella pneumoniae in an effort to identify the genes that make it hypervirulent so they can figure out how to stop it in its tracks.
"Infections due to highly resistant bacteria are becoming increasingly problematic," says Russo. "We are continually threatened by a 'post-antibiotic' era. The combination of a bacterium that is both highly virulent and resistant to antimicrobials is double-trouble."
The researchers' concern stems from the fact that classical Klebsiella pneumoniae is one of the bacterial species that can easily acquire mobile genetic units, called plasmids, that contain multiple genes that confer high levels of antimicrobial resistance.
"That's in part why we're concerned," says Russo. "We know that this bacterium has the potential to acquire these plasmids and it almost certainly will."
He notes that most bacteria that have proven to be resistant to most or all of the drugs currently available do not usually infect healthy members of the community.
"What is alarming about the hypervirulent Klebsiella pneumoniae is that they do possess the potential to infect healthy people," says Russo. "If this hypervirulent bacterium also becomes highly resistant to antimicrobials, we will have a significant problem to manage. We hope that our research and that of others can prevent this possibility."
While the new hypervirulent variant was first seen exclusively in in the Pacific Rim, it has now been found in several cities in North America, including Buffalo, and in Europe, Canada, Israel and South Africa as well. The UB researchers characterize it as "under-recognized" both by physicians and microbiology laboratories.
The disease most commonly presents as a liver abscess, which is not typical for otherwise healthy patients.
"This new variant presents with unique and scary features: first is its tendency to infect young, healthy people in the community and the second is its unique propensity for metastatic spread to other parts of the body," says Russo. "It spreads to sites beyond the initial source of the infection, such as the lungs, the central nervous system and the eye, potentially causing loss of vision. If infection spreads to the brain, there can be brain damage as well. Between 10 and 30 percent of cases are fatal."
In Buffalo, this hypervirulent variant of Klebsiella pneumoniae was identified in an otherwise healthy, young person several years ago. The patient, who was in his 20s, was hospitalized for several months before making a full recovery. Similar cases are causing concern throughout the international infectious disease community.
At the moment, most cases of hypervirulent Klebsiella pneumoniae resolve if treated aggressively with antibiotics and drainage of abscesses; however, some infections, despite optimal treatment, result in a persistent morbidity or death, Russo says.
He notes that the potential for the bug to acquire drug resistance is adding a sense of urgency to the research.
Russo says that microbiology labs should be aware that an important characteristic of these hypervirulent strains (also known as hypermucoviscous strains) is that when bacterial colonies grown on a solid surface in the laboratory are stretched by a common microbiology tool, called an inoculation loop, they form a viscous "string" greater than 5 millimeters in length.
**Source: University at Buffalo
"But in the last 10 to 15 years, a new variant of it has begun causing community-acquired infection in young, healthy individuals," he says. "This variant causes serious, life-threatening, invasive infections and is able to spread to other organs from the initial site of infection."
Perhaps most important, says Russo, these hypervirulent strains of Klebsiella pneumoniae have the potential to become highly resistant to antibiotics, similar to Escherichia coli and classical Klebsiella pneumoniae.
"These hypervirulent strains are the next 'superbugs' -in-waiting," he says. "If they become resistant to antibiotics, they will become difficult, if not impossible to treat."
With recent funding from the National Institutes of Health under a program to fund high-risk, high-reward research, Russo and his UB colleagues are studying the microbiology of the new variant of Klebsiella pneumoniae in an effort to identify the genes that make it hypervirulent so they can figure out how to stop it in its tracks.
"Infections due to highly resistant bacteria are becoming increasingly problematic," says Russo. "We are continually threatened by a 'post-antibiotic' era. The combination of a bacterium that is both highly virulent and resistant to antimicrobials is double-trouble."
The researchers' concern stems from the fact that classical Klebsiella pneumoniae is one of the bacterial species that can easily acquire mobile genetic units, called plasmids, that contain multiple genes that confer high levels of antimicrobial resistance.
"That's in part why we're concerned," says Russo. "We know that this bacterium has the potential to acquire these plasmids and it almost certainly will."
He notes that most bacteria that have proven to be resistant to most or all of the drugs currently available do not usually infect healthy members of the community.
"What is alarming about the hypervirulent Klebsiella pneumoniae is that they do possess the potential to infect healthy people," says Russo. "If this hypervirulent bacterium also becomes highly resistant to antimicrobials, we will have a significant problem to manage. We hope that our research and that of others can prevent this possibility."
While the new hypervirulent variant was first seen exclusively in in the Pacific Rim, it has now been found in several cities in North America, including Buffalo, and in Europe, Canada, Israel and South Africa as well. The UB researchers characterize it as "under-recognized" both by physicians and microbiology laboratories.
The disease most commonly presents as a liver abscess, which is not typical for otherwise healthy patients.
"This new variant presents with unique and scary features: first is its tendency to infect young, healthy people in the community and the second is its unique propensity for metastatic spread to other parts of the body," says Russo. "It spreads to sites beyond the initial source of the infection, such as the lungs, the central nervous system and the eye, potentially causing loss of vision. If infection spreads to the brain, there can be brain damage as well. Between 10 and 30 percent of cases are fatal."
In Buffalo, this hypervirulent variant of Klebsiella pneumoniae was identified in an otherwise healthy, young person several years ago. The patient, who was in his 20s, was hospitalized for several months before making a full recovery. Similar cases are causing concern throughout the international infectious disease community.
At the moment, most cases of hypervirulent Klebsiella pneumoniae resolve if treated aggressively with antibiotics and drainage of abscesses; however, some infections, despite optimal treatment, result in a persistent morbidity or death, Russo says.
He notes that the potential for the bug to acquire drug resistance is adding a sense of urgency to the research.
Russo says that microbiology labs should be aware that an important characteristic of these hypervirulent strains (also known as hypermucoviscous strains) is that when bacterial colonies grown on a solid surface in the laboratory are stretched by a common microbiology tool, called an inoculation loop, they form a viscous "string" greater than 5 millimeters in length.
**Source: University at Buffalo
Científicos españoles indagan si la obesidad y el cáncer tienen un origen común
En los países desarrollados cada vez hay más obesidad. La obesidad es uno de los principales factores de riesgo para desarrollar cáncer. Estos hechos, combinados, están haciendo que no engordar empiece a ser considerado tan importante para prevenir el cáncer como no fumar, y también han convertido en un reto acuciante el esclarecer la relación entre obesidad y cáncer. En este contexto emerge una idea revolucionaria, a medida que los investigadores profundizan en las causas de ambas enfermedades: ¿Y si la obesidad y el cáncer tuvieran un origen común?
Se engorda en el cerebro. Y en concreto en el hipotálamo, la región cerebral donde se regulan las ganas de comer —vía las sensaciones de saciedad y hambre—, y el gasto metabólico. Son las entradas y salidas de energía en el organismo: la obesidad llega cuando sistemáticamente las calorías que entran con la ingesta superan a las que quema el metabolismo. El proceso está finísimamente regulado sobre todo por ciertas poblaciones de neuronas en el hipotálamo, que integran la información enviada en forma de hormonas por órganos periféricos como el intestino, el páncreas y la propia grasa corporal.
El estudio de todas estas señales químicas es un área en auge que en los últimos 15 años no ha dejado de producir novedades. Una de ellas es precisamente el hallazgo de que la capa de grasa corporal, el tejido adiposo, hace mucho más que simplemente añadir volumen o, como mucho, aislar: ahora se sabe que los michelines son un importante emisor de señales químicas al resto del organismo.
Pero por ahora ninguno de los avances logrados ha dado con una cura de la obesidad, un tratamiento farmacológico que regule la ingesta y el gasto calórico de forma que el organismo no engorde.
Se engorda en el cerebro. Y en concreto en el hipotálamo, la región cerebral donde se regulan las ganas de comer —vía las sensaciones de saciedad y hambre—, y el gasto metabólico. Son las entradas y salidas de energía en el organismo: la obesidad llega cuando sistemáticamente las calorías que entran con la ingesta superan a las que quema el metabolismo. El proceso está finísimamente regulado sobre todo por ciertas poblaciones de neuronas en el hipotálamo, que integran la información enviada en forma de hormonas por órganos periféricos como el intestino, el páncreas y la propia grasa corporal.
El estudio de todas estas señales químicas es un área en auge que en los últimos 15 años no ha dejado de producir novedades. Una de ellas es precisamente el hallazgo de que la capa de grasa corporal, el tejido adiposo, hace mucho más que simplemente añadir volumen o, como mucho, aislar: ahora se sabe que los michelines son un importante emisor de señales químicas al resto del organismo.
Pero por ahora ninguno de los avances logrados ha dado con una cura de la obesidad, un tratamiento farmacológico que regule la ingesta y el gasto calórico de forma que el organismo no engorde.
-En Santiago buscan el papel del gen P53 en el control metabólico
En última instancia ese es el objetivo último de los grupos de Rubén Nogueiras y Miguel López, en la Universidad de Santiago de Compostela. Ambos son Cajales —con un contrato que no garantiza permanencia—, ambos se doctoraron en Santiago bajo la dirección de Carlos Diéguez y ambos han obtenido este año sendas ayudas del Consejo Europeo de Investigación (ERC, en sus siglas en inglés), las prestigiosas y competitivas Starting Grant para llevar adelante sus proyectos durante cinco años —más tiempo incluso que lo que duran sus contratos—.
El proyecto de Nogueiras se titula “P53 como nuevo mediador del balance energético en el cerebro”. Y lo primero que llama la atención es que P53 es un gen que lleva décadas copando titulares por su papel crucial en el cáncer, en concreto como protector ante su desarrollo. Pero en los últimos años se ha descubierto que P53 interviene, además, en el envejecimiento, en diabetes, en enfermedades neurodegenerativas y en otros muchos procesos, entre ellos el metabolismo. Lo que conduce a la obesidad.
En última instancia ese es el objetivo último de los grupos de Rubén Nogueiras y Miguel López, en la Universidad de Santiago de Compostela. Ambos son Cajales —con un contrato que no garantiza permanencia—, ambos se doctoraron en Santiago bajo la dirección de Carlos Diéguez y ambos han obtenido este año sendas ayudas del Consejo Europeo de Investigación (ERC, en sus siglas en inglés), las prestigiosas y competitivas Starting Grant para llevar adelante sus proyectos durante cinco años —más tiempo incluso que lo que duran sus contratos—.
El proyecto de Nogueiras se titula “P53 como nuevo mediador del balance energético en el cerebro”. Y lo primero que llama la atención es que P53 es un gen que lleva décadas copando titulares por su papel crucial en el cáncer, en concreto como protector ante su desarrollo. Pero en los últimos años se ha descubierto que P53 interviene, además, en el envejecimiento, en diabetes, en enfermedades neurodegenerativas y en otros muchos procesos, entre ellos el metabolismo. Lo que conduce a la obesidad.
-Nadie ha dado con un fármaco que regule la ingesta y el gasto calórico
“Está claro que hay una relación entre el cáncer y la obesidad”, explica Nogueiras. “Las personas obesas tienen bastante más probabilidad de tener cáncer, y se sabe muy poco sobre por qué ocurre esto. Creemos que P53 puede ayudar a entenderlo”.
Lo innovador de su proyecto es que trata de averiguar el papel de P53 en el centro de control de la obesidad en el hipotálamo. No es un tiro a ciegas. Hace unos años se descubrió que en las células del tejido adiposo de los ratones obesos, en concreto en la llamada grasa blanca, P53 no se expresa de forma normal. “Además", explica Nogueiras, “cuando se elimina P53 solo de las células de grasa blanca la sensibilidad a la insulina cambia”. La insulina es una de las hormonas mensajeras que los órganos periféricos —en este caso el páncreas— envía al cerebro para regular la ingesta; una respuesta anómala de las células a la insulina se relaciona con diabetes y obesidad.
La pregunta ahora es qué pasa con P53 en las poblaciones de neuronas que regulan la ingesta y el gasto metabólico. Es un terreno que nadie ha explorado aún, de ahí la importancia que ha concedido el ERC al trabajo de Nogueiras. El grupo de este investigador necesitará al menos un año para crear ratones que no expresen P53 justo en determinadas poblaciones de neuronas, y otro tanto o más para ver y analizar qué pasa y obtener los primeros resultados.
“Está claro que hay una relación entre el cáncer y la obesidad”, explica Nogueiras. “Las personas obesas tienen bastante más probabilidad de tener cáncer, y se sabe muy poco sobre por qué ocurre esto. Creemos que P53 puede ayudar a entenderlo”.
Lo innovador de su proyecto es que trata de averiguar el papel de P53 en el centro de control de la obesidad en el hipotálamo. No es un tiro a ciegas. Hace unos años se descubrió que en las células del tejido adiposo de los ratones obesos, en concreto en la llamada grasa blanca, P53 no se expresa de forma normal. “Además", explica Nogueiras, “cuando se elimina P53 solo de las células de grasa blanca la sensibilidad a la insulina cambia”. La insulina es una de las hormonas mensajeras que los órganos periféricos —en este caso el páncreas— envía al cerebro para regular la ingesta; una respuesta anómala de las células a la insulina se relaciona con diabetes y obesidad.
La pregunta ahora es qué pasa con P53 en las poblaciones de neuronas que regulan la ingesta y el gasto metabólico. Es un terreno que nadie ha explorado aún, de ahí la importancia que ha concedido el ERC al trabajo de Nogueiras. El grupo de este investigador necesitará al menos un año para crear ratones que no expresen P53 justo en determinadas poblaciones de neuronas, y otro tanto o más para ver y analizar qué pasa y obtener los primeros resultados.
-Grasa en las neuronas
Cuando Miguel López, de 38 años, estudió biología molecular las neuronas solo comían glucosa. O al menos eso se decía en los libros de texto. Uno de los hallazgos importantes de los últimos tiempos es que las neuronas también necesitan grasa —en el término técnico, lípidos—. Las neuronas usan los lípidos para fabricar moléculas con que se comunican entre sí.
El proyecto de López financiado por el Consejo Europeo de Investigación (ERC) investiga una idea atrevida: la posibilidad de que la obesidad tenga que ver con que las neuronas del centro de control de la obesidad en el cerebro se hayan envenenado con lípidos tóxicos.
Como los demás hallazgos recientes en este terreno, esta hipótesis elimina el sentimiento de culpa que a menudo ataca a los obesos, acusados socialmente de no saber contenerse.
La obesidad no es resultado del pecado de la gula, sino “una enfermedad compleja producto de la interacción entre genes y ambiente”, explica López. Si se confirmara la teoría de la toxicidad de los lípidos, la obesidad —o al menos alguna de sus formas— aparecería en personas que producen en exceso estas grasas, para ellos venenosas. Se sabe hace tiempo que determinados lípidos, cuando se metabolizan, generan moléculas tóxicas en distintos órganos del cuerpo. Pero la idea nunca se ha estudiado en el cerebro.
López actuará sobre distintos grupos de neuronas en el hipotálamo —son poblaciones de apenas unos cientos de neuronas, una prueba de que la regulación de lo que come y gasta el organismo es un proceso realmente fino—. En última instancia, esperan obtener datos para desarrollar en el futuro fármacos contra la obesidad.
Para entonces ya tendrá los suyos Manuel Serrano, del Centro Nacional de Investigaciones Oncológicas (CNIO), que también obtuvo en 2009 una ayuda del ERC —en su caso para investigadores senior— para estudiar la relación entre el cáncer y el envejecimiento. Junto con María Blasco, también en el CNIO, Serrano ha demostrado en ratones que el vínculo entre ambos procesos no es inverso: alterando determinados genes, entre ellos P53, los animales pueden vivir mucho más tiempo y además sin cáncer.
Es un cambio de paradigma, porque hasta hace poco se asumía que la aparición de tumores era un impuesto obligado si el organismo vive más tiempo. Ahora la interpretación es otra: “Creemos que lo que hacen genes protectores, como P53, es evitar no solo el cáncer, sino el daño celular en su conjunto [alteraciones normales en el funcionamiento de la célula que aparecen y se van acumulando a lo largo de su vida]”, explica Serrano. “Y al hacerlo protegen al organismo del envejecimiento, del cáncer, de la resistencia a la insulina, la diabetes, la obesidad, las enfermedades cardiovasculares...”.
Si esa visión se confirma la obesidad y el cáncer podrían ser tratados como facetas distintas de un mismo síndrome en el que también cabría —quizás lo englobaría todo— el envejecimiento. Y puede que en un futuro baste con tocar unos pocos genes clave para curar ese síndrome y lograr así una vejez más tardía y más sana.
Cuando Miguel López, de 38 años, estudió biología molecular las neuronas solo comían glucosa. O al menos eso se decía en los libros de texto. Uno de los hallazgos importantes de los últimos tiempos es que las neuronas también necesitan grasa —en el término técnico, lípidos—. Las neuronas usan los lípidos para fabricar moléculas con que se comunican entre sí.
El proyecto de López financiado por el Consejo Europeo de Investigación (ERC) investiga una idea atrevida: la posibilidad de que la obesidad tenga que ver con que las neuronas del centro de control de la obesidad en el cerebro se hayan envenenado con lípidos tóxicos.
Como los demás hallazgos recientes en este terreno, esta hipótesis elimina el sentimiento de culpa que a menudo ataca a los obesos, acusados socialmente de no saber contenerse.
La obesidad no es resultado del pecado de la gula, sino “una enfermedad compleja producto de la interacción entre genes y ambiente”, explica López. Si se confirmara la teoría de la toxicidad de los lípidos, la obesidad —o al menos alguna de sus formas— aparecería en personas que producen en exceso estas grasas, para ellos venenosas. Se sabe hace tiempo que determinados lípidos, cuando se metabolizan, generan moléculas tóxicas en distintos órganos del cuerpo. Pero la idea nunca se ha estudiado en el cerebro.
López actuará sobre distintos grupos de neuronas en el hipotálamo —son poblaciones de apenas unos cientos de neuronas, una prueba de que la regulación de lo que come y gasta el organismo es un proceso realmente fino—. En última instancia, esperan obtener datos para desarrollar en el futuro fármacos contra la obesidad.
Para entonces ya tendrá los suyos Manuel Serrano, del Centro Nacional de Investigaciones Oncológicas (CNIO), que también obtuvo en 2009 una ayuda del ERC —en su caso para investigadores senior— para estudiar la relación entre el cáncer y el envejecimiento. Junto con María Blasco, también en el CNIO, Serrano ha demostrado en ratones que el vínculo entre ambos procesos no es inverso: alterando determinados genes, entre ellos P53, los animales pueden vivir mucho más tiempo y además sin cáncer.
Es un cambio de paradigma, porque hasta hace poco se asumía que la aparición de tumores era un impuesto obligado si el organismo vive más tiempo. Ahora la interpretación es otra: “Creemos que lo que hacen genes protectores, como P53, es evitar no solo el cáncer, sino el daño celular en su conjunto [alteraciones normales en el funcionamiento de la célula que aparecen y se van acumulando a lo largo de su vida]”, explica Serrano. “Y al hacerlo protegen al organismo del envejecimiento, del cáncer, de la resistencia a la insulina, la diabetes, la obesidad, las enfermedades cardiovasculares...”.
Si esa visión se confirma la obesidad y el cáncer podrían ser tratados como facetas distintas de un mismo síndrome en el que también cabría —quizás lo englobaría todo— el envejecimiento. Y puede que en un futuro baste con tocar unos pocos genes clave para curar ese síndrome y lograr así una vejez más tardía y más sana.
**Puûblicado en "EL PAIS"
A single protein helps the body keep watch over the Epstein-Barr virus
Some 90 percent of people are exposed to the Epstein Barr virus (EBV) at some point in their life. Even though it is quickly cleared from the body, the virus can linger silently for years in small numbers of infected B cells. According to researchers at Children's Hospital Bostonand the Immune Disease Institute (IDI), the immune system subdues the virus by watching for a single viral protein called LMP1, knowledge that has already helped suggest two new treatments for the EBV-fueled cancers seen in some immunosuppressed patients. The study team, led by Klaus Rajewksy, MD, and Baochun Zhang, MD, PhD, of the Program in Cellular and Molecular Medicine at Children Hospital Boston and the IDI, reported their results online this week in the journal Cell.
While the immune system's T cells rapidly clear most EBV-infected B cells, about one in a million infected cells escapes destruction. Within these cells, the virus enters a latent phase, kept in check by the watchful eye of so-called memory T cells. This uneasy relationship usually holds steady the rest of a person's life, unless something -- such as infection with HIV or use of anti-rejection drugs following a transplant -- suppresses the immune system and breaks the surveillance. The virus can then reawaken and drive the development of B cell cancers like AIDS-associated B cell lymphoma and post-transplant lymphoproliferative disorder.
To better understand how the immune system maintains its watch and how the virus turns cells cancerous, Rajewsky and his team had generated a model mimicking latent EBV infection by engineering mice whose B cells contained an inducible version of viral LMP1. Researchers have long known that EBV needs LMP1 to turn B cells cancerous, but modeling this relationship in vivo had proven challenging.
"We had previously attempted to develop an animal model of LMP1 transformation of B cells," said Rajewsky, who recently moved to the Max Delbrück Center for Molecular Medicinein Germany, "but we had never been able to get the mice in our models to actually produce any mature B cells. The immune response against the LMP1-producing B cells was so robust that the cells were eliminated very early on."
Their breakthrough came when Zhang and colleagues reengineered the model to lack T cells. "The mice were initially fine, but succumbed within two to three months to aggressive B cell lymphomas," Rajewsky said. "The profile mimicked very closely what we see in immunosuppressed lymphoma patients." In additional experiments with Rajewsky's original model, the team eliminated the mice's T cells before activating the viral protein in B cells, sparking a similar but even more rapid fatal disease.
**Source: Children's Hospital Boston
While the immune system's T cells rapidly clear most EBV-infected B cells, about one in a million infected cells escapes destruction. Within these cells, the virus enters a latent phase, kept in check by the watchful eye of so-called memory T cells. This uneasy relationship usually holds steady the rest of a person's life, unless something -- such as infection with HIV or use of anti-rejection drugs following a transplant -- suppresses the immune system and breaks the surveillance. The virus can then reawaken and drive the development of B cell cancers like AIDS-associated B cell lymphoma and post-transplant lymphoproliferative disorder.
To better understand how the immune system maintains its watch and how the virus turns cells cancerous, Rajewsky and his team had generated a model mimicking latent EBV infection by engineering mice whose B cells contained an inducible version of viral LMP1. Researchers have long known that EBV needs LMP1 to turn B cells cancerous, but modeling this relationship in vivo had proven challenging.
"We had previously attempted to develop an animal model of LMP1 transformation of B cells," said Rajewsky, who recently moved to the Max Delbrück Center for Molecular Medicinein Germany, "but we had never been able to get the mice in our models to actually produce any mature B cells. The immune response against the LMP1-producing B cells was so robust that the cells were eliminated very early on."
Their breakthrough came when Zhang and colleagues reengineered the model to lack T cells. "The mice were initially fine, but succumbed within two to three months to aggressive B cell lymphomas," Rajewsky said. "The profile mimicked very closely what we see in immunosuppressed lymphoma patients." In additional experiments with Rajewsky's original model, the team eliminated the mice's T cells before activating the viral protein in B cells, sparking a similar but even more rapid fatal disease.
**Source: Children's Hospital Boston
Día Mundial del Síndrome de Asperger
Su principal obstáculo es en la esfera social y la de los sentimientos. A las personas con Síndrome de Asperger a menudo se las tilda de raras, excéntricas, maleducadas y egoístas. Pero, lo que muchos pasan por alto, es que estas actitudes o comportamientos, lejos de un capricho, tienen que ver con un trastorno severo del desarrollo que está encuadrado dentro del espectro autista.
Este síndrome, cuyo Día Mundial fue el 18 de febrero, les produce dificultades para la relación entre sus iguales, para empatizar y entender los sentimientos de los demás, y para comprender las normas y convencionalismos sociales. Por eso, no saben comportarse adecuadamente, hablan a destiempo y parecen ir 'por libre'.
Su apariencia y aspecto suele ser bastante normales y su inteligencia en algunos casos está por encima de la media. Sin embargo, se les distingue porque tienen un estilo muy particular para aprender y, frecuentemente, tienen habilidades especiales en áreas restringidas.
Hasta ahora, en España, tres de cada 1.000 niños son diagnosticados con el Síndrome de Asperger. Sin embargo, estudios recientes elevan esta cifra a uno de cada 250. No obstante, no existe una estadística real.
El psiquiatra y pediatra austriaco Hans Asperger, nacido el 18 de febrero de 1906, fue el que definió en 1944 las características de este síndrome y propuso una pedagogía curativa para los afectados
Este síndrome, cuyo Día Mundial fue el 18 de febrero, les produce dificultades para la relación entre sus iguales, para empatizar y entender los sentimientos de los demás, y para comprender las normas y convencionalismos sociales. Por eso, no saben comportarse adecuadamente, hablan a destiempo y parecen ir 'por libre'.
Su apariencia y aspecto suele ser bastante normales y su inteligencia en algunos casos está por encima de la media. Sin embargo, se les distingue porque tienen un estilo muy particular para aprender y, frecuentemente, tienen habilidades especiales en áreas restringidas.
Hasta ahora, en España, tres de cada 1.000 niños son diagnosticados con el Síndrome de Asperger. Sin embargo, estudios recientes elevan esta cifra a uno de cada 250. No obstante, no existe una estadística real.
El psiquiatra y pediatra austriaco Hans Asperger, nacido el 18 de febrero de 1906, fue el que definió en 1944 las características de este síndrome y propuso una pedagogía curativa para los afectados
UofL research shows substituting with smokeless tobacco saves lives
Substituting smokeless tobacco products can save smokers' lives, and there is a scientific foundation that proves it. That is the message Brad Rodu, D.D.S., professor of medicine at the University of Louisville (UofL) School of Medicine and the Endowed Chair in Tobacco Harm Reduction at UofL's James Graham Brown Cancer Center, delivered at the Annual Meeting of the American Association for the Advancement of Science Feb. 18. Rodu spoke at the session, "Harm Reduction: Policy Change to Reduce the Global Toll of Smoking-Related Disease."
"Quit or die: That's been the brutal message delivered to 45 million American smokers, and it has helped contribute to 443,000 deaths per year, according to statistics from the Centers for Disease Control and Prevention," Rodu said. "The truth, however, is that total nicotine and tobacco abstinence is unattainable and unnecessary for many smokers."
Rodu's presentation, "Transforming Tobacco Use: The Potential of Tobacco Harm Reduction," was based on his almost 20 years of research. His work shows that smokers can greatly reduce their risk of disease and death by replacing smoking products with e-cigarettes or modern, spit-free smokeless tobacco. These products provide a much safer alternative for those smokers who are unable or unwilling to quit smoking because they continue to deliver nicotine without the harmful effect of smoking.
"Nicotine is addictive, but it is not the cause of any smoking-related disease. Like caffeine, nicotine can be used safely by consumers," Rodu said.
Decades of epidemiologic research bear out Rodu's findings. While no tobacco product is completely safe, smokeless products have been shown to be 98 percent safer than cigarettes. In the United Kingdom, the Royal College of Physicians reported in 2002 that smokeless tobacco is up to 1,000 times less hazardous than smoking, and in 2007, further urged world governments to seriously consider instituting tobacco harm reduction strategies as a means to save lives.
To see the proof of what tobacco harm reduction can do, look to Sweden, Rodu said. "Over the past 50 years, Swedish men have had Europe's highest per capita consumption of smokeless tobacco as well as Europe's lowest cigarette use. During the same time, they also have the lowest rate of lung cancer than men in any other European country."
In the United States., steps have been made to document the value of tobacco harm reduction. In 2006, a National Cancer Institute-funded study estimated that if tobacco harm reduction was "responsibly communicated" to smokers, 4 million would switch to smokeless tobacco. The American Council on Science and Health -- which organized Rodu's session at the AAAS Annual Meeting -- concluded in the same year that tobacco harm reduction "shows great potential as a public health strategy to help millions of smokers."
Rodu is well aware of the controversy his research findings generate. Opponents of any use of nicotine delivery products maintain that smokeless tobacco puts the user at great risk for oral cancer, a position not supported by research.
*Source: University of Louisville
"Quit or die: That's been the brutal message delivered to 45 million American smokers, and it has helped contribute to 443,000 deaths per year, according to statistics from the Centers for Disease Control and Prevention," Rodu said. "The truth, however, is that total nicotine and tobacco abstinence is unattainable and unnecessary for many smokers."
Rodu's presentation, "Transforming Tobacco Use: The Potential of Tobacco Harm Reduction," was based on his almost 20 years of research. His work shows that smokers can greatly reduce their risk of disease and death by replacing smoking products with e-cigarettes or modern, spit-free smokeless tobacco. These products provide a much safer alternative for those smokers who are unable or unwilling to quit smoking because they continue to deliver nicotine without the harmful effect of smoking.
"Nicotine is addictive, but it is not the cause of any smoking-related disease. Like caffeine, nicotine can be used safely by consumers," Rodu said.
Decades of epidemiologic research bear out Rodu's findings. While no tobacco product is completely safe, smokeless products have been shown to be 98 percent safer than cigarettes. In the United Kingdom, the Royal College of Physicians reported in 2002 that smokeless tobacco is up to 1,000 times less hazardous than smoking, and in 2007, further urged world governments to seriously consider instituting tobacco harm reduction strategies as a means to save lives.
To see the proof of what tobacco harm reduction can do, look to Sweden, Rodu said. "Over the past 50 years, Swedish men have had Europe's highest per capita consumption of smokeless tobacco as well as Europe's lowest cigarette use. During the same time, they also have the lowest rate of lung cancer than men in any other European country."
In the United States., steps have been made to document the value of tobacco harm reduction. In 2006, a National Cancer Institute-funded study estimated that if tobacco harm reduction was "responsibly communicated" to smokers, 4 million would switch to smokeless tobacco. The American Council on Science and Health -- which organized Rodu's session at the AAAS Annual Meeting -- concluded in the same year that tobacco harm reduction "shows great potential as a public health strategy to help millions of smokers."
Rodu is well aware of the controversy his research findings generate. Opponents of any use of nicotine delivery products maintain that smokeless tobacco puts the user at great risk for oral cancer, a position not supported by research.
*Source: University of Louisville
Faulty fat sensor implicated in obesity and liver disease
Defects in a protein that functions as a dietary fat sensor may be a cause of obesity and liver disease, according to a study published in the journal Nature, led by researchers at Imperial College London. The findings highlight a promising target for new drugs to treat obesity and metabolic disorders. The protein GPR120 is found on the surface of cells in the gut, liver and fat tissue and allows cells to detect and respond to unsaturated fatty acids from the diet, especially the omega-3 fatty acids which are believed to have a beneficial impact on health. Scientists found that mice deficient in GPR120 were more prone to developing obesity and liver disease when fed a high-fat diet. They also found that people with a certain mutation in the gene encoding GPR120, which stops the protein from responding to omega-3 fatty acids, were significantly more likely to be obese.
In the gut, when unsaturated fatty acids from food bind to GPR120, this stimulates the release of hormones that suppress appetite and stimulate the pancreas to secrete insulin. When fat cells sense high levels of fat in the blood through GPR120, it stimulates them to divide to produce more fat cells to store all the fat, reducing the risk of fatty liver and furring of the arteries. This mechanism could be an important pathway for bringing about some of the healthy effects of omega-3s.
When they were fed on a high-fat diet, mice that lacked GPR120 not only became obese but also had fatty livers, lower numbers of fat cells, and poor control of blood glucose. The researchers believe that mice that are deficient in GPR120 have difficulty storing excess fat in fat tissue. Instead, their bodies store fat in areas where it can cause health problems, like the liver, the muscles and in the walls of arteries. In humans, this pattern of obesity is associated with type 2 diabetes and heart disease.
The study involved scientists in the UK, France and Japan. It was led by Professor Philippe Froguel, from the School of Public Health at Imperial College London.
"Being overweight is not always unhealthy if you can make more fat cells to store fat," said Professor Froguel. "Some people seem to be unable to do this, and instead they deposit fat around their internal organs, which is very unhealthy. Our study suggests that in both mice and humans, defects in GPR120 combined with a high-fat diet greatly increase the risk of this unhealthy pattern of obesity. We think GPR120 could be a useful target for new drugs to treat obesity and liver diseases."
The researchers analysed the gene for GPR120 in 6,942 obese people and 7,654 controls to test whether differences in the code that carries instructions for making the protein contribute to obesity in humans. They found that one mutation that renders the protein dysfunctional increases a person's risk of obesity by 60 per cent. The researchers think this mutation mimics the effect of a bad diet lacking in unsaturated omega-3 fat.
*Source: Imperial College London
In the gut, when unsaturated fatty acids from food bind to GPR120, this stimulates the release of hormones that suppress appetite and stimulate the pancreas to secrete insulin. When fat cells sense high levels of fat in the blood through GPR120, it stimulates them to divide to produce more fat cells to store all the fat, reducing the risk of fatty liver and furring of the arteries. This mechanism could be an important pathway for bringing about some of the healthy effects of omega-3s.
When they were fed on a high-fat diet, mice that lacked GPR120 not only became obese but also had fatty livers, lower numbers of fat cells, and poor control of blood glucose. The researchers believe that mice that are deficient in GPR120 have difficulty storing excess fat in fat tissue. Instead, their bodies store fat in areas where it can cause health problems, like the liver, the muscles and in the walls of arteries. In humans, this pattern of obesity is associated with type 2 diabetes and heart disease.
The study involved scientists in the UK, France and Japan. It was led by Professor Philippe Froguel, from the School of Public Health at Imperial College London.
"Being overweight is not always unhealthy if you can make more fat cells to store fat," said Professor Froguel. "Some people seem to be unable to do this, and instead they deposit fat around their internal organs, which is very unhealthy. Our study suggests that in both mice and humans, defects in GPR120 combined with a high-fat diet greatly increase the risk of this unhealthy pattern of obesity. We think GPR120 could be a useful target for new drugs to treat obesity and liver diseases."
The researchers analysed the gene for GPR120 in 6,942 obese people and 7,654 controls to test whether differences in the code that carries instructions for making the protein contribute to obesity in humans. They found that one mutation that renders the protein dysfunctional increases a person's risk of obesity by 60 per cent. The researchers think this mutation mimics the effect of a bad diet lacking in unsaturated omega-3 fat.
*Source: Imperial College London
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