terça-feira, 16 de setembro de 2014

For electronics beyond silicon, a new contender emerges

 

Now, using a quantum material called a correlated oxide, Harvard researchers have achieved a reversible change in electrical resistance of eight orders of magnitude, a result the researchers are calling "colossal." In short, they have engineered this material to perform comparably with the best silicon switches.

The finding arose in what may seem an unlikely spot: a laboratory usually devoted to studying fuel cells -- the kind that run on methane or hydrogen -- led by Shriram Ramanathan, Associate Professor of Materials Science at the Harvard School of Engineering and Applied Sciences (SEAS). The researchers' familiarity with thin films and ionic transport enabled them to exploit chemistry, rather than temperature, to achieve the dramatic result.

Because the correlated oxides can function equally well at room temperature or a few hundred degrees above it, it would be easy to integrate them into existing electronic devices and fabrication methods. The discovery, published in Nature Communications, therefore firmly establishes correlated oxides as promising semiconductors for future three-dimensional integrated circuits as well as for adaptive, tunable photonic devices.

Challenging silicon

Although electronics manufacturers continue to pack greater speed and functionality into smaller packages, the performance of silicon-based components will soon hit a wall.

"Traditional silicon transistors have fundamental scaling limitations," says Ramanathan. "If you shrink them beyond a certain minimum feature size, they don't quite behave as they should."

Yet silicon transistors are hard to beat, with an on/off ratio of at least 104 required for practical use. "It's a pretty high bar to cross," Ramanathan explains, adding that until now, experiments using correlated oxides have produced changes of only about a factor of 10, or 100 at most, near room temperature. But Ramanathan and his team have crafted a new transistor, made primarily of an oxide called samarium nickelate, that in practical operation achieves an on/off ratio of greater than 105 -- that is, comparable to state-of-the-art silicon transistors.

In future work the researchers will investigate the device's switching dynamics and power dissipation; meanwhile, this advance represents an important proof of concept.

"Our orbital transistor could really push the frontiers of this field and say, you know what? This is a material that can challenge silicon," Ramanathan says.

Solid-state chemical doping

Materials scientists have been studying the family of correlated oxides for years, but the field is still in its infancy, with most research aimed at establishing the materials' basic physical properties.

"We have just discovered how to dope these materials, which is a foundational step in the use of any semiconductor," says Ramanathan.

Doping is the process of introducing different atoms into the crystal structure of a material, and it affects how easily electrons can move through it -- that is, to what extent it resists or conducts electricity. Doping typically effects this change by increasing the number of available electrons, but this study was different. The Harvard team manipulated the band gap, the energy barrier to electron flow.

"By a certain choice of dopants -- in this case, hydrogen or lithium -- we can widen or narrow the band gap in this material, deterministically moving electrons in and out of their orbitals," Ramanathan says. That's a fundamentally different approach than is used in other semiconductors. The traditional method changes the energy level to meet the target; the new method moves the target itself.

In this orbital transistor, protons and electrons move in or out of the samarium nickelate when an electric field is applied, regardless of temperature, so the device can be operated in the same conditions as conventional electronics. It is solid-state, meaning it involves no liquids, gases, or moving mechanical parts. And, in the absence of power, the material remembers its present state -- an important feature for energy efficiency.

"That's the beauty of this work," says Ramanathan. "It's an exotic effect, but in principle it's highly compatible with traditional electronic devices."

Quantum materials

Unlike silicon, samarium nickelate and other correlated oxides are quantum materials, meaning that quantum-mechanical interactions have a dominant influence over the material properties -- and not just at small scales.

"If you have two electrons in adjacent orbitals, and the orbitals are not completely filled, in a traditional material the electrons can move from one orbital to another. But in the correlated oxides, the electrons repulse each other so much that they cannot move," Ramanathan explains. "The occupancy of the orbitals and the ability of electrons to move in the crystal are very closely tied together -- or 'correlated.' Fundamentally, that's what dictates whether the material behaves as an insulator or a metal."

Ramanathan and others at SEAS have successfully manipulated the metal-insulator transition in vanadium oxide, too. In 2012, they demonstrated a tunable device that can absorb 99.75% of infrared light, appearing black to infrared cameras.

Similarly, samarium nickelate is likely to catch the attention of applied physicists developing photonic and optoelectronic devices.

"Opening and closing the band gap means you can now manipulate the ways in which electromagnetic radiation interacts with your material," says Jian Shi, lead author of the paper in Nature Communications. He completed the research as a postdoctoral fellow in Ramanathan's lab at Harvard SEAS and joined the faculty of Rensselaer Polytechnic Institute this fall. "Just by applying an electric field, you're dynamically controlling how light interacts with this material."

Further ahead, researchers at the Center for Integrated Quantum Materials, established at Harvard in 2013 through a grant from the National Science Foundation, aim to develop an entirely new class of quantum electronic devices and systems that will transform signal processing and computation.

Ramanathan compares the current state of quantum materials research to the 1950s, when transistors were newly invented and physicists were still making sense of them. "We are basically in that era for these new quantum materials," he says. "This is an exciting time to think about establishing the basic, fundamental properties. In the coming decade or so, this could really mature into a very exciting device platform."

You Zhou, a graduate student at Harvard SEAS, was co-lead author of the paper in Nature Communications. The research was supported by grants from the National Science Foundation (NSF) (CCF-0926148) and the National Academy of Sciences, as well as an NSF Faculty Early Career Development (CAREER) Award to Prof. Ramanathan (DMR-0952794).

Snap 2014-09-12 at 18.10.27

Scientists twist radio beams to send data: Transmissions reach speeds of 32 gigibits per second

 


Graphic showing the intensity of the radio beams after twisting.

Building on previous research that twisted light to send data at unheard-of speeds, scientists at USC have developed a similar technique with radiowaves, reaching high speeds without some of the hassles that can go with optical systems.

The researchers, led by electrical engineering professor Alan Willner of the USC Viterbi School of Engineering, reached data transmission rates of 32 gigabits per second across 2.5 meters of free space in a basement lab at USC.

For reference, 32 gigabits per second is fast enough to transmit more than 10 hour-and-a-half-long HD movies in one second and is 30 times faster than LTE wireless.

"Not only is this a way to transmit multiple spatially collocated radio data streams through a single aperture, it is also one of the fastest data transmission via radio waves that has been demonstrated," Willner said.

Faster data transmission rates have been achieved -- Willner himself led a team two years ago that twisted light beams to transmit data at a blistering 2.56 terabits per second -- but methods to do so rely on light to carry the data.

"The advantage of radio is that it uses wider, more robust beams. Wider beams are better able to cope with obstacles between the transmitter and the receiver, and radio is not as affected by atmospheric turbulence as optics," Willner said.

Willner is the corresponding author of an article about the research that will be published in Nature Communications on Sept. 16. The study's co-lead authors Yan Yan and Guodong Xie are both graduate students at USC Viterbi, and other contributors came from USC, the University of Glasgow, and Tel Aviv University.

To achieve the high transmission rates, the team took a page from Willner's previous work and twisted radio beams together. They passed each beam -- which carried its own independent stream of data -- through a "spiral phase plate" that twisted each radio beam into a unique and orthogonal DNA-like helical shape. A receiver at the other end of the room then untwisted and recovered the different data streams.

"This technology could have very important applications in ultra-high-speed links for the wireless 'backhaul' that connects base stations of next-generation cellular systems," said Andy Molisch of USC Viterbi. Molisch, whose research focuses on wireless systems, co-designed and co-supervised the study with Willner.

Future research will focus on attempting to extend the transmission's range and capabilities.

The work was supported by Intel Labs University Research Office and the DARPA InPho (Information in a Photon) Program.


Story Source:

The above story is based on materials provided by University of Southern California. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yan Yan, Guodong Xie, Martin P. J. Lavery, Hao Huang, Nisar Ahmed, Changjing Bao, Yongxiong Ren, Yinwen Cao, Long Li, Zhe Zhao, Andreas F. Molisch, Moshe Tur, Miles J. Padgett, Alan E. Willner. High-capacity millimetre-wave communications with orbital angular momentum multiplexing. Nature Communications, 2014; 5: 4876 DOI: 10.1038/ncomms5876

First water-based nuclear battery can be used to generate electrical energy

 


Artist's concept (stock illustration).

From cell phones to cars and flashlights, batteries play an important role in everyday life. Scientists and technology companies constantly are seeking ways to improve battery life and efficiency. Now, for the first time using a water-based solution, researchers at the University of Missouri have created a long-lasting and more efficient nuclear battery that could be used for many applications such as a reliable energy source in automobiles and also in complicated applications such as space flight.

"Betavoltaics, a battery technology that generates power from radiation, has been studied as an energy source since the 1950s," said Jae W. Kwon, an associate professor of electrical and computer engineering and nuclear engineering in the College of Engineering at MU. "Controlled nuclear technologies are not inherently dangerous. We already have many commercial uses of nuclear technologies in our lives including fire detectors in bedrooms and emergency exit signs in buildings."

The battery uses a radioactive isotope called strontium-90 that boosts electrochemcial energy in a water-based solution. A nanostructured titanium dioxide electrode (the common element found in sunscreens and UV blockers) with a platinum coating collects and effectively converts energy into electrons.

"Water acts as a buffer and surface plasmons created in the device turned out to be very useful in increasing its efficiency," Kwon said. "The ionic solution is not easily frozen at very low temperatures and could work in a wide variety of applications including car batteries and, if packaged properly, perhaps spacecraft."


Story Source:

The above story is based on materials provided by University of Missouri-Columbia. Note: Materials may be edited for content and length.


Journal Reference:

  1. Baek Hyun Kim, Jae W. Kwon. Plasmon-assisted radiolytic energy conversion in aqueous solutions. Scientific Reports, 2014; 4 DOI: 10.1038/srep05249

Medications for Obesity: Naltrexone/Bupropion

 

Pharmacist-in-Drugstore-Brad-Wilson-Getty.jpg - Brad Wilson/Getty Images

Brad Wilson/Getty Images

Updated September 12, 2014.
Written or reviewed by a board-certified physician. See About.com's
Medical Review Board.

On September 10, 2014, the U.S. Food and Drug Administration (FDA) approved a new medication for the treatment of obesity. The medication, known by the brand name Contrave® and marketed by Takeda Pharmaceuticals, is a combination of two other drugs, naltrexone hydrochloride and bupropion hydrochloride.

For Whom Is Naltrexone/Bupropion Intended?

According to the FDA news release of September 10, 2014, this new drug is approved for use in adult patients with a body mass index (BMI) of 30 or greater, or in adult patients with a BMI of 27 or greater who have at least one weight-related condition (such as high blood pressure, high cholesterol, obstructive sleep apnea, or Type 2 diabetes).

As noted by the FDA, this medication is meant to be a “treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity.” It is not meant to replace lifestyle changes that include a healthy diet and exercise.

What Is Naltrexone/Bupropion?

What kind of drug is naltrexone/bupropion? It is a fixed-dose combination of two medications: naltrexone, which is an opioid receptor antagonist and has been used for many years primarily for the management of alcohol and/or opioid dependence; and bupropion, which has been and continues to be used for the treatment of depression as well as for smoking cessation. This fixed-dose combination is in an extended-release formulation as Contrave®.

How Effective Is It?

Multiple clinical trials were conducted to evaluate the effectiveness of the naltrexone/bupropion fixed-dose combination now known as Contrave®. These trials included approximately 4,500 obese and overweight individuals over the course of one year. In one clinical trial, patients had an average weight loss of 4.1% more when taking Contrave® (when compared to placebo; all patients received lifestyle modification that included a reduced-calorie diet and regular physical activity). This trial also found that 42% of the patients who were taking Contrave® lost at least 5% of their body weight, compared to 17% of patients who did the same while taking placebo.

In another clinical trial that looked at patients who were obese or overweight and also had Type 2 diabetes, those who took Contrave® were found to have an average weight loss of 2% more than placebo at one year. This trial also found that 36% of the patients who were treated with Contrave® lost at least 5% of their body weight, compared to 18% of patients treated with placebo.

It is worth noting that the percentage of patients in these trials who lost weight on placebo was still substantial—meaning that dietary and physical activity modifications, known as “lifestyle changes,” do make a difference.

Further, the FDA states that Contrave® should be discontinued if a patient has not lost at least 5% of baseline body weight after 12 weeks on the drug.

Black Box Warning

The FDA has given Contrave® a black box warning because it contains bupropion. This warning notes that there can be an increased risk of suicidal thoughts and behaviors associated with antidepressant drugs, including bupropion. The warning also notes that “serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation.”

Possible Side Effects

Common side effects reported during the clinical trials with Contrave® included nausea, vomiting, constipation, diarrhea, headache, dizziness, insomnia and dry mouth.

The FDA’s news release noted that Contrave® can cause seizures and should therefore not be used in patients with seizure disorders. Another serious potential side effect is the possibility of an increase in blood pressure and heart rate on Contrave®; for this reason, the medication is contraindicated in patients with uncontrolled high blood pressure. Blood pressure and pulse should be monitored while a patient is taking Contrave®. In addition, other products containing bupropion should not be taken along with Contrave®.

Because of its naltrexone component, Contrave® is also contraindicated in patients who are taking opioids or who are being treated for opioid dependence. Patients who are abruptly discontinuing benzodiazepines, alcohol, barbiturates, or antiepileptic drugs should also not take Contrave®.

Contrave® is also contraindicated in women who are pregnant or trying to become pregnant.

Snap 2014-09-16 at 15.40.12

References:

U.S. Food and Drug Administration. FDA approves weight-management drug Contrave. Accessed online at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm on September 11, 2014.

Vitamin E intake critical during 'the first 1,000 days'

 


Sunflower seeds and oil are a particularly good dietary source of vitamin E.

Amid conflicting reports about the need for vitamin E and how much is enough, a new analysis published today suggests that adequate levels of this essential micronutrient are especially critical for the very young, the elderly, and women who are or may become pregnant.

A lifelong proper intake of vitamin E is also important, researchers said, but often complicated by the fact that this nutrient is one of the most difficult to obtain through diet alone. It has been estimated that only a tiny fraction of Americans consume enough dietary vitamin E to meet the estimated average requirement.

Meanwhile, some critics have raised unnecessary alarms about excessive vitamin E intake while in fact the diet of most people is insufficient, said Maret Traber, a professor in the College of Public Health and Human Sciences at Oregon State University, principal investigator with the Linus Pauling Institute and national expert on vitamin E.

"Many people believe that vitamin E deficiency never happens," Traber said. "That isn't true. It happens with an alarming frequency both in the United States and around the world. But some of the results of inadequate intake are less obvious, such as its impact on things like nervous system and brain development, or general resistance to infection."

Some of the best dietary sources of vitamin E -- nuts, seeds, spinach, wheat germ and sunflower oil -- don't generally make the highlight list of an average American diet. One study found that people who are highly motivated to eat a proper diet consume almost enough vitamin E, but broader surveys show that 90 percent of men and 96 percent of women don't consume the amount currently recommended, 15 milligrams per day for adults.

In a review of multiple studies, published in Advances in Nutrition, Traber outlined some of the recent findings about vitamin E. Among the most important are the significance of vitamin E during fetal development and in the first years of life; the correlation between adequate intake and dementia later in life; and the difficulty of evaluating vitamin E adequacy through measurement of blood levels alone.

Findings include:

  • Inadequate vitamin E is associated with increased infection, anemia, stunting of growth and poor outcomes during pregnancy for both the infant and mother.
  • Overt deficiency, especially in children, can cause neurological disorders, muscle deterioration, and even cardiomyopathy.
  • Studies with experimental animals indicate that vitamin E is critically important to the early development of the nervous system in embryos, in part because it protects the function of omega-3 fatty acids, especially DHA, which is important for brain health. The most sensitive organs include the head, eye and brain.
  • One study showed that higher vitamin E concentrations at birth were associated with improved cognitive function in two-year-old children.
  • Findings about diseases that are increasing in the developed world, such as non-alcoholic fatty liver disease and diabetes, suggest that obesity does not necessarily reflect adequate micronutrient intake.
  • Measures of circulating vitamin E levels in the blood often rise with age as lipid levels also increase, but do not prove an adequate delivery of vitamin E to tissues and organs.
  • Vitamin E supplements do not seem to prevent Alzheimer's disease occurrence, but have shown benefit in slowing its progression.
  • A report in elderly humans showed that a lifelong dietary pattern that resulted in higher levels of vitamins B,C, D and E were associated with a larger brain size and higher cognitive function.
  • Vitamin E protects critical fatty acids such as DHA throughout life, and one study showed that people in the top quartile of DHA concentrations had a 47 percent reduction in the risk of developing all-cause dementia.

"It's important all of your life, but the most compelling evidence about vitamin E is about a 1000-day window that begins at conception," Traber said. "Vitamin E is critical to neurologic and brain development that can only happen during that period. It's not something you can make up for later."

Traber said she recommends a supplement for all people with at least the estimated average requirement of vitamin E, but that it's particularly important for all children through about age two; for women who are pregnant, nursing or may become pregnant; and for the elderly.

Snap 2014-09-12 at 18.10.27

The biomethane market needs clear frame conditions for further growth, experts urge

 

September 11, 2014

Helmholtz Centre For Environmental Research - UFZ

Biomethane as a substitute for the fossil energy carrier natural gas offers a variety of options and applications for a sustainable energy supply. Nevertheless, a consequent market penetration is still pending because of a lack of standardized and transnational frame conditions. Scientists have now summarized how the biomethane market developed in the IEA (International Energy Agency) member states and which factors are necessary for further growing.


According to the report around 280 biogas upgrading plants in different countries with a production capacity of around 100,000 Nm³/h of biomethane are already in operation.

Biomethane as a substitute for the fossil energy carrier natural gas offers a variety of options and applications for a sustainable energy supply. Nevertheless, a consequent market penetration is still pending because of a lack of standardized and transnational frame conditions. Scientists of the Helmholtz Centre for Environmental Research (UFZ) and the German Biomass Research Centre (DBFZ) and other Members of the IEA Task 37 (Energy from Biogas) and the Task 40 (Sustainable Bioenergy Trade) just summarized how the biomethane market developed in the IEA (International Energy Agency) member states and which factors are necessary for further growing.

In most of the IEA member states the fossil energy carrier natural gas still plays an important and increasing role in the national energy supply. This is due to a well-developed infrastructure of gas networks, gas stations, and various modes of transportation by e.g. vessels. However, mainly due to the significantly lower greenhouse gas emissions, the energy security and the protection of finite resources, several countries initiated support programs for biomethane (methane from biomass). This is due to a well-developed infrastructure of gas networks, gas stations, and various modes of transport by tanker trucks or ships. Still have, mainly due to the significantly lower greenhouse gas emissions, energy security and the protection of finite resources already several countries initiated the gradual transition from fossil natural gas resource on renewable energy sources biomethane (methane from biomass).

The newly published study "Biomethane -- status and factors affecting market development and trade," gives an up-to-date and comprehensive overview of the production technologies of biomethane (upgrading of biogas and Bio-SNG), the grid injection and the use in various IEA member states. Moreover, besides the description of the framework, the options and needs for the development of larger biomethane supply strategies are also illustrated. The authors finalize the study with concrete recommendations how the remaining barriers can be removed and the market development can be promoted step by step.

Greenhouse gas reduction potential of more than 80 percent

Due to the benefits (i) independence from natural gas imports, (ii) the strengthening of rural areas, (iii) and its promising application areas (fuel, cogeneration, heat), biomethane is considered as a promising alternative to fossil fuels. As far as the final composition of the biomethane is consistent with the various natural gas quality levels in the market it can serve as a substitute for natural gas. In addition, biomethane can also be transported and stored as natural gas. Last but not least, greenhouse gas emissions, depending on the plant design and operation as well as the accounting method, can be reduced in comparison to fossil fuels by more than 80 percent. The study already stated a transnational increasing interest in biomethane. According to the report around 280 biogas upgrading plants in different countries with a production capacity of around 100,000 Nm³/h of biomethane are already in operation.

Transnational frame conditions are required

A transnational biomethane market is, according to the study, still at the beginning. However, various strategies, investment programs, funding and utilization concepts have been adopted in the investigated countries. Due to the complex supply chain there are various ecological, economic, administrative and political barriers for a market implementation of biomethane. For a sustainable and international implementation appropriate technical standards, sustainability requirements and political as well as financial support (compensation / promotion / preference), in order to significantly advance the development of an international biomethane trade, are necessary.

Further information: http://www.bioenergytrade.org/downloads/t40-t37-biomethane-2014.pdf


Story Source:

The above story is based on materials provided by Helmholtz Centre For Environmental Research - UFZ. Note: Materials may be edited for content and length.

Low-cost water purifiers use chip packets to kill off dangerous bacteria

 

The water runs through a piece of piping, which rests in a trench-shaped structure coated ...

The water runs through a piece of piping, which rests in a trench-shaped structure coated in reflective metal

Image Gallery (3 images)

Armed with plywood, a glass tube and some empty chip packets, mechanical engineering students from the University of Adelaide have developed a low-cost water purification system capable of killing off harmful bacteria. The solution is designed for remote communities in Papua New Guinea (PNG), an area where water is particularly susceptible to pathogen infestation.

The water treatment system was developed in collaboration with ChildFund Australia, an organization dedicated to promoting children's rights across the globe. One of the team's main design focuses was to provide a solution that could easily be adapted by local communities in PNG. As such, it was critical that the materials were both cheap, light and accessible.

"Our priority was to develop a system with, and not just for, the end-users," says Dr Cristian Birzer, lecturer at the School of Mechanical Engineering and supervisor of the project. "We wanted something where we could provide design guidelines and let the local communities build and install their own systems using readily available materials that could be easily maintained and replaced."

As a starting point, the students built a system using high quality materials. The water runs through a piece of piping, which rests in a trench-shaped structure coated in reflective metal. This material directs the sunlight onto the water, harnessing its UVA radiation to kill off pathogens. They then replicated this model with the plywood, glass tube and high-density polyethylene plastic sheeting coated in the chip packet wrapping, shaped to capture the maximum amount of sunlight and direct it onto the water running through the glass tube.

The students found that the rudimentary version worked just as well as the high-quality one, and was a very cost-effective solution at AU$67 (US$60). In testing, the system was able to reduce high amounts of E-coli to undetectable levels in under 30 minutes.

"The system can successfully treat close to 40 liters (10.5 gal) in four hours and the beauty is that it's designed to be modular, so more modules can be added for greater quantities of water," says Dr Birzer.

The University of Adelaide students Michael Watchman, Harrison Evans, Mark Padovan and Anthony Liew took out the National Student Environmental Engineering and Sustainability Award from Engineers Australia's Sustainable Engineering Society for the project.

Snap 2014-09-16 at 09.46.44

Their research is set to be published in the journal Procedia Engineering.

Source: University of Adelaide

Combining Epilepsy Drug, Morphine Can Result in Less Pain, Lower Opioid Doses

 


Adding a common epilepsy drug to a morphine regimen can result in better pain control with fewer side effects. Moreover, the combination can reduce the dosage of the opioid needed to be effective, according to a team of pain researchers at Indiana University.

The result could bring significant relief to many patients with neuropathic pain, a difficult-to-treat condition often felt in the arms and legs and associated with nerve tissue damage.

"There is a huge unmet need for better treatments for neuropathic pain," said Fletcher A. White, Ph.D., the Vergil K. Stoelting Professor of Anesthesia at the Indiana University School of Medicine.

In laboratory tests using rodents, White and his colleagues found that while morphine lost its pain-relieving effectiveness three weeks after nerve injury, a combination therapy of morphine and carbamazepine -- used to prevent epileptic seizures -- could effectively reverse this loss of drug action. Their findings were reported in the journal PLOS ONE.

Although morphine and related opioid drugs are effective in treating pain, they can result in dependence and produce side effects including respiratory depression, nausea, constipation and other problems. In addition, such drugs can, paradoxically, actually cause pain, a condition called opioid-induced hyperalgesia.

"People immediately think, 'Oh, it's tolerance, the patient needs more of the drug for pain control,'" Dr. White said.

In fact, research indicates that the pain of hyperalgesia occurs because the morphine latches on not only to cellular targets that reduce pain sensation but to other "non-opioid" targets that result in activation of pain-sensing neurons. Dr. White and his colleagues had previously identified a key cellular factor -- known to be a specific voltage-gated sodium ion channel -- involved in that non-opioid process of pain nerve stimulation. Meanwhile another IU School of Medicine researcher, Theodore Cummins, Ph.D., professor of pharmacology and toxicology, had previously determined that carbamazepine alone has the opposite effect on the same ion channel.

Combining the two drugs could prevent the escalating doses of opioids that are sometimes prescribed to provide pain relief in the clinic.

"We know that opioids have benefits," Dr. White said. "If we can diminish the off-target effects, that's good. If we can diminish the opioid dosages required for pain relief, then you've really got something."

Because both drugs are approved for use by the Food and Drug Administration, physicians have tested the combination with patients, resulting in anecdotal reports of significantly improved pain management, Dr. White said. More formally, Dr. White and physician-researchers have begun testing the combination of morphine and a close relative of carbamazepine with patients in a small clinical trial at the Indiana University Melvin and Bren Simon Cancer Center.

In addition to Dr. White, researchers contributing to the study were Michael R. Due, Xiao-Fang Yang, Yohance M. Allette, Aaron L. Randolph, Matthew S. Ripsch, Sarah M. Wilson and Erik T. Dustrude of the IU School of Medicine; and Rajesh Khanna of the College of Medicine, University of Arizona.

The research was funded by National Institutes of Health grants NIDDK DK100905 and NIDA DA026040 and the Indiana Spinal Cord and Brain Injury Research Fund.


Story Source:

The above story is based on materials provided by Indiana University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Michael R. Due, Xiao-Fang Yang, Yohance M. Allette, Aaron L. Randolph, Matthew S. Ripsch, Sarah M. Wilson, Erik T. Dustrude, Rajesh Khanna, Fletcher A. White. Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain. PLoS ONE, 2014; 9 (9): e107399 DOI: 10.1371/journal.pone.0107399

Drugs and Alcohol

 

People have been using substances to lift their spirits for millennia. Techniques for fermenting beer and related tipples are known from Egypt and Sumeria 4000 years ago, and they soon spread across the inhabited world. Coca leaves (the source of cocaine), tobacco, and caffeine were also popular with ancient cultures.

Humans may even have an evolutionary pre-disposition to seek out narcotics, even though they can be addictive and damaging. Some people may have genes which make them more genetically prone to drug addiction than others. Even some animals - jaguars, lemurs and bees, for example - have a habit of getting high.

There is an enormous amount of research on drug taking, examining both legal highs, such as alcohol, nicotine and caffeine, and illegal stimulants, such as marijuana, LSD, cocaine, ecstasy, amphetamines, heroin and magic mushrooms and the so-called date-rape drugs rohypnol and GHB.

Alcohol - Some experts believe that the world's first impromptu breweries might have been created when grain stores became drenched with rain and warmed in the sun. Ever since, humans have discovered that alcohol reduces their inhibitions, impairs their judgement, affects sexual desire and performance, creates beer bellies and leads to hangovers (and dubious cures).

Binge drinking is an ever-increasing health concern, and when not consumed in moderation, alcohol can lead to liver problems, brain damage and infertility. Drinking whilst pregnant can also damage the unborn child. It is not all bad news though: studies show that some types of booze, such as red wine, are rich in antioxidant polyphenols which can help prevent heart disease and cancer.

Marijuana, once the preserve of hippies, is now regularly smoked by millions of people in the US and UK. Around 14.6 million Americans have used marijuana in the last 30 days. Though still controversial, support for controlled legalisation of this most common illegal drug is growing.

That support is bolstered by research showing that cannabis (and psychoactive extracts such as THC or cannabinoids) can provide relief for sufferers of multiple sclerosis, Alzheimer's disease and epilepsy. Cannabis can also help to improve appetite and decrease weight loss in AIDS victims and may be able to slow the growth of cancerous tumours.

However, detractors argue that the long-term effects of smoking dope on the brain are unclear, that it decreases fertility, damages the unborn foetus, can contribute to cot death in babies born to dope-smoking parents, and may lead to memory loss, schizophrenia, depression and other illnesses.

Ecstasy, or MDMA, was allegedly first prescribed as an anti-depressant. It was also used by American marriage counsellors and psychotherapists in the 1970s. The drug made patients feel less anxious and more open, accepting and empathic. But notoriety for the drug in the UK did not come until it was popularised by the rave dance scene in fields and warehouses in the late 1980s. Use of the drug is now common in main stream clubs and 2 million or more British youngsters pop the tablets at weekends. Clubbers enjoy the feelings of emotional closeness, rushes of energy, increased stamina heightened sense of touch and other effects.

Critics say that regular ecstasy use is a recipe for causing memory loss and lasting damage to the brain's serotonin-producing neurons. Users can die from fatal overheating or a dangerous build-up of water on the brain. Ecstasy causes other problems such as stifling sex drive and damaging babies in the womb.

Tablets contaminated with other compounds are part of the problem and many tests have been developed to check for purity. Controversial research found evidence of a link between ecstasy and Parkinson's disease in 2002, though the finding was later retracted. Other animal studies conversely hinted that ecstasy might actually help treat the symptoms of Parkinson's disease. Some experts point to the fact that despite the drug's massive popularity, ecstasy deaths remain extremely rare: downhill skiing kills more people. Controversial medical trials are testing the use of MDMA to treat post-traumatic stress disorder in victims of rape and violent crime.

Cocaine comes from the coca plant, the leaves of which have been used by Native South Americans for 3000 years as a mild stimulant. Cocaine itself was first developed as a local anaesthetic, but has been a popular street drug since the 1970s. Today it is used by millions of people in the US alone and up to 150,000 end up in emergency rooms with heart attacks or other side effects. It acts on the brain's dopamine system, and is thought to mimic the thrill of desire and anticipation.

Cocaine is highly addictive - many users become dependent after a year or two, and some research suggests that just a single dose could get you hooked. Use of the drug is linked to high blood pressure, deadly heart conditions and violent behaviour. Therapies to help addicts conquer their dependence include vaccines and related methods, which use antibodies to bind cocaine and stop it reaching its target in the brain. Other drugs can block cocaine cravings.

It's time to criminalise serious scientific misconduct

 

Why should research misconduct be illegal?
After 30 years of observing how science deals with the problem, I have sadly come to the conclusion that it should be a crime, for three main reasons. First, in a lot of cases, people have been given substantial grants to do honest research, so it really is no different from financial fraud or theft. Second, we have a whole criminal justice system that is in the business of gathering and weighing evidence – which universities and other employers of researchers are not very good at. And finally, science itself has failed to deal adequately with research misconduct.

How can we recognise honest mistakes?
It's quite difficult. Clearly not every minor misconduct should be regarded as a crime. And as with all laws, it will take time to establish what merits prosecution and what can be dealt with by a reprimand. But we know peer review doesn't detect all misconduct. If research seems wrong or impossible, we start with the assumption that it's just an honest mistake and then look into it. You can sometimes detect fraud statistically, because if you invent data you tend to come up with a recurrent pattern. But in most cases, it is detected because somebody blows a whistle.

Are there cases in which you think researchers should have been prosecuted?
There are cases where someone demonstrated intent, not simply made a horrible mistake. For example, I was involved in the case of a researcher named Malcolm Pearce, who published two papers in the British Journal of Obstetrics and Gynaecology. One was a
case report of successfully re-implanting an ectopic pregnancy into a patient's womb and another was a randomised trial about treating recurrent miscarriage. It turned out the case study patient did not exist, and there was also no record that he had actually conducted this randomised trial. Those aren't honest errors. The facts speak for themselves.

Does scientific misconduct often cause real social harm?
To begin with, there is the loss of confidence in science. But another example of clear, obvious harm is the infamous MMR-vaccine paper by Andrew Wakefield that was published in The Lancet. It suggested that the vaccine was a cause of autism, and that idea absolutely took off, causing dramatic drops in childhood vaccinations. This in turn caused outbreaks of diseases such as measles. Eventually, when claims in the paper were proven to be false, The Lancet
retracted it.

These types of things often ruin researchers' careers. Is that punishment enough?
There are many examples in which researchers have simply carried on with their careers. I believe scientists should be held to a higher standard. Those who commit research misconduct cannot be trusted. It's too easy to be tempted into ignoring or destroying data that undermines your work. It may seem an inhuman way to be, but a true scientist is delighted when his or her favourite hypothesis is destroyed by good data.

The evolution of human intelligence

 

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The nature and origins of hominid intelligence is a much-studied and much-debated topic, of natural interest to humans as the most successful and intelligent hominid species.

There is no universally accepted definition of intelligence, one definition is "the ability to reason, plan, solve problems, think abstractly, comprehend ideas and language, and learn." The evolution of hominid intelligence can be traced over its course for the past 10 million years, and attributed to specific environmental challenges.

It is a misunderstanding of evolutionary theory, however, to see this as a necessary process, and an even greater misunderstanding to see it as one directed to a particular outcome.

There are primate species which have not evolved any greater degree of intelligence than they had 10 million years ago: this is because their particular environment has not demanded this particular adaptation of them.

Intelligence as an adaptation to the challenge of natural selection is no better or worse than any other adaptation, such as the speed of the cheetah or the venomous bite of the cobra.

It is, however, the only adaptation which has allowed a species to establish complete domination over the rest of the natural world.

Whether our species has yet acquired sufficient intelligence to manage this responsibility is a matter for debate.

Note: This article excerpts material from the Wikipedia article "The evolution of human intelligence", which is released under the GNU Free Documentation License.

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Snap 2014-09-12 at 18.10.27

Evolutionary tools improve prospects for sustainable development

 


The pink bollworm, a global pest of cotton, has evolved resistance to genetically modified cotton in India, but not in Arizona where farmers have planted refuges of conventional cotton to reduce selection for resistance.

Solving societal challenges in food security, emerging diseases and biodiversity loss will require evolutionary thinking in order to be effective in the long run. Inattention to this will only lead to greater challenges such as short-lived medicines and agricultural treatments, problems that may ultimately hinder sustainable development, argues a new study published online today in Science Express, led by University of California, Davis and the Center for Macroecology, Evolution and Climate at the University of Copenhagen.

For the first time, scientists have reviewed progress in addressing a broad set of challenges in agriculture, medicine and environmental management using evolutionary approaches, approaches that consider species' evolutionary histories and the likelihood of rapid evolutionary adaptation to human activities.

The study finds an urgent need for better implementation of these approaches, for example in managing the use of antibiotics and pesticides in order to reduce the escalating problem of resistance evolution. Furthermore, current efforts are found insufficient to reduce the accumulating costs from chronic disease and biodiversity loss, two challenges ultimately caused by exposure to food and environments to which people and threatened wildlife are poorly adapted.

The study also assessed the potential for less commonly implemented strategies including gene therapies to treat human disease, the breeding of "climate change proof" crop varieties, such as flood tolerant rice, and translocating exotic strains for ecological restoration and forestry that will be better adapted to near-future conditions.

"Applying evolutionary biology has tremendous potential, because it takes into account how unwanted pests or pathogens may adapt rapidly to our interventions and how highly valued species including humans on the other hand are often very slow to adapt to changing environments through evolution. Not considering such aspects may result in outcomes opposite of those desired, making the pests more resistant to our actions, humans more exposed to diseases and vulnerable species less able to cope with new conditions," says biologist Peter Søgaard Jørgensen, one of the lead-authors and PhD from the Center for Macroecology, Evolution and Climate at the University of Copenhagen.

"To succeed in avoiding such unwanted outcomes however, we need to learn from successes and progress in all fields using evolutionary biology as a tool. Currently there is no such coordination, says Scott P. Carroll, lead-author and biologist at the University of California Davis and Director of the Institute for Contemporary Evolution. He continues:

"A particular worry is that the unaddressed need for management of evolution that spans multiple sectors will lead to the spread of new infectious diseases and antimicrobial resistance genes between natural, human health and agricultural systems. It is clear that we need to strengthen evolutionary biology linkages across nature conservation, food production and human health and develop a shared strategy."

Many evolutionary solutions are already at hand

Whereas we might have to wait for new solutions from human gene therapy, genetic engineering of crops and development of new medicines to replace old ones, many innovative solutions based on applying evolutionary biology already exist.

For example, farmers in the United States and Australia have used planting of pest-friendly refuges to delay evolution of insect resistance to genetically engineered corn and cotton. These genetically modified crops kill certain pests, but without refuges the pests quickly adapt. Providing refuges of conventional plants has been especially effective for suppressing resistance in the pink bollworm, an invasive pest of cotton.

However, Peter Jørgensen also cautions: "In many cases, decision makers must pay more attention to assuring that long-term benefits of applying these solutions do not come at a short-term cost for some individuals, for example from yield loss due to localised effects of pests in a particular year. By encouraging cost sharing, local communities and governments play a crucial role in ensuring that everybody gains from the benefits of using evolutionary biology to realise the long-term goals of sustainable development such as increasing food security, protecting biodiversity and improving human health and well-being."

The article is published today in Science Express. Peter Jørgensen will also present the research at the upcoming Sustainability Science Congress in Copenhagen from October 22nd to 24th.

Snap 2014-09-12 at 18.10.27


Story Source:

The above story is based on materials provided by Faculty of Science - University of Copenhagen. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. P. Carroll, P. S. Jorgensen, M. T. Kinnison, C. T. Bergstrom, R. F. Denison, P. Gluckman, T. B. Smith, S. Y. Strauss, B. E. Tabashnik. Applying evolutionary biology to address global challenges. Science, 2014; DOI: 10.1126/science.1245993

Piglet health: A better understanding of the immune response to intestinal parasites

 

September 12, 2014

Veterinärmedizinische Universität Wien

Parasitologists are closer to understanding the disease process behind porcine neonatal coccidiosis. The disease affects piglets during the first days of their life and can cause heavy diarrhea in the animals. The parasite Cystoisospora suis damages the intestinal mucosa to such a degree that it threatens the growth and survival of the pigs. The researchers have now analyzed the immune response to the infection.


Piglets.

Parasitologists from the University of Veterinary Medicine of Vienna are closer to understanding the disease process behind porcine neonatal coccidiosis. The disease affects piglets during the first days of their life and can cause heavy diarrhea in the animals. The parasite Cystoisospora suis damages the intestinal mucosa to such a degree that it threatens the growth and survival of the pigs. The researchers have now analysed the immune response to the infection. The results were published in the journal Parasite Immunology.

Porcine neonatal coccidiosis is a serious parasitic infection of young piglets that severely damages the intestinal mucosa, leading to diarrhea and reduced nutritional intake. As the infection reduces animal growth, and because secondary infections can result in increased mortality, the disease is responsible for substantial economic losses at affected pig farms.

"The developing immune system of neonatal piglets is not yet mature enough to deal with the parasites. For this reason, an infection shortly after birth results in weakened intestinal tissue with appropriate consequences. By comparison, Cystoisospora suisis absolutely harmless for adult pigs and their mature immune systems," explains first author Simone Gabner.

Immune cells grow more quickly in the intestines of infected piglets than in healthy ones

Scientists from the Institute of Parasitology at the Vetmeduni Vienna investigated how the developing immune system of piglets responds to an infection with Cystoisospora suis. For the purpose of the study, 25 animals aged three days were infected and observed in comparison with another 26 healthy, non-infected animals. The researchers analysed various different immune cells in the intestines of both groups over the course of the first days of life. High levels of so-called gamma delta T cells, a type of cell that recognizes tissue damage and activates the immune system, were found in infected piglets as early as four days after infection. Cytotoxic T-cells were detected eleven days after an infection. These are responsible for the cell death of infected cells and appear to have an immunologic memory function with regard to porcine neonatal coccidiosis.

Both types of T cells were detected significantly earlier in infected piglets than in non-infected animals. In healthy piglets, the T cells begin to settle in the intestine from about the third week of life.

"Before this, we didn't know which T cells played a part in porcine neonatal coccidiosis. Now we also know at which point they appear in the course and development of the disease. Their exact role in the intestines of the animals, however, remains unclear," Gabner says. "Cystoisospora suis affects epithelial cells in the intestine and destroys the natural barrier against pathogens. This makes secondary infections likely. We still don't know whether the T cells reduce the overall damage to the intestinal mucosa or if they perhaps cause the damage to the intestinal cells."

Innate immune system activated

Gabner and her colleagues also researched various receptors of the innate immune system in the piglets as well as signalling substances which play a part in the inflammatory response. Just four days after infection, the researchers found increased expression of certain pathogen receptors (TLR-2 and NOD2) and signalling molecules involved in inflammatory reactions (TNF-α) in the intestine of the infected animals. The parasite thus triggers the activation of the immune system. "Our research shows which signalling pathways could be involved. The immune response possibly begins even earlier. This is something to be investigated in future studies. We are one step closer to better understanding the disease," says Gabner.

Mother's milk a source of protection

Previous studies by the research group showed that protective antibodies against porcine neonatal coccidiosis are transferred to the piglets through the sow's milk directly after birth. Sows that had been exposed to the pathogen produced the respective antibodies from which the piglets could then benefit. In a follow-up study, the researchers went one step further. They deliberately infected sows with the parasites during gestation in order to increase the antibody levels in the maternal animals. The aim was to supply the piglets with as many antibodies from the mother's milk during their first days of life as possible. This "milk vaccination" was a success. The piglets of infected sows exhibited a less severe development of the disease than piglets of non-infected sows. The more antibodies a sow transferred to its piglets, the weaker the symptoms exhibited by the piglets.


Story Source:

The above story is based on materials provided by Veterinärmedizinische Universität Wien. Note: Materials may be edited for content and length.


Journal Reference:

  1. Simone Gabner, Hanna Lucia Worliczek, Kirsti Witter, Florian R. L. Meyer, Wilhelm Gerner, Anja Joachim. Immune response to Cystoisospora suis in piglets: local and systemic changes in T-cell subsets and selected mRNA transcripts in the small intestine. Parasite Immunology, 2014; DOI: 10.1111/pim.12116

Boosting armor for nuclear-waste eating microbes

 


A microbe developed to clean up nuclear waste and patented by a Michigan State University researcher has just been improved.

In earlier research, Gemma Reguera, MSU microbiologist, identified that Geobacter bacteria's tiny conductive hair-like appendages, or pili, did the yeoman's share of remediation. By increasing the strength of the pili nanowires, she improved their ability to clean up uranium and other toxic wastes.

In new research, published in the current issue of Applied and Environmental Microbiology, Reguera has added an additional layer of armor to her enhanced microbes.

The microbes also use the pili to stick to each other and grow a film on just about any surface, similar to the bacterial film that forms on teeth. The Geobacter biofilm, encased by a network of nanowires and slime, gives the bacteria a shield and increases their ability to neutralize even more uranium. The improvement also allows the bacteria to survive longer even when exposed to higher concentrations of the radioactive material.

Geobacter immobilizing uranium can be described as nature's version of electroplating. The beefed-up microbes engulf the uranium and turn it into a mineral, preventing the toxic material from leaching into groundwater.

Reguera's team had previously linked the conductive pili to the ability of the microbe to mineralize the soluble uranium. As the biofilm concentrates many nanowires around the Geobacter cells, more uranium can be bound and mineralized. The pili are immersed in a matrix of slime, which surrounds the biofilm cells and boosts the Geobacter's pili armor, so the biofilm now can pull double duty by helping mineralize uranium.

The shield keeps the uranium from penetrating deep into the Geobacter biofilm. By keeping this process on the surface of the film, the bacteria are not exposed to uranium and, as a community, they are able to clean up more toxic waste.

"The results surpassed our most optimistic predictions," Reguera said. "Even thin biofilms immobilized uranium like sponges. They reduced it to a mineral, all while not suffering any damage to themselves, for prolonged periods of time."

Even when exposed to extremely high and toxic concentrations of uranium, levels that would destroy individual Geobacter cells, the biofilms didn't just survive, they thrived, she added.

Additional MSU researchers contributing to the study include Dena Cologgi, Allison Speers and Blair Bullard. Shelly Kelly with EXAFS Analysis, also contributed to the study.

Reguera's future research on this front will focus on deciphering how the biofilm matrix that encases the cells shields them so effectively and how to improve its properties further.

Snap 2014-09-12 at 18.10.27


Story Source:

The above story is based on materials provided by Michigan State University. Note: Materials may be edited for content and length.


Journal Reference:

  1. D. L. Cologgi, A. M. Speers, B. A. Bullard, S. D. Kelly, G. Reguera. Enhanced uranium immobilization and reduction by Geobacter sulfurreducens biofilms. Applied and Environmental Microbiology, 2014; DOI: 10.1128/AEM.02289-14

Technological leap in treating PCB contamination in the environment: Three new bacteria could break down PCB

 

September 15, 2014

National University of Singapore

Scientists have developed a novel approach that could greatly enhance the effectiveness of destroying polychlorinated biphenyls (PCBs) in the environment. They discovered three powerful bacteria that can degrade PCBs. In addition, the researchers also developed an effective method of culturing these PCB dechlorinators in large quantities to enhance their degradation efficiency.


A team of researchers from the National University of Singapore (NUS) Faculty of Engineering have developed a novel approach that could greatly enhance the effectiveness of destroying polychlorinated biphenyls (PCBs) in the environment. They discovered three powerful bacteria from a genus called Dehalococcoides which can degrade PCBs. In addition, the researchers also developed an effective method of culturing these PCB dechlorinators in large quantities to enhance their degradation efficiency.

Working with A*STAR's Genome Institute of Singapore (GIS), the team was able to identify the functional genes responsible for breaking down PCBs. With these research findings, it is now possible to design and engineer methods which can rid our environment of harmful PCBs more effectively. Their findings were recently published in the journal, Proceedings of the National Academy of Sciences (PNAS).

PCB contamination and challenges posed to environment

PCBs are synthetic organic chemical compounds of chlorine and biphenyl. They have been widely used as coolant fluids in many electrical products. However, they are toxic and exposure to PCBs has been known to show symptoms almost immediately. Though PCBs are no longer used (they have been banned since the 1970s), they are virtually indestructible and can possibly remain in the environment forever. Hence they continue to contaminate rivers, lakes and harbours worldwide, posing a threat to human and ecosystem health.

There have only been seven known enzymes associated with Dehalococcoides found to have confirmed function on chlorinated compounds. The NUS-GIS research team is proud to add the three new bacteria to the list -- each with distinct specificities.

An in-situ microbial detoxification strategy, which involves applying microbes directly to break down (dechlorinate) PCBs on-site, would be very effective for PCB bioremediation. However, these microbes are extremely hard to culture, hence limiting efforts to characterise them for such applications.

Currently, the only treatment is capping or dredging and landfilling the PCBs. An example is the ongoing SuperFund project to dredge the upper Hudson River to remove PCBs which has already cost nearly US$1 billion. In this regard, the novel technique developed by the research team to culture PCB dechlorinators could pave the way for alternative, and possibly more effective, methods of degrading PCBs on-site.

Novel substrate for culturing PCB dechlorinators

Associate Professor He Jianzhong, who is from the NUS Department of Civil & Environmental Engineering, explained, "While the scientific community has found out that certain bacteria can dechlorinate PCBs and make them more susceptible to oxidation, it was not until three decades ago that some were identified. However, challenges still remain in growing these organisms in quantities that will make an impact. Their low biomass has also prevented us from studying closely the process, especially in identifying the enzymes responsible. Furthermore, as PCBs are extremely insoluble, they are unsuitable as substrates for culturing the helpful bacteria."

To overcome this problem, the NUS team came out with an alternative substrate called Terrachloroethene (PCE) which can be used to boost the cell numbers of PCB dechlorinators.

"This discovery is a quantum leap forward in our understanding of microbial PCB dechlorination and hence open up new possibilities of developing more effective ways of destroying PCBs in our environment," said Assoc Prof He.

Genomic technologies to the fore

Dr Niranjan Nagarajan, who leads the research at GIS, said, "Through synergy generated from traditional culture techniques combined with state of the art genomic technologies, we could successfully cultivate and characterise three PCB dechlorinating microbial strains. From these efforts, we were able to be the first to identify the functional genes responsible for breaking down PCBs. These genes could be very useful as biomarkers for monitoring PCB bioremediation."

Assoc Prof He added, "Finding useful bacteria can be tough. Our work shows how advanced genomic technologies can be combined with culturing to sift through bacteria in the environment and find the gems. This is a big step forward in the development of in-situ microbial detoxification technologies for PCB bioremediation."

These discoveries promise to move the bioremediation technology for PCBs into the realm of reality because for the first time, bioaugmentation is feasible. The impact of this outstanding research is tremendous, which makes in-situ bioremediation possible by saving significant amount of time and labor. Future research will be focused on application of genomic technologies for in-situ degradation of PCBs and other halogenated compounds.

Snap 2014-09-12 at 18.10.27


Story Source:

The above story is based on materials provided by National University of Singapore. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. Wang, K. R. Chng, A. Wilm, S. Zhao, K.-L. Yang, N. Nagarajan, J. He. Genomic characterization of three unique Dehalococcoides that respire on persistent polychlorinated biphenyls. Proceedings of the National Academy of Sciences, 2014; 111 (33): 12103 DOI: 10.1073/pnas.1404845111