Newly designed molecule blocks chlamydia bacteria

Posted by Biomechanism 

Researchers at Duke University Medical Center have discovered a way to block the damaging actions of Chlamydia, the bacteria responsible for the largest number of sexually transmitted infections in the United States.

The team, which included Duke University microbiologists and chemists, designed a molecule that takes away the bacteria’s self-defense mechanisms.

Digital photographs taken with light microscopy. Hela Cells infected with Chlamydia trachomatis (Ct) at 24 hours post infection.

The therapies that could come from this discovery mark a new type of antimicrobial approach. Instead of directly killing the bacteria, they will disarm a central weapon of Chlamydia, and let the body take care of the rest.

Chlamydia infections are symptomless at the beginning, but can become chronic in women and lead to pelvic inflammatory disease and infertility as it infects cells in the uterus and fallopian tubes. It’s generally harmless to men. While these infections can be treated with antibiotics, Chlamydia can be easily reacquired and arise as a greater problem again. There are more than nearly 3 million new cases in the U.S. each year.

A virulence factor that Chlamydia produces, called CPAF, emerged as a promising target to shut down because it plays an important role in protecting the bacteria within hiding places (vacuoles) in human cells. CPAF also prevents the human cell from committing suicide when it senses that it has been invaded by a pathogen (a common self-defense mechanism), giving Chlamydia bacteria an extended chance to multiply and stay hidden.

The study was the cover story in the July 21 print edition of Cell Host and Microbe.

Microbiologists and genetics experts led by Raphael Valdivia, Ph.D., an associate professor in the Duke Department of Molecular Genetics and Microbiology, completed the work that narrowed down the search to an enzyme that Chlamydia produces, a protease called CPAF.

“Chlamydia makes this master protease that takes over the whole cell and prevents it from mounting an effective, pathogen-killing immune response,” Valdivia said. “Chlamydia is unique among pathogens, in that it can co-exist within humans without causing symptoms for a long time. This reflects a careful balance between the host and the pathogen. We think CPAF is central to this balance. Therefore, if we disarm it, we can tilt the equation toward the human host and mount an effective immune response that will not only clear the infection but prevent it from re-emerging.”

The Duke chemists, led by Dewey McCafferty, Ph.D., a professor in the Duke Departments of Chemistry and Biochemistry, designed a molecule that could block the CPAF activity inside of human cells.

“Typically, to design a potent, specific, and cell-permeable inhibitor is a complicated undertaking and inhibitor designs don’t work right away,” McCafferty said. “But in this case, it worked on the first try. Professor Valdivia’s group of microbiologists and my group of chemical biologists worked to establish which qualities we needed to incorporate into a CPAF inhibitor. The results are very exciting, because we have an inhibitor lead molecule that may form the basis for a new class of anti-Chlamydial drugs.”

They found that when CPAF was blocked over time by their designed molecule, the protective home that the bacteria make for themselves within the infected cells degraded, and CPAF no longer could degrade the proteins in the cell that would normally mount an immune response to the infection.

When CPAF is inhibited, the infected human cells effectively “commit suicide,” Valdivia said. “When the infected human cell dies, so does Chlamydia, and this ends the infection.”

Valdivia said that the findings could yield new therapeutic approaches that might turn a natural infection into a vaccination.

“By stopping the cloaking response of the bacteria, we are essentially revealing where they are in the cell and allowing our own immune system to take over and destroy the pathogens,” McCafferty said.

Scripps Research scientists create vaccine against heroin high

Posted by Biomechanism 

reak their heroin addiction.

Researchers at The Scripps Research Institute have developed a highly successful vaccine against a heroin high and have proven its therapeutic potential in animal models.

The new study, published recently online ahead of print by the American Chemical Society’s Journal of Medicinal Chemistry, demonstrates how a novel vaccine produces antibodies (a kind of immune molecule) that stop not only heroin but also other psychoactive compounds metabolized from heroin from reaching the brain to produce euphoric effects.

“Heroin No. 4″ and is made by adding ether and hydrochloric acid to heroin base. A white powder heroin is the result. The heroin is filtered and dried and compressed into bricks with a heroin press. Heroin of this quality has a purity of 80 to 90 percent.

“In my 25 years of making drug-of-abuse vaccines, I haven’t seen such a strong immune response as I have with what we term a dynamic anti-heroin vaccine,” said the study’s principal investigator, Kim D. Janda, the Ely R. Callaway, Jr. Chair in Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research. “It is just extremely effective. The hope is that such a protective vaccine will be an effective therapeutic option for those trying to break their addiction to heroin.”

“We saw a very robust and specific response from this heroin vaccine,” said George F. Koob, chair of the Scripps Research Committee on the Neurobiology of Addictive Disorders and a co-author of the new study. “I think a humanized version could be of real help to those who need and want it.”

A Worldwide Epidemic

While injection drug abuse is a debilitating worldwide epidemic, heroin abuse and addiction are especially destructive, with costs estimated at $22 billion in the United States due to loss of productivity, criminal activity, medical care, and social welfare, the authors say in their study.

Heroin abuse and addiction are also driving forces in the spread of HIV through needle sharing.

Using an approach termed “immunopharmacotherapy,” Janda and his Scripps Research colleagues previously created vaccines that used immune molecules to blunt the effects of other abused drugs such as cocaine, methamphetamine, and nicotine. Human clinical trials are under way for the cocaine and nicotine vaccines.

Attempts by other researchers over the past four decades to create a clinically viable heroin vaccine, however, have fallen short, in part due to the fact that heroin is an elusive target metabolized into multiple substances each producing psychoactive effects.

An Innovative Approach

To overcome this problem, in the new study the Scripps Research team used a “dynamic” approach, targeting not only heroin itself, but also the chemical it quickly degrades into, 6-acetylmorphine (6AM), and morphine.

“Heroin is lipophilic and is rapidly degraded to 6AM,” said G. Neil Stowe, a research associate in Janda’s laboratory who is first author of the new study. “Both readily cross the blood-brain barrier and gain access to the opioid receptors in the brain.”

The researchers linked a heroin-like hapten (a small molecule that elicits an immune response) to a generic carrier protein called keyhole limpet hemocyanin or KLH, and mixed it with Alum, an adjuvant (vaccine additive), to create a vaccine “cocktail.” This mixture slowly degraded in the body, exposing the immune system to different psychoactive metabolites of heroin such as 6AM and morphine.

“Critically, the vaccine produces antibodies to a constantly changing drug target,” said Stowe. “Such an approach has never before been engaged with drug-of-abuse vaccines.”

To compare the results of a non-dynamic approach, the team also prepared a vaccine simply targeting morphine, a substance related to heroin. Both vaccines were then injected into rats and the effects were examined in Koob’s laboratory.

Promising Results

The results showed that the rats rapidly generated robust polyclonal antibodies in response to the dynamic heroin vaccine.

In addition, the study found that addicted rats were less likely to “self-administer” heroin by pressing on a lever after several booster shots of the vaccine. Only three of the seven rats that received the heroin vaccine self-administered heroin. In contrast, all of the control rats, including those given the morphine vaccine, self-administered the drug.

The effect of the heroin vaccine “was very dramatic; as dramatic as we have ever seen in experiments of this kind,” said Koob. “To have an animal vaccinated and not show a response to heroin is pretty amazing.”

The team also found that the heroin vaccine was highly specific, meaning that it only produced an antibody response to heroin and 6AM, and not to the other opioid-related drugs tested, such as oxycodone as well as drugs used for opioid dependence—methadone, naltrexone, and naloxone. “The importance of this,” said Janda, “is that it indicates these vaccines could be used in combination with other heroin rehabilitation therapies.”

The Scripps Research team has recently begun an exciting collaboration with researchers at the Walter Reed Army Institute of Research to see if it is feasible to develop a dual-purpose vaccine against HIV and for the treatment of heroin addiction in a single shot, Janda said.

Team shows how the honey bee tolerates some synthetic pesticides

Posted by Biomechanism 

A new study reveals how enzymes in the honey bee gut detoxify pesticides commonly used to kill mites in the honey bee hive. This is the first study to tease out the precise molecular mechanisms that allow a pollinating insect to tolerate exposure to these potentially deadly compounds.

The findings appear in the Proceedings of the National Academy of Sciences.

Caption: Exposure to naturally occurring defensive compounds in flowers may have allowed honey bees to better tolerate some synthetic pesticides used to kill mites in the hive. Credit: L. Brian Stauffer.

Previous studies have shown that honey bee hives are contaminated with an array of agricultural chemicals, many of which the bees themselves bring back to the hive in the form of contaminated pollen and nectar, said University of Illinois entomology professor and department head May Berenbaum, who led the new research.

“There are agricultural pesticides everywhere,” she said. “They accumulate in the wax of bee hives, so bees in particular are exposed. And their habit of foraging very broadly across a staggering diversity of plant species also tends to expose them to many different types of habitats, which may also have different types of chemical residues.”

Other chemicals are applied directly to the hives, she said. For the past 20 years, beekeepers have used acaricides – chemicals designed to kill mites but not bees – in the hive.

While evidence so far does not support the idea that exposure to synthetic pesticides is a cause or significant contributor to colony collapse disorder, the massive die-off of honey bees first reported in late 2006, “it’s abundantly clear that pesticides aren’t really very good for any insect,” Berenbaum said. “So we figured it was about time somebody knew something about how pollinators process toxins.”

The researchers focused on cytochrome P450s, enzymes that are well-known agents of detoxification “in most air-breathing organisms,” Berenbaum said. Other studies had shown that cytochrome P450s in honey bees play a key role in their tolerance of pyrethroid pesticides, such as tau-fluvalinate, which is used to kill mites in the hive. But no previous study had identified specific cytochrome P450s in bees or in other pollinating insects that contribute to pyrethroid tolerance, Berenbaum said.

In a series of experiments, the team identified three cytochrome P450s in the honey bee midgut that metabolize tau-fluvalinate. They discovered that these enzymes also detoxify coumaphos, a structurally different organophosphate pesticide that also is used to kill mites in bee hives.

“This suggests that these honey bee cytochrome P450s are not particularly specialized,” Berenbaum said. “That raises the possibility that a nontoxic dose of tau-fluvalinate may become toxic if an enzyme that is principally involved in its detoxification is otherwise occupied with a different chemical.”

The evidence also suggests that honey bees were “pre-adapted” to detoxify pyrethroid pesticides, Berenbaum said. Pyrethroids are similar in structure to naturally occurring defensive compounds, called pyrethrins, produced by some flowering plants. Honey bees have likely had a long history of contact with pyrethrins, which are found even in some flowers in the daisy family. It appears that the same enzymes that helped the honey bees detoxify the pyrethrins in nature may also help them tolerate this relatively new pesticide exposure.

The new findings should enhance efforts to develop mite control methods that are even less toxic to bees, Berenbaum said.

________________

New tool helps kid to read

New tool helps kid to read

THE UNIVERSITY OF WAIKATO

The tool also has the potential to assist in teaching a second language. Image: kate_sept2004/iStockphoto A team of Waikato University computer science students have come up with an innovative way to help children learn to read. Software Development Ashley Steel, Luke Bjerring and André Meister have worked with a curriculum co-ordinator in Switzerland and primary teachers in New Zealand to develop software, called BookieMonster, which performs the role of a reading coach. It is intended to provide extra reading support for those who would otherwise miss out due to limited teaching resources. Microsoft Imagine Cup The BookieMonster project reached the national finals of the Microsoft Imagine Cup, a global student technology competition focusing on finding solutions to real-world issues. The solutions are generally related to the UN’s Millennium Goals: hunger relief, poverty, education, disease control, healthcare and the environment. BookieMonster computerises a proven method of learning tuition, dubbed “repeated reading” using computer-generated voices and speech recognition. Learning to Read Children using the software listen to text being read aloud by the computer, following the words as they are progressively highlighted on-screen in time with the voice, similar to karaoke. After hearing a text read to them a few times, they then read it back to the computer via a microphone. The software recognises their speech and provides the same progressive text highlighting that they received while being read to. The students now have a working prototype and are setting up trials in local schools. Ultimately they hope to see their software distributed via existing initiatives in developing nations where literacy in some places is as low as 50 per cent. It also has the potential to assist in teaching a second language, they say.

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Movement of Black Holes Powers Quasars, the Universe's Brightest Lights

Jets of streaming radiation expelled by the central black hole of a massive spiral galaxy light up this composite image of Centaurus A. The jets emanating from Cen A are over a million light-years long. (Credit: ESO/WFI (visible); MPIfR/ESO/APEX/A. Weiss et al. (microwave); NASA/CXC/CfA/R. Kraft et al. (X-ray))

Science Daily  — Whether on their own or orbiting as a pair, black holes don't typically sit still. Not only do they spin, they can also move laterally across their host galaxy. And according to astrophysicists at Brigham Young University, both types of movement power massive jets of energy known as quasars.

These spectacular jets stream out of galaxies that contain discs of debris and gas, the remnants of stars ripped apart by the force from black holes.The study, which appears in the current issue of Proceedings of the National Academy of Sciences, is the first to compute what may fuel some of the brightest persistent lights in the universe.

"The black hole is like a generator spinning around in these magnetic fields," said BYU professor David Neilsen, lead author of the study. "The way the field lines get twisted around and pulled by the spinning black hole creates electromagnetic tension that gets turned into radiation and energy that goes out."

One black hole in the galaxy Centauras A propels radiation in a jet measuring 1 million light-years long.

The spin of black holes has been believed to play a role since the idea was put forward in 1977. The new study confirms this theory while also introducing a totally new component: that a black hole's lateral movement also powers these jets.

"Rotational kinetic energy contributes, but the simple movement like a billiard ball can also contribute to this," said BYU professor Eric Hirschmann, a co-author of the study. "The two processes don't compete with each other, they combine with each other to give you the overall energy that streams away from the black hole."

In other words, the biggest and brightest quasars could come from black holes that both spin fast and traverse their host galaxy at high speeds.

Researchers from six other institutions appear as co-authors on the new study

Breakthrough in Quantum Computing: Researchers Develop System That Resists 'Quantum Bug'

Quantum computing uses quantum bits, or qubits, to encode information. (Credit: © Anterovium / Fotolia)

Science Daily — Scientists have taken the next major step toward quantum computing, which will use quantum mechanics to revolutionize the way information is processed.

Using high magnetic fields, Susumu Takahashi, assistant professor in the USC Dornsife College of Letters, Arts and Sciences, and his colleagues managed to suppress decoherence, which is one of the key stumbling blocks in quantum computing.Quantum computers will capitalize on the mind-bending properties of quantum particles to perform complex calculations that are impossible for today's traditional computers.

"High magnetic fields reduce the level of the noises in the surroundings, so they can constrain the decoherence very efficiently," Takahashi said. Decoherence has been described as a "quantum bug" that destroys fundamental properties that quantum computers would rely on.

This research will appear in the online version of Naturemagazine on June 20.

Quantum computing uses quantum bits, or qubits, to encode information in the form of ones and zeros. Unlike a traditional computer that uses traditional bits, a quantum computer takes advantage of the fact seemingly impossible fact that qubits can exist in multiple states at the same time, which is called "superposition."

While can a bit can represent either a one or a zero, a qubit can represent a one and a zero at the same time due to superposition. This allows for simultaneous processing of calculations in a truly parallel system, skyrocketing computing ability.

Though the concepts underpinning quantum computing are not new, problems such as decoherence have hindered the construction of a fully functioning quantum computer.

Think of decoherence as a form of noise or interference, knocking a quantum particle out of superposition -- robbing it of that special property that makes it so useful. If a quantum computer relies on a quantum particle's ability to be both here and there, then decoherence is the frustrating phenomenon that causes a quantum particle to be either here or there.

The researchers calculated all sources of decoherence in his experiment as a function of temperature, magnetic field, and by nuclear isotopic concentrations, and suggested the optimum condition to operate qubits, reducing decoherence by approximately 1,000 times.

Qubits in his experiment lasted about 500 microseconds at the optimum condition -- ages, relatively speaking.

Decoherence in qubit systems falls into two general categories. One is an intrinsic decoherence caused by constituents in the qubit system, and the other is an extrinsic decoherence caused by imperfections of the system, for example, impurities and defects.

In their study, Takahashi and his colleagues investigated single crystals of molecular magnets. Because of their purity, molecular eliminate the extrinsic decoherence, allowing researchers to calculate intrinsic decoherence precisely.

"For the first time we've been able to predict and control all the environmental decoherence mechanisms in a very complex system -- in this case a large magnetic molecule," said Phil Stamp, UBC professor of physics and astronomy and director of the Pacific Institute of Theoretical Physics.

Using crystalline molecular magnets allowed researchers to build qubits out of multiple quantum particles, rather than a single quantum object -- the way most proto-quantum computers are built at the moment.

"This will obviously increase signals from the qubit drastically, so the detection of the qubit in the molecular magnets is much easier," Takahashi said.

Takahashi conducted his research as a project scientist in the Institute of Terahertz Science and Technology and Department of Physics at the University of California Santa Barbara and analyzed the data while at UCSB and USC. Takahashi has been in the USC Dornsife College since 2010.

Research for the article was performed in collaboration with Phil Stamp and Igor Tupitsyn of the University of British Columbia, Johan van Tol of Florida State University, and David Hendrickson of UC San Diego.

This work was supported by the National Science Foundation, the W. M. Keck Foundation, the Pacific Institute of Theoretical Physics at UBC, by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institute for Advanced Research and the USC startup funds.