Innate immunity

Public release date: 4-Jun-2013
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Contact: Kathrin Bilgeri
kathrin.bilgeri@lmu.de
49-892-180-6938
Ludwig-Maximilians-Universitt Mnchen

When DNA is out of place

In animal cells, DNA molecules are normally restricted to the cell nucleus and the mitochondria. When DNA appears outside these organelles in the so-called cytosol - it most probably originates from a bacterial pathogen or a DNA virus. This is why cytosolic DNA triggers a strong response by the innate immune system. However, various types of insult can also lead to the release into the cytosol of the cell's own DNA. In this case, the resulting immune response may precipitate an autoimmune disease.

The innate immune system is the body's first line of defense against invasive pathogens. It reacts to intruders by inducing the production of interferon proteins that alert the adaptive arm of the immune system. However, the protein that recognizes DNA which is "out of place" in the cytosol resisted identification until a short time ago. "It was only recently discovered that the enzyme cGAS serves as the sensor," says Professor Karl-Peter Hopfner of LMU's Genzentrum. Hopfner and his colleagues have now determined the three-dimensional structure of this DNA detector.

Cytosolic DNA activates enzyme

Indeed, as they report in the journal Nature, the LMU researchers not only delineated the structure of the cGAS molecule itself, they also elucidated the conformation of the complex formed when it binds to DNA. Careful analysis of both structures, together with further functional studies carried out in collaboration with Professor Veit Hornung of Bonn University, enabled the scientists to work out how cGAS recognizes, and is activated by, cytosolic DNA. Binding of the DNA alters the structure of cGAS, enabling the enzyme to catalyze the synthesis of a cyclic dinucleotide. This molecule then activates a transmembrane protein, which in turn stimulates the production of interferon. "In a second study, published simultaneously in Nature, we also determined the structure of the dinucleotide, and show that it represents a previously unknown form of this class of signaling molecule," Hornung adds.

To their surprise, the researchers also found that cGAS is structurally and mechanistically related to an antiviral enzyme that triggers an immune response upon detection of foreign RNA in the cytosol. "With this finding we have the first evidence for a mechanistic and evolutionary link between DNA- and RNA-induced immune reactions," Hopfner comments.

The new results are also very interesting from a clinical standpoint, as a better understanding of the interferon response could have implications for therapy, in two respects. On the one hand, targeted stimulation of interferon production could enhance immunotherapies directed against tumors. Conversely, the ability to attenuate misdirected immune responses against the body's own antigens could lead to better treatments for autoimmune conditions.

###

(Nature 2013)

Publications:

Structural mechanism of cytosolic DNA sensing by cGAS
Filiz Civril, Tobias Deimling, Carina C. de Oliveira Mann, Andrea Ablasser, Manuela Moldt, Gregor Witte, Veit Hornung, Karl-Peter Hopfner
Nature 2013
doi: 10.1038/nature12305

cGAS produces a 2'-5'-linked, cyclic dinucleotide second messenger that activates STING
Andrea Ablasser, Marion Goldeck, Taner Cavlar, Tobias Deimling, Gregor Witte, Ingo Rhl, Karl-Peter Hopfner, Janos Ludwig, Veit Hornung
Nature 2013
doi: 10.1038/nature12306

Contact:

Prof. Dr. Karl-Peter Hopfner
Genzentrum, LMU Munich
Phone: +49 (0) 2180 76953
Fax: +49 (0) 2180 76999
Email: hopfner@genzentrum.lmu.de
Web: http://www.hopfner.genzentrum.lmu.de

---

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Public release date: 4-Jun-2013
[ | E-mail | Share ]

Contact: Kathrin Bilgeri
kathrin.bilgeri@lmu.de
49-892-180-6938
Ludwig-Maximilians-Universitt Mnchen

When DNA is out of place

In animal cells, DNA molecules are normally restricted to the cell nucleus and the mitochondria. When DNA appears outside these organelles in the so-called cytosol - it most probably originates from a bacterial pathogen or a DNA virus. This is why cytosolic DNA triggers a strong response by the innate immune system. However, various types of insult can also lead to the release into the cytosol of the cell's own DNA. In this case, the resulting immune response may precipitate an autoimmune disease.

The innate immune system is the body's first line of defense against invasive pathogens. It reacts to intruders by inducing the production of interferon proteins that alert the adaptive arm of the immune system. However, the protein that recognizes DNA which is "out of place" in the cytosol resisted identification until a short time ago. "It was only recently discovered that the enzyme cGAS serves as the sensor," says Professor Karl-Peter Hopfner of LMU's Genzentrum. Hopfner and his colleagues have now determined the three-dimensional structure of this DNA detector.

Cytosolic DNA activates enzyme

Indeed, as they report in the journal Nature, the LMU researchers not only delineated the structure of the cGAS molecule itself, they also elucidated the conformation of the complex formed when it binds to DNA. Careful analysis of both structures, together with further functional studies carried out in collaboration with Professor Veit Hornung of Bonn University, enabled the scientists to work out how cGAS recognizes, and is activated by, cytosolic DNA. Binding of the DNA alters the structure of cGAS, enabling the enzyme to catalyze the synthesis of a cyclic dinucleotide. This molecule then activates a transmembrane protein, which in turn stimulates the production of interferon. "In a second study, published simultaneously in Nature, we also determined the structure of the dinucleotide, and show that it represents a previously unknown form of this class of signaling molecule," Hornung adds.

To their surprise, the researchers also found that cGAS is structurally and mechanistically related to an antiviral enzyme that triggers an immune response upon detection of foreign RNA in the cytosol. "With this finding we have the first evidence for a mechanistic and evolutionary link between DNA- and RNA-induced immune reactions," Hopfner comments.

The new results are also very interesting from a clinical standpoint, as a better understanding of the interferon response could have implications for therapy, in two respects. On the one hand, targeted stimulation of interferon production could enhance immunotherapies directed against tumors. Conversely, the ability to attenuate misdirected immune responses against the body's own antigens could lead to better treatments for autoimmune conditions.

###

(Nature 2013)

Publications:

Structural mechanism of cytosolic DNA sensing by cGAS
Filiz Civril, Tobias Deimling, Carina C. de Oliveira Mann, Andrea Ablasser, Manuela Moldt, Gregor Witte, Veit Hornung, Karl-Peter Hopfner
Nature 2013
doi: 10.1038/nature12305

cGAS produces a 2'-5'-linked, cyclic dinucleotide second messenger that activates STING
Andrea Ablasser, Marion Goldeck, Taner Cavlar, Tobias Deimling, Gregor Witte, Ingo Rhl, Karl-Peter Hopfner, Janos Ludwig, Veit Hornung
Nature 2013
doi: 10.1038/nature12306

Contact:

Prof. Dr. Karl-Peter Hopfner
Genzentrum, LMU Munich
Phone: +49 (0) 2180 76953
Fax: +49 (0) 2180 76999
Email: hopfner@genzentrum.lmu.de
Web: http://www.hopfner.genzentrum.lmu.de

---

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Source: http://www.eurekalert.org/pub_releases/2013-06/lm-ii060413.php

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Can We Invent Technology to Record Our Dreams?

Do you remember the dream you had last night? Last week? Last month? Probably not. Our sleepy imagination just vanishes without a trace. But... what if we could record our dreams? Like invent some sort of dream DVR. Then we would never forget.

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Source: http://feeds.gawker.com/~r/gizmodo/full/~3/S7Zi8ucmX7I/can-we-invent-technology-to-record-our-dreams-511131124

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Dogs, humans affected by OCD have similar brain abnormalities

Public release date: 4-Jun-2013
[ | E-mail | Share ]

Contact: Rushmie Nofsinger
rushmie.nofsinger@tufts.edu
508-839-7910
Tufts University, Health Sciences Campus

NORTH GRAFTON, Mass. Another piece of the puzzle to better understand and treat obsessive compulsive disorder (OCD) has fallen into place with the publication of new research that shows that the structural brain abnormalities of Doberman pinschers afflicted with canine compulsive disorder (CCD) are similar to those of humans with OCD. The research suggests that further study of anxiety disorders in dogs may help find new therapies for OCD and similar conditions in humans.

Published online in advance of print on April 13 in Progress in Neuro-Psychopharmacology & Biological Psychiatry, the findings are a collaboration between veterinarians at the Cummings School of Veterinary Medicine at Tufts University and researchers at the McLean Imaging Center at McLean Hospital, in Belmont, Mass.

The causes of OCD, which affects about 2 percent of the population, are not well understood and the disorder often goes untreated or undiagnosed for decades. People with OCD often exhibit repetitive behaviors or persistent thoughts that are time consuming and interfere with daily routines. Dogs with CCD engage in repetitious and destructive behaviors such as flank- and blanket-sucking, tail chasing, and chewing. However, both OCD and CCD often respond to similar treatments.

"While the study sample was small and further research is needed, the results further validate that dogs with CCD can provide insight and understanding into anxiety disorders that affect people. Dogs exhibit the same behavioral characteristics, respond to the same medication, have a genetic basis to the disorder, and we now know have the same structural brain abnormalities as people with OCD," said Nicholas Dodman, BVMS, DACVB, professor of clinical sciences at the Cummings School of Veterinary Medicine at Tufts University.

The Tufts/McLean research team, led by Niwako Ogata, BVSc, Ph.D., who was a behavior researcher at the Cummings School of Veterinary Medicine and is now an assistant professor of animal behavior at Purdue University College of Veterinary Medicine, examined a sample of 16 Dobermans. Comparing MRI brain images of eight Dobermans with CCD to the control group, Ogata found that the CCD group had higher total brain and gray matter volumes, lower gray matter densities in the dorsal anterior cingulate cortex and right anterior insula, and higher fractional anisotropy in the splenium of the corpus callosum (the degree of which correlated with the severity of the behavioral traits). These findings are consistent with those reported in humans with OCD.

"It has been very gratifying to me to use our imaging techniques developed to diagnose human brain disorders to better understand the biological basis for anxiety/compulsive disorders in dogs, which may lead to better treatments for dogs and humans with these disorders," said Marc J. Kaufman, Ph.D., associate professor of psychiatry at Harvard Medical School and director of the McLean Hospital Translational Imaging Laboratory.

"Canines that misbehave are often labeled as 'bad dogs' but it is important to detect and show the biological basis for certain behaviors," said Ogata. "Evidence-based science is a much better approach to understanding a dog's behavior."

The study builds on existing research to better understand the etiology of compulsive disorders in animals such as CCD, which affects Doberman pinschers and other canine breeds. In 2010, researchers from the Cummings School of Veterinary Medicine, the University of Massachusetts Medical School and the Broad Institute at the Massachusetts Institute of Technology identified a genetic locus on canine chromosome 7 that coincides with an increased risk of OCD.

###

Ogata N, et al, Brain structural abnormalities in Doberman pinschers with canine compulsive disorder, Prog Neuro-Psychopharmacol Biol Psychiatry (2013), http://dx.doi.org/10.1016/j.pnpbp.2013.04.002

About the Cummings School of Veterinary Medicine at Tufts University Founded in 1978 in North Grafton, Mass., Cummings School of Veterinary Medicine at Tufts University is internationally esteemed for academic programs that impact society and the practice of veterinary medicine; three hospitals and two clinics that combined log more than 80,000 animal cases each year; and groundbreaking research that benefits animal, public, and environmental health.

---

[ | E-mail | Share ]

?

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Public release date: 4-Jun-2013
[ | E-mail | Share ]

Contact: Rushmie Nofsinger
rushmie.nofsinger@tufts.edu
508-839-7910
Tufts University, Health Sciences Campus

NORTH GRAFTON, Mass. Another piece of the puzzle to better understand and treat obsessive compulsive disorder (OCD) has fallen into place with the publication of new research that shows that the structural brain abnormalities of Doberman pinschers afflicted with canine compulsive disorder (CCD) are similar to those of humans with OCD. The research suggests that further study of anxiety disorders in dogs may help find new therapies for OCD and similar conditions in humans.

Published online in advance of print on April 13 in Progress in Neuro-Psychopharmacology & Biological Psychiatry, the findings are a collaboration between veterinarians at the Cummings School of Veterinary Medicine at Tufts University and researchers at the McLean Imaging Center at McLean Hospital, in Belmont, Mass.

The causes of OCD, which affects about 2 percent of the population, are not well understood and the disorder often goes untreated or undiagnosed for decades. People with OCD often exhibit repetitive behaviors or persistent thoughts that are time consuming and interfere with daily routines. Dogs with CCD engage in repetitious and destructive behaviors such as flank- and blanket-sucking, tail chasing, and chewing. However, both OCD and CCD often respond to similar treatments.

"While the study sample was small and further research is needed, the results further validate that dogs with CCD can provide insight and understanding into anxiety disorders that affect people. Dogs exhibit the same behavioral characteristics, respond to the same medication, have a genetic basis to the disorder, and we now know have the same structural brain abnormalities as people with OCD," said Nicholas Dodman, BVMS, DACVB, professor of clinical sciences at the Cummings School of Veterinary Medicine at Tufts University.

The Tufts/McLean research team, led by Niwako Ogata, BVSc, Ph.D., who was a behavior researcher at the Cummings School of Veterinary Medicine and is now an assistant professor of animal behavior at Purdue University College of Veterinary Medicine, examined a sample of 16 Dobermans. Comparing MRI brain images of eight Dobermans with CCD to the control group, Ogata found that the CCD group had higher total brain and gray matter volumes, lower gray matter densities in the dorsal anterior cingulate cortex and right anterior insula, and higher fractional anisotropy in the splenium of the corpus callosum (the degree of which correlated with the severity of the behavioral traits). These findings are consistent with those reported in humans with OCD.

"It has been very gratifying to me to use our imaging techniques developed to diagnose human brain disorders to better understand the biological basis for anxiety/compulsive disorders in dogs, which may lead to better treatments for dogs and humans with these disorders," said Marc J. Kaufman, Ph.D., associate professor of psychiatry at Harvard Medical School and director of the McLean Hospital Translational Imaging Laboratory.

"Canines that misbehave are often labeled as 'bad dogs' but it is important to detect and show the biological basis for certain behaviors," said Ogata. "Evidence-based science is a much better approach to understanding a dog's behavior."

The study builds on existing research to better understand the etiology of compulsive disorders in animals such as CCD, which affects Doberman pinschers and other canine breeds. In 2010, researchers from the Cummings School of Veterinary Medicine, the University of Massachusetts Medical School and the Broad Institute at the Massachusetts Institute of Technology identified a genetic locus on canine chromosome 7 that coincides with an increased risk of OCD.

###

Ogata N, et al, Brain structural abnormalities in Doberman pinschers with canine compulsive disorder, Prog Neuro-Psychopharmacol Biol Psychiatry (2013), http://dx.doi.org/10.1016/j.pnpbp.2013.04.002

About the Cummings School of Veterinary Medicine at Tufts University Founded in 1978 in North Grafton, Mass., Cummings School of Veterinary Medicine at Tufts University is internationally esteemed for academic programs that impact society and the practice of veterinary medicine; three hospitals and two clinics that combined log more than 80,000 animal cases each year; and groundbreaking research that benefits animal, public, and environmental health.

---

[ | E-mail | Share ]

?

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Source: http://www.eurekalert.org/pub_releases/2013-06/tuhs-dha060313.php

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New kind of antibiotic may be more effective at fighting tuberculosis, anthrax, and other diseases

June 3, 2013 ? Diseases such as tuberculosis, anthrax and shigellosis -- a severe food-borne illness -- eventually could be treated with an entirely new and more-effective kind of antibiotic, thanks to a team of scientists led by Kenneth Keiler, an associate professor of biochemistry and molecular biology at Penn State. The team describes 46 previously untested molecules that target and disrupt an important step in the process of protein synthesis in bacteria, thereby making the bacteria incapable of replicating.

This important step, known as "trans-translation," is a quality-control mechanism that is found in all species of bacteria. "If you imagine a bacterium's protein-synthesis pathway as a factory assembly line, trans-translation is responsible for keeping the assembly line moving," Keiler said. "Faulty messenger RNA -- which conveys genetic information from DNA to proteins -- can block the bacterium's synthesis machinery. But the trans-translation mechanism removes these blockages from the assembly line, thereby keeping the bacterium's system running smoothly." Keiler explained. "The bacterium would not be able to synthesize the proteins that it needs for survival without the trans-translation mechanism." Plants and animals, do not seem to have or need this trans-translation process.

Keiler discovered the previously unknown trans-translation process in bacteria when he was a graduate student in 1996. Since then, he has been working to find molecules capable of disrupting this part of bacteria's protein-synthesis pathway. "The idea is to throw a wrench into the protein-synthesis assembly line and prevent bacterial organisms from making copies of themselves," Keiler said.

To discover which small molecules might be capable of disrupting trans-translation, the team began with a process called high-throughput screening -- a method of trying out many thousands of small molecules with the hope of discovering one or more that might be effective at combatting certain pathogens. "Our team tested about 663,000 different molecules against a strain of E. coli bacteria and monitored how they were affecting its trans-translation process," Keiler said. At the end of this phase of testing, Keiler and his team had found 46 different molecules that appeared to be effective in disrupting the trans-translation process.

The next step was to test these molecules' performance in another genus of bacteria (Shigella) that is known to cause food poisoning. This genus is related to Salmonella and to the organism that causes anthrax (Bacillus anthracis), which sometimes can be lethal in humans and other animals. "Of the 46 molecules that were shown to affect trans-translation, one called KKL-35 jumped out as the most promising," Keiler said. "We found that the KKL-35 molecule inhibits the growth of very distantly related bacteria, and this suggests that it may have antibiotic activity against a very broad spectrum of species."

As for the Shigella and Bacillus anthracis bacteria, Keiler said his team was able to show that, "in the presence of the KKL-35 molecule, these cells died specifically because the molecule halted the trans-translation process." Keiler's team also found that, compared with currently used tuberculosis drug therapies, the KKL-35 molecule was 100-times more effective at inhibiting the growth of the strain of bacteria that causes tuberculosis (Mycobacterium tuberculosis).

Keiler added that one of the most exciting features of an antibiotic designed from the KKL-35 molecule is that drug resistance is not very likely to develop in mutant strains of the targeted bacteria. "In our laboratory experiments, we found no mutant strains that were resistant to KKL-35," Keiler said. "Resistant mutants probably could evolve eventually, but at least it looks like it will be very difficult. That means resistant mutants might be slow to arise and spread."

The research was funded by the National Institutes of Health.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/most_popular/~3/BOWhk8G8H6k/130603163809.htm

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Red Cross pushing for access to Syria's besieged Qusair

By Stephanie Nebehay

GENEVA (Reuters) - The International Committee of the Red Cross said on Monday it was still seeking a formal Syrian response to its request for urgent access to the besieged town of Qusair after a minister said aid efforts should wait until the fighting was over.

Humanitarian groups say as many as 1,500 wounded people may be trapped in Qusair by fighting between rebels and President Bashar al-Assad's forces, who are backed by fighters from Lebanon's militant Shi'ite group Hezbollah.

This verified video from the Syrian Observatory for Human Rights, an activist group, shows continued bombardment of Qusair as Red Cross personnel were barred from the town until fighting ceased.

At least 80,000 people have lost their lives in the two-year uprising against Assad, whose Alawite minority is an offshoot of Shi'ite Islam.

"We remain alarmed about the current situation in Qusair where food, water and medical supplies are reported to be very scarce," ICRC spokesman Alexis Heeb said.

"We want access. We have requested this access," he said. "When we get the green light we also have to make sure the security conditions are acceptable to send the assistance."

He was speaking a day after Syria's Foreign Minister Walid al-Moualem told U.N. Secretary General Ban Ki-moon that Syria would grant the Red Cross and the Syrian Arab Red Crescent access to Qusair "as soon as military operations are over".

The assault on Qusair began two weeks ago after an ultimatum from the army and Hezbollah to evacuate civilians. Several thousand sought shelter in a nearby town and in neighbouring Lebanon, the UNHCR refugee agency said, but others remain.

Warning: Graphic content. This verified video, posted by the Qusair Media Center, shows a city resident burying someone familiar to him. In the background a mass grave is shown in anticipation of casualties from days of fighting.

Assad's soldiers and Hezbollah have since all but surrounded Qusair, which had been used by rebels as a transit point for weapons and fighters smuggled from Lebanon into Syria, and appear to hold much of the town itself.

But rebels say they have brought fighters from the northern province of Aleppo and other regions of Syria, slipping them through the army's lines to reinforce the town.

Assad's efforts to recapture Qusair follow a series of counter-offensives in southern Syria and east of Damascus that have consolidated his hold over central Syria ahead of planned peace talks promoted by the United States and Russia.

Warning: Graphic content. This verified video, also uploaded by the activist group Qusair Media Center, shows injured patients being treated in a medical clinic, in which staff talk about supplies they are missing. Needles are being boiled for sterilization until fresh supplies arrive.

But he has lost control over many parts of northern and eastern Syria, relying on air power and artillery to contain the rebels in those areas. An anti-Assad monitoring group, the Syrian Observatory for Human Rights, said 26 people were killed in a rocket attack overnight on Kafr Hamra in Aleppo province.

MOSCOW AND WASHINGTON DIVIDED

The 47-year-old president says he supports negotiations in principle, but last week dimmed prospects for a breakthrough by saying that any change to his powers must be approved in a referendum, undermining chances for political transition.

Despite Washington and Moscow's joint push for talks, they are still divided over Syria's civil war, which has driven 1.6 million refugees out of the country and escalated regional sectarian tensions. The United States has provided non-lethal aid to rebels, while Russia supplies Damascus with arms.

Russian and U.S. officials will meet in Geneva on Wednesday, along with the U.N. and Arab League envoy for Syria, Lakhdar Brahimi, to assess prospects for the talks, which were originally planned for June but are likely to be pushed back to July.

Russian Deputy Foreign Minister Sergei Ryabkov said on Monday the United States was not doing enough to get the opposition to participate in the talks.

"In our view, the United States is definitely not working hard enough in terms of putting influence on Syrian opposition groups so that (they) will come to the international conference," Russia's RIA quoted Ryabkov as saying.

He said the United States "should not allow the opposition to try to issue ultimatums and impose preconditions. The main such condition ... is the demand for Syrian President Bashar al-Assad's exit."

Russia's Foreign Ministry also echoed the Syrian government account of the fighting in Qusair, saying the army and Hezbollah were carrying out a "counter-terrorist operation against militants who have been terrorising the population".

It said Russia had blocked a U.N. Security Council declaration on Qusair because it amounted to a demand for a unilateral ceasefire by government forces.

The European Union, which last week let lapse a ban on weapons supplies to Syrian rebels, said it was deeply concerned over the fighting in Qusair and urged both sides to ensure safe access for aid.

EU foreign policy chief Catherine Ashton's office said she was appalled at the level of violence in and around the city, adding that there would be "no impunity for the perpetrators".

The fighting in Syria has raised tensions in neighbouring Lebanon, which suffered its own 1975-1990 civil war and whose society reflects the same sectarian divisions as its larger and once-dominant neighbour.

Overnight fighting in the northern city of Tripoli left six people dead and 38 wounded, security and medical sources said.

Most people in the mainly Sunni Muslim city of Tripoli support the Syrian uprising, but a small community of pro-Assad Alawites - the same minority sect as the president - live in a district overlooking the centre of the city.

To the south, in the Mediterranean city of Sidon, a Sunni Muslim cleric survived an assassination attempt when gunmen fired on him as he walked to his mosque for dawn prayers, security sources said. The gunmen missed their target and fled when his guards returned fire.

(Additional reporting by Steve Gutterman in Moscow and Justyna Pawlak; Writing by Dominic Evans; Editing by Will Waterman)

Source: http://news.yahoo.com/red-cross-pushing-access-syrias-besieged-qusair-180857882.html

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'After Earth': How Jaden Smith Became A Man On Set

After gaining 20 pounds and growing four inches during the shoot, the 14-year-old actor told MTV News, 'I was pretty stoked.'
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