Lung stem cells offer therapeutic clues

ScienceDaily (Oct. 27, 2011) — Guided by insights into how mice recover after H1N1 flu, researchers at Harvard Medical School and Brigham and Women's Hospital, together with researchers at A*STAR of Singapore, have cloned three distinct stem cells from the human airways and demonstrated that one of these cells can form into the lung's alveoli air sac tissue. What's more, the researchers showed that these same lung stem cells are rapidly deployed in a dynamic process of lung regeneration to combat damage from infection or chronic disease.

"These findings suggest new cell- and factor-based strategies for enhancing lung regeneration following acute damage from infection, and even in chronic conditions such as pulmonary fibrosis," said Frank McKeon, professor of cell biology at Harvard Medical School. Other senior authors on the paper include Wa Xian of the Institute of Medical Biology in Singapore and Brigham and Women's Hospital, and Christopher Crum, Director of Women's and Perinatal Pathology at Brigham and Women's Hospital. The researchers worked as part of an international consortium involving scientists from Singapore and France.

The findings will be reported in the Oct. 28 issue of Cell.

For many years, clinicians have observed that patients who survive acute respiratory distress syndrome (ARDS), a form of airway damage involving wholesale destruction of large regions of lung tissue, often recover considerable pulmonary function within six to 12 months. But researchers did not know whether that recovery was due to lung regeneration or to some other kind of adaptive remodeling.

"This study helps clear up the uncertainty," said McKeon. "We have found that the lungs do in fact have a robust potential for regeneration, and we've identified the specific stem cells responsible."

To probe the potential for lung regeneration, Xian, McKeon and colleagues infected mice with a sublethal dosage of a virulent strain of H1N1 influenza A virus. After two weeks of infection, these mice showed a loss of nearly 60 percent of tissue in the lung air sacs after two weeks of infection, but -- remarkably -- by three months, the lungs appeared completely normal by all histological criteria.

These findings demonstrated true lung regeneration, but raised the question of the nature of the stem cells underlying this regenerative process.

Adapting the methods for cloning epidermal skin stem cells pioneered by Howard Green, the George Higginson Professor of Cell Biology at HMS and the 2010 Warren Alpert Foundation Prize recipient, the researchers cloned stem cells from the lung airway in a dish and watched as they differentiated to unusual structures with gene profiles similar to alveoli, the cells in the lung's air sacs.

"This was startling to us," Xian said, "and even more so as we observed the same stem cell populations involved in alveoli formation during the peak of H1N1 infections in mice." The researchers genetically traced the formation of new alveoli to a discrete population of stem cells in the fine endings of the conducting airways that rapidly divide in response to infection and migrate to sites of lung damage.

The scientists were intrigued when molecular dissection of these incipient alveoli revealed the presence of an array of signaling molecules known to control cell behavior, suggesting the possibility that these molecules coordinate the regeneration process itself.

Currently the team is testing the possibility that the secreted factors they observed might promote regeneration, suggesting a therapeutic approach for conditions such as chronic obstructive pulmonary disease and even asthma. They also foresee the possibility that these distal airway stem cells could contribute to repairing lungs scarred by irreversible fibrosis, conditions resistant to present therapies.

This work was supported by the National Heart, Lung, and Blood Institute, the Institute of General Medical Sciences, the National Cancer Institute, and the Defense Advanced Research Projects Agency.

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Pooja A. Kumar, Yuanyu Hu, Yusuke Yamamoto, Neo Boon Hoe, Tay Seok Wei, Dakai Mu, Yan Sun, Lim Siew Joo, Rania Dagher, Elisabeth M. Zielonka, De Yun Wang, Bing Lim, Vincent T. Chow, Christopher P. Crum, Wa Xian, Frank McKeon. Distal Airway Stem Cells Yield Alveoli In Vitro and during Lung Regeneration following H1N1 Influenza Infection. Cell, 28 October 2011 DOI: 10.1016/j.cell.2011.10.001

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Body’s molecular sensors may trigger autoimmune disease

ScienceDaily (Oct. 27, 2011) — Bruce Beutler, MD, a co-recipient of the 2011 Nobel Prize in Medicine, has coauthored an article describing a novel molecular mechanism that can cause the body to attack itself and trigger an autoimmune disease. The article is published online ahead of print in the Journal of Interferon & Cytokine Research, a peer-reviewed journal published by Mary Ann Liebert, Inc.

In the article, entitled "Intracellular Nucleic Acid Sensors and Autoimmunity," Argyrios Theofilopoulos, Dwight Kono, Bruce Beutler, and Roberto Baccala, The Scripps Research Institute (La Jolla, California), review the scientific evidence that supports the role of molecular sensors located inside cells in the initiation not only of protective and inflammatory immune responses, but also in an autoimmune response. These sensors recognize nucleic acid signatures that may be shared by foreign pathogens and the body's own DNA and RNA.

Dr. Beutler is one of three recipients awarded the Nobel Prize in Physiology and Medicine. He shares half of the prize with Jules Hoffman, PhD for their discoveries related to how the body's immune system fights disease through the activation of an innate immune response. The third recipient, Ralph Steinman, MD, who died before the Nobel Prizes were announced, previously published an article in AIDS Research and Human Retroviruses. Mary Ann Liebert, Inc. congratulates the three winners for the work and contributions to medicine for which they are being recognized.

The Journal of Interferon & Cytokine Research, led by Co-Editors-in-Chief Ganes C. Sen, PhD, Chairman, Department of Molecular Genetics, Cleveland Clinic Foundation, and Thomas A. Hamilton, PhD, Chairman, Department of Immunology, Cleveland Clinic Foundation, is an authoritative peer-reviewed journal published monthly in print and online that covers all aspects of interferons and cytokines from basic science to clinical applications. Journal of Interferon & Cytokine Research is the Official Journal of the International Society for Interferon and Cytokine Research. Tables of content and a free sample issue may be viewed online at www.liebertpub.com/jir

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Argyrios N. Theofilopoulos, Dwight H. Kono, Bruce Beutler, Roberto Baccala. Intracellular Nucleic Acid Sensors and Autoimmunity. Journal of Interferon & Cytokine Research, 2011; 111027061355005 DOI: 10.1089/jir.2011.0092Ralf Ignatius, Yang Wei, Sylvie Beaulieu, Agegnehu Gettie, Ralph M. Steinman, Melissa Pope, Svetlana Mojsov. Short Communication: The Immunodeficiency Virus Coreceptor, Bonzo/STRL33/TYMSTR, Is Expressed by Macaque and Human Skin- and Blood-Derived Dendritic Cells. AIDS Research and Human Retroviruses, 2000; 16 (11): 1055 DOI: 10.1089/08892220050075318

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What role do cytokines play in autoimmune diseases?

ScienceDaily (Oct. 27, 2011) — Cytokines, a varied group of signaling chemicals in the body, have been described as the software that runs the immune system, but when that software malfunctions, dysregulation of the immune system can result in debilitating autoimmune diseases such as lupus, arthritis, and diabetes. Leading experts in the field of cytokine research present their most up-to-date findings and unique perspectives on the role of cytokines in autoimmune diseases in a special issue of the Journal of Interferon & Cytokine Research, a peer-reviewed publication of Mary Ann Liebert, Inc.

Dhan Kalvakolanu, PhD, University of Maryland School of Medicine, Journal Co-Editors-in-Chief Ganes C. Sen, PhD, and Thomas A. Hamilton, PhD, Cleveland Clinic Foundation, together with Guest Editors Kamal Moudgil, MD, PhD, University of Maryland School of Medicine, and Divaker Choubey, PhD, University of Cincinnati have compiled a wealth of in-depth review articles, original research, and insightful perspectives from expert researchers on the evolving understanding of how cytokines can both contribute to the initiation of autoimmune diseases and control the inflammation associated with the acute phase of these diseases. This special issue of the Journal is the first in a two-volume collection of articles.

In his introductory Editorial, Dr. Kalvakolanu identifies cytokines as the first step in the onset of immune responses in which the body attacks its own cells and tissues, leading to the development of autoimmune diseases. Drs. Moudgil and Choubey present an overview of the role cytokines play in the induction, regulation, and treatment of autoimmunity. An original research article, "Critical Cytokine Pathways to Cardiac Inflammation," by Noel Rose, PhD, The Johns Hopkins Schools of Medicine and Public Health (Baltimore, MD), describes a mouse model of autoimmune myocarditis -- inflammation of the heart muscles -- that is triggered by infection with Coxsackievirus B3. The model allows researchers to study the cytokine pathways involved in this disease, with the goal of identifying chemical markers that could be used to predict patients more likely to experience an autoimmune reaction after infection.

The Journal of Interferon & Cytokine Research is an authoritative peer-reviewed journal published monthly in print and online that covers all aspects of interferons and cytokines from basic science to clinical applications. Journal of Interferon & Cytokine Research is the Official Journal of the International Society for Interferon and Cytokine Research. Tables of content and a free sample issue may be viewed online at www.liebertpub.com/jir

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Belief in god cuts two ways, study finds

ScienceDaily (Oct. 27, 2011) — Being reminded of the concept of God can decrease people's motivation to pursue personal goals but can help them resist temptation, according to new research published by the American Psychological Association.

"More than 90 percent of people in the world agree that God or a similar spiritual power exists or may exist," said the study's lead author, Kristin Laurin, PhD, of the University of Waterloo in Canada. "This is the first empirical evidence that simple reminders of God can diminish some types of self-regulation, such as pursuing one's goals, yet can improve others, such as resisting temptation."

A total of 353 college students, with an average age 19 and 186 of whom were women, participated in six experiments to determine how the idea of God can indirectly influence people's motivations, even among those who said they were not religious. The students did not have to have an opinion on the existence of a god or any other spiritual power. The findings were reported in the online version of the Journal of Personality and Social Psychology®.

In one experiment, engineering students completed a "warm-up" word task. They were asked to form grammatically correct sentences using four words from sets of five. Some students were provided either God or God-related words (divine, sacred, spirit and prophet), while the control group used more neutral words (ball, desk, sky, track and box). Next, each student had to form as many words as they could in five minutes, using any combination of specific letters. The researchers determined the students' motivation level by the number of words they produced. The more motivated they were, the more words they produced. They were told that a good performance could help predict if they would succeed in an engineering career.

Several weeks before this experiment, the students had been asked if they believed outside factors (other people, beings, forces beyond their control) had an influence on their careers. Among participants who said outside factors such as God might influence their career success, those who did the God-related word task performed worse than those who used neutral words. There was no difference in performance among the participants who did not believe outside factors influenced their career success.

Researchers also measured the importance participants placed on a number of values, including achievement. Participants reminded of God placed the same value on achievement as did participants primed with the more neutral words. "This suggests that our findings did not emerge because the participants reminded of God devalued achievement," said Laurin.

A second set of experiments looked at participants' ability to resist temptation after being reminded about God. In one study, participants who said eating healthy food was important to them ate fewer cookies after reading a short passage about God than those who read a passage unrelated to God.

Participants who read a short God-related passage reported greater willingness to resist temptations to achieve a major goal, such as maintaining a healthy weight, finding a long-term relationship or having a successful career. This effect was found only among participants who had previously said they believe an omniscient entity watches over them and notices when they misbehave.

The level of participants' religious devotion had no impact on the outcomes in any of the experiments, according to the researchers.

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Kristin Laurin, Aaron C. Kay, Gráinne M. Fitzsimons. Divergent effects of activating thoughts of god on self-regulation. Journal of Personality and Social Psychology, 2011; DOI: 10.1037/a0025971

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'Pacman' nebula gets some teeth

ScienceDaily (Oct. 28, 2011) — To visible-light telescopes, this star-forming cloud appears to be chomping through the cosmos, earning it the nickname the "Pacman" nebula, like the famous Pac-Man video game that debuted in 1980. When viewed in infrared light by NASA's Wide-field Infrared Survey Explorer, or WISE, the Pacman takes on a new appearance. In place of its typical, triangle-shaped mouth is a new set of lower, sharp-looking teeth. The Pacman is located at the top of the picture, taking a bite in the direction of the upper left corner.

The teeth are actually pillars where new stars may be forming. These structures were formed when radiation and winds from massive stars in a central cluster blew gas and dust away, leaving only the densest of material. The red dots sprinkled throughout the picture are thought to be the youngest stars, still forming in cocoons of dust.

The Pacman nebula, also called NGC 281, is located 9,200 light years away in the constellation Cassiopeia.

This image was made from observations by all four infrared detectors aboard WISE. Blue and cyan (blue-green) represent infrared light at wavelengths of 3.4 and 4.6 microns, respectively, which is primarily from stars, the hottest objects pictured. Green and red represent light at 12 and 22 microns, respectively, which is primarily from warm dust (with the green dust being warmer than the red dust).

JPL is managed for NASA by the California Institute of Technology in Pasadena.

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Healthy mouth bacteria provide ideal conditions for gum disease

ScienceDaily (Oct. 27, 2011) — Normal bacteria which live in our mouths provide the catalyst for the development of gum disease, a debilitating condition which leads to painful gums and the loosening of teeth, new research from Queen Mary, University of London has found.

The unexpected finding could pave the way for the development of preventative measures in tackling gum, or periodontal disease*, by manipulating the normal bacteria in the same way that probiotic yoghurt works to protect the intestine.

Researchers at Queen Mary's Blizard Institute, including Medical Research Council Clinical Research Training Fellow Mark Payne, worked with scientists in the US and published their findings in the journal Cell Host and Microbe.

The scientists introduced the oral bacterium Porphyromonas gingivalis to mice living in two different test conditions. The mice with normal bacteria in their mouths developed periodontal bone loss but the mice raised under germ-free conditions, in the absence of any normal bacteria, remained disease-free.

Professor Mike Curtis, Director of the Blizard Institute and co-author on the paper, said when the oral bacterium P. gingivalis was introduced under normal conditions "it stimulated the growth of normal bugs leading to a large increase in the number of those organisms already there."

"P. gingivalis was introduced at very low levels yet it had a major affect on both the immune system and the inflammatory system," he said.

"This oral bacterium only appears in small numbers but appears to have a major influence on the overall ecology. It has a keystone effect in a community -- working in the same way that starfish, which have relatively small numbers, control the shell fish communities in the sea.

Professor Curtis said although the findings were encouraging in terms of understanding the way gum disease develops, there was still "some way to go" before there was a similar product on the market for gum disease as a probiotic yoghurt is available for the intestine.

"Now we know that periodontal disease only develops through P. gingivalis interacting with the existing bacteria in our mouths, we need to understand the role played by our normal bacteria in both the development of disease and protection from it," he said.

"This may then provide the means to develop preventative measures for the disease."

Professor Farida Fortune, Dean for Dentistry at Queen Mary said the research was encouraging for people who suffer from gum disease which results in bleeding gums and ultimately loose teeth which cause difficulty in both speaking and eating.

"The public still need to be mindful of the way they look after their teeth and gums. People need to pay more attention to their oral hygiene. Their local hygienist, dental therapist and dentist can all assist in teaching them effective cleaning techniques."

"Just these simple preventative measures, as well as not smoking, will go some way to helping them avoid developing gum disease."

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Michael A. Curtis, Camille Zenobia, Richard P. Darveau. The Relationship of the Oral Microbiotia to Periodontal Health and Disease. Cell Host and Microbe, 2011; 10 (4): 302-306 DOI: 10.1016/j.chom.2011.09.008

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Scientists measure dream content for the first time: Dreams activate the brain in a similar way to real actions

ScienceDaily (Oct. 28, 2011) — The ability to dream is a fascinating aspect of the human mind. However, how the images and emotions that we experience so intensively when we dream form in our heads remains a mystery. Up to now it has not been possible to measure dream content. Max Planck scientists working with colleagues from the Charité hospital in Berlin have now succeeded, for the first time, in analysing the activity of the brain during dreaming.

They were able to do this with the help of lucid dreamers, i.e. people who become aware of their dreaming state and are able to alter the content of their dreams. The scientists measured that the brain activity during the dreamed motion matched the one observed during a real executed movement in a state of wakefulness.

The research is published in the journal Current Biology.

Methods like functional magnetic resonance imaging have enabled scientists to visualise and identify the precise spatial location of brain activity during sleep. However, up to now, researchers have not been able to analyse specific brain activity associated with dream content, as measured brain activity can only be traced back to a specific dream if the precise temporal coincidence of the dream content and measurement is known. Whether a person is dreaming is something that could only be reported by the individual himself.

Scientists from the Max Planck Institute of Psychiatry in Munich, the Charité hospital in Berlin and the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig availed of the ability of lucid dreamers to dream consciously for their research. Lucid dreamers were asked to become aware of their dream while sleeping in a magnetic resonance scanner and to report this "lucid" state to the researchers by means of eye movements. They were then asked to voluntarily "dream" that they were repeatedly clenching first their right fist and then their left one for ten seconds.

This enabled the scientists to measure the entry into REM sleep -- a phase in which dreams are perceived particularly intensively -- with the help of the subject's electroencephalogram (EEG) and to detect the beginning of a lucid phase. The brain activity measured from this time onwards corresponded with the arranged "dream" involving the fist clenching. A region in the sensorimotor cortex of the brain, which is responsible for the execution of movements, was actually activated during the dream. This is directly comparable with the brain activity that arises when the hand is moved while the person is awake. Even if the lucid dreamer just imagines the hand movement while awake, the sensorimotor cortex reacts in a similar way.

The coincidence of the brain activity measured during dreaming and the conscious action shows that dream content can be measured. "With this combination of sleep EEGs, imaging methods and lucid dreamers, we can measure not only simple movements during sleep but also the activity patterns in the brain during visual dream perceptions," says Martin Dresler, a researcher at the Max Planck Institute for Psychiatry.

The researchers were able to confirm the data obtained using MR imaging in another subject using a different technology. With the help of near-infrared spectroscopy, they also observed increased activity in a region of the brain that plays an important role in the planning of movements. "Our dreams are therefore not a 'sleep cinema' in which we merely observe an event passively, but involve activity in the regions of the brain that are relevant to the dream content," explains Michael Czisch, research group leader at the Max Planck Institute for Psychiatry.

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Martin Dresler, Stefan P. Koch, Renate Wehrle, Victor I. Spoormaker, Florian Holsboer, Axel Steiger, Philipp G. Sämann, Hellmuth Obrig, Michael Czisch. Dreamed Movement Elicits Activation in the Sensorimotor Cortex. Current Biology, Published online Oct. 27, 2011 DOI: 10.1016/j.cub.2011.09.029

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