Scientists use parasite's internal clock to attack sleeping sickness

Trypanosoma brucei is a parasite that causes the deadly sleeping sickness. Scientists have determined the parasite has its own biological clock that makes it more vulnerable to medications in the afternoon.

The parasite that causes deadly sleeping sickness has its own biological clock that makes it more vulnerable to medications during the afternoon, according to international research that may help improve treatments for one of Africa's most lethal diseases.

The finding from the Peter O'Donnell Jr. Brain Institute could be especially beneficial for patients whose bodies can't handle side effects of toxic treatments used to eradicate the parasite. By knowing the optimal time to administer these medications - which can be fatal - doctors hope to reduce the duration and dosage of the treatment and save more lives.

"This research has opened a door," said Dr. Filipa Rijo-Ferreira, first author of the study from the O'Donnell Brain Institute at UT Southwestern Medical Center. "If the same therapeutic effect can be obtained with a lower dose, then it may be possible to reduce the mortality associated with the treatment."

Establishing that parasites have their own internal clock is a key step in finding new ways to treat a variety of parasitic conditions, from sleeping sickness to malaria. While many of these diseases are often not deadly, sleeping sickness has been among the most lethal.

The condition - known formally as African trypanosomiasis - is transmitted through the bite of the Tsetse fly and threatens tens of millions of people in sub-Saharan African countries. After entering the body, the parasite causes such symptoms as inverted sleeping cycles, fever, muscle weakness, and itching. It eventually invades the central nervous system and, depending on its type, can kill its host in anywhere from a few months to several years.

Control efforts have significantly reduced the number of cases over the last decade. However, an unknown number of people still die annually from sleeping sickness as scientists continue seeking a vaccine and alternative treatments to the arsenic-based medications that are occasionally fatal to patients.
Dr. Joseph S. Takahashi, who oversaw the collaborative study published in Nature

Microbiology with Dr. Luisa Figueiredo at the University of Lisbon in Portugal, said the finding will likely apply to all types of parasites and perhaps lead to improved treatment for their associated conditions.



"There have been many observations of the presence of daily patterns in parasites, but until now we didn't know if this was the result of an intrinsic molecular clock. In the future, we may consider biological rhythms when defining therapies to treat sleeping sickness and potentially other infections," said Dr. Takahashi, Chairman of Neuroscience at UT Southwestern, holder of the Loyd B. Sands Distinguished Chair in Neuroscience, and Investigator with the Howard Hughes Medical Institute.

Researchers from UT Southwestern and the Institute of Molecular Medicine at the University of Lisbon in Portugal made their finding after isolating the parasite - known as Trypanosoma brucei - in the lab and obtaining a type of genetic fingerprint to gauge its daily cycles independent of a host. They found the parasite has daily metabolic cycles that make it more vulnerable to treatments in the afternoon.

Scientists now hope to learn what drives the parasite's internal clock so they can target specific genes and disrupt its circadian rhythms. Much like humans struggle to cope when their sleep cycle is interrupted, scientists expect the parasite would become weaker if its cycle is disturbed.

"We know that in other organisms if we mutate their clock they are less adapted to the world," said Dr. Rijo-Ferreira, an HHMI Associate. "We're trying to jetlag these parasites, trying to make them less fit."

5 parasite diseases to watch for in the U.S.

While deadly sleeping sickness is primarily transmitted in rural regions of Africa, millions of people in the U.S. are exposed to other forms of parasitic diseases. Here are five such diseases the U.S. Centers for Disease Control and Prevention lists as public-health priorities.

Chagas: This disease is most commonly acquired through contact with the feces of an infected kissing bug, a blood-sucking insect. There may be swelling where the parasite enters the body, and in rare cases the disease results in life-threatening inflammation of the heart or brain. If untreated, infection is lifelong. CDC estimates about 300,000 people in the U.S. have the condition.

Toxoplasmosis: This condition is a leading cause of death related to food-borne illness in the U.S. More than 30 million Americans carry the parasite, though few show symptoms because their immune systems protect against the illness. People can become infected by eating undercooked, contaminated meat, and women who are infected during pregnancy sometimes pass the parasite to their unborn children. This transfer can result in a miscarriage, a stillborn child, eye disease, or unusual head size.



Toxocariasis: Caused by two species of roundworm and is typically spread through the feces of dogs and cats. Most infected people don't show symptoms, though in some cases the parasite can travel through parts of the body such as the liver, lungs, or central nervous system. The larvae can also travel to the eye and cause blindness. Each year about 70 people, mostly children, are blinded by the condition.

Cysticercosis: Spread through ingesting larval cysts of a tapeworm, causing infections in the muscles, brain, or other tissue. People become infected when they drink water or eat food contaminated with tapeworm eggs, or if they put contaminated fingers in their mouths. Cysts in the brain or spinal cord commonly cause seizures or headaches. The condition may also cause life-threatening brain swelling or strokes. CDC estimates that at least 1,000 people are hospitalized each year with the more severe brain-related form of the disease.

Trichomoniasis The parasite that causes trichomoniasis is transferred from human to human during sex. About 3.7 million people in the U.S. have the condition, though most do not know they have it. Symptoms may include itching, burning, redness or soreness in the infected areas. The parasite can be eradicated through medications. Without treatment, the infection can last for months or years.

Source: Nature Microbiology - Provided by: UT Southwestern Medical Center

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Mindfulness Meditation and Anxiety Disorders

Research evaluates the effects of meditation training on patients’ biological reaction to stress

Characterized by persistent and excessive worry, generalized anxiety disorder affects nearly seven million adults in the U.S

Those who are prone to anxiety tend to have greater difficulty managing and coping with stress, experts say, where chronic stress is shown to have physiologic effects including raising heart rate and blood pressure and increasing one's risk for heart attack and stroke. In an effort to find calm, research shows those struggling with anxiety may be well-served by turning to mindfulness meditation – a technique that involves focusing on the present and non-judgmentally paying attention to thoughts and feelings as they arise.

“If you think of anxiety – there are anxious thoughts and there are anxious feelings, and those go together,” says Judson Brewer, director of research for the Center for Mindfulness at the University of Massachusetts Medical School. “There are two ways that we can deal with them.”

One is our natural learned response that since anxiety feels bad, he says, we need to do something to make it feel better. “So we avoid it, we suppress it, we repress it – we do all these things to distract ourselves from the anxiety itself.” However, attempts to avoid uncomfortable thoughts and feelings may worsen anxiety. “The paradox here is that mindfulness helps us turn toward those and learn to change our relationship to the actual thoughts and the physical sensations, rather than try to change them in any way,” Brewer says. “By changing that relationship, we actually stop feeding those cyclical processes and they start to die off on their own.” By learning mindfulness-based stress reduction – an approach first developed at UMass that uses meditation to lower stress levels – research finds many people report reduced anxiety and stress levels.



Taking that a step further, a recent National Institutes of Health-funded study published in January in the journal Psychiatry Research also looked at the biological responses of patients with generalized anxiety disorder to stress, after they’d undergone MBSR. In the study, 70 participants were randomly assigned either to receive the mindfulness meditation training or to undergo stress management education – the study’s control group. “This was a sort of a wellness class where there was a series of lectures on different topics, like sleep improvement and exercise and nutrition,” says Dr. Elizabeth Hoge, an associate professor of psychiatry at Georgetown University Medical Center in Washington. Hoge conducted the research while she was a postdoctoral researcher at Massachusetts General Hospital.

Participants were asked to give an impromptu speech in front of an audience of testers – a typically stress-inducing experience – before and after the 8-week intervention, either the mindfulness meditation training or the stress management class. They were also asked to do mental arithmetic: “Start with the number 996 and subtract by seven all the way down to zero, which is really hard to do in front of an audience,” Hoge notes. “The testers had all the numbers in front of them on a clipboard and they were wearing white lab coats, and we videotaped and had microphones and photography flood lamps. [We] basically set up the laboratory stress test to be like the worst kind of speech challenge that a person can experience.”

Even so, blood testing revealed that study participants had significantly lower levels of the stress hormone ACTH and inflammatory reactions to stress (measured by looking at inflammatory proteins IL-6 and TNF-α) following mindfulness meditation training. That compared to the control group for whom biological stress responses actually increased somewhat the second time they underwent the social stress test.



The results offer biological data showing how mindfulness meditation training can affect the ability of a person with generalized anxiety disorder to be resilient in the face of stressful circumstances. “You can’t fake that,” Hoge says; nor could the results be explained by the placebo effect or a patient’s expectation that meditation would help, since their reactions were measured at a physiological level. “For people who have generalized anxiety disorder, our research provides evidence that this might be a reasonable treatment option,” she says.

Hoge says one of the reasons she was interested in pursuing the research was to look at alternatives to standard treatments for anxiety disorders, typically antidepressant medication and psychotherapy. “It’s hard for some people to get those treatments, either because of insurance, financial limitations and also the stigma that’s involved with coming to a psychiatric clinic for treatment," she says. "And a lot of people don’t want to go on medications.”

Though standard treatments work well for many patients, experts say it’s important to provide various options to match individual preference.

One question that remains is whether the stress levels – measured on a biological level – would be reduced over the long term by meditative techniques, says Dr. Madhav Goyal, an internist at NorthBay Healthcare in Vacaville, California, and an assistant professor of general internal medicine at Johns Hopkins University School of Medicine in Baltimore. Goyal has done research on meditation programs to address stress and improve well-being. “We know that people who are more stressed in general tend to be more susceptible to getting infections” among other health issues, Goyal says.



If meditation can treat anxiety disorder and help those with anxiety better cope with stress, it could also improve a person’s overall health in the long term. But more research is needed to determine the impact that meditation might have on chronic stress levels, Goyal says.

In the immediate term, for individuals considering meditation to treat anxiety disorder, Brewer suggests MBSR, which has been well-studied in this regard. The Center for Mindfulness has a worldwide online directory of MBSR teachers certified by the UMass Center for
Mindfulness.

Ultimately, experts say, meditation may help those with anxiety gain a greater understanding of more troubling underlying emotions, such as sadness or anger, while improving their ability to cope with stress. “Instead of being drawn into these long worry bouts, people can have more freedom to deal with those thoughts in a way that’s more constructive,” Hoge says.
Writer: Michael O. Schroeder / Health.news.com

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The Internet and your brain are more alike than you think

Salk scientist finds similar rule governing traffic flow in engineered and biological systems. Credit: Salk Institute

A similar rule governs traffic flow in engineered and biological systems, reports a researcher. An algorithm used for the Internet is also at work in the human brain, says the report, an insight that improves our understanding of engineered and neural networks and potentially even learning disabilities.

Although we spend a lot of our time online nowadays -- streaming music and video, checking email and social media, or obsessively reading the news -- few of us know about the mathematical algorithms that manage how our content is delivered. But deciding how to route information fairly and efficiently through a distributed system with no central authority was a priority for the Internet's founders. Now, a Salk Institute discovery shows that an algorithm used for the Internet is also at work in the human brain, an insight that improves our understanding of engineered and neural networks and potentially even learning disabilities.



"The founders of the Internet spent a lot of time considering how to make information flow efficiently," says Salk Assistant Professor Saket Navlakha, coauthor of the new study that appears online in Neural Computation on February 9, 2017. "Finding that an engineered system and an evolved biological one arise at a similar solution to a problem is really interesting."
In the engineered system, the solution involves controlling information flow such that routes are neither clogged nor underutilized by checking how congested the Internet is. To accomplish this, the Internet employs an algorithm called "additive increase, multiplicative decrease" (AIMD) in which your computer sends a packet of data and then listens for an acknowledgement from the receiver: If the packet is promptly acknowledged, the network is not overloaded and your data can be transmitted through the network at a higher rate. With each successive successful packet, your computer knows it's safe to increase its speed by one unit, which is the additive increase part. But if an acknowledgement is delayed or lost your computer knows that there is congestion and slows down by a large amount, such as by half, which is the multiplicative decrease part. In this way, users gradually find their "sweet spot," and congestion is avoided because users take their foot off the gas, so to speak, as soon as they notice a slowdown. As computers throughout the network utilize this strategy, the whole system can continuously adjust to changing conditions, maximizing overall efficiency.

Navlakha, who develops algorithms to understand complex biological networks, wondered if the brain, with its billions of distributed neurons, was managing information similarly. So, he and coauthor Jonathan Suen, a postdoctoral scholar at Duke University, set out to mathematically model neural activity.



Because AIMD is one of a number of flow-control algorithms, the duo decided to model six others as well. In addition, they analyzed which model best matched physiological data on neural activity from 20 experimental studies. In their models, AIMD turned out to be the most efficient at keeping the flow of information moving smoothly, adjusting traffic rates whenever paths got too congested. More interestingly, AIMD also turned out to best explain what was happening to neurons experimentally.

It turns out the neuronal equivalent of additive increase is called long-term potentiation. It occurs when one neuron fires closely after another, which strengthens their synaptic connection and makes it slightly more likely the first will trigger the second in the future. The neuronal equivalent of multiplicative decrease occurs when the firing of two neurons is reversed (second before first), which weakens their connection, making the first much less likely to trigger the second in the future. This is called long-term depression. As synapses throughout the network weaken or strengthen according to this rule, the whole system adapts and learns.

"While the brain and the Internet clearly operate using very different mechanisms, both use simple local rules that give rise to global stability," says Suen. "I was initially surprised that biological neural networks utilized the same algorithms as their engineered counterparts, but, as we learned, the requirements for efficiency, robustness, and simplicity are common to both living organisms and the networks we have built."



Understanding how the system works under normal conditions, could help neuroscientists better understand what happens, when these results are disrupted, for example, in learning disabilities. "Variations of the AIMD algorithm are used in basically every large-scale distributed communication network," says Navlakha. "Discovering that the brain uses a similar algorithm may not be just a coincidence."
Story Source:
Materials provided by Salk Institute.

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How Life began? A New Discovery in Astrobiology

The Ribonucleic Acid, vital element for living, is product of evolution and a “Mother” molecule may help give birth to the RNA.

All life on Earth uses DNA to encode and store genes, and to pass them on from one generation to the next. RNA, a close molecular relative of DNA, is used within living cells to carry out a wide variety of important biological functions, including protein synthesis.

DNA and RNA are both extremely complex molecules, a fact that has fueled a long-standing debate about the origins of life. RNA looks potentially older and more versatile than DNA so many scientists believe that RNA came before DNA. But did life begin with RNA, or was there something even simpler that preceded it?

Scientists have found it difficult to deduce the chemical environment on early Earth when life began. Nevertheless, there have been a number of notable successes in this area of research, including the discovery of reactions that produce the building blocks of RNA. However, a reaction that produces actual polymers of RNA has not been found, causing many scientists to conclude that RNA is the product of evolution.

“The origin of RNA is something I’ve been working on for two decades,” said Nicholas Hud, head of the Georgia Institute of Technology’s Center for Chemical Evolution, where researchers are attempting to figure out how life began. “It is easy to speculate that some other molecule came before RNA, but determining the structure of molecules that might actually have come before RNA is a major challenge for chemists.”



A recent paper by Hud and his team found that pro-flavine, a small planar molecule that binds between adjacent base pairs of a DNA, can dramatically increase the stability of DNA or RNA in the lab when single strands of the complex molecules are synthetically bound to an unnatural nucleic acid. (“Unnatural” means that these are molecules similar to natural DNA or RNA, but with different backbone structures.)

“Proflavine can cause the formation of a duplex from two nucleic acids that otherwise do not form duplexes at all,” Hud said.
He added that their results are important for two reasons. The first is that duplexes formed by DNA and an unnatural nucleic acid could be used to create dynamic structures that assemble only when proflavine, or a similar molecule, is present. This property has potential applications in nanotechnology, or the technology of very small things.

A second and more fundamental implication of this work has to do with our understanding of the “RNA World” hypothesis, the theory that RNA was the first molecule of life. After decades of unsuccessful attempts to create RNA in model prebiotic (non-biological) reactions, many chemists that study the origin of life believe that there must have been some other RNA-like polymer before RNA. Hud said the first of these polymers could be called a ‘proto-RNA‘, and each evolutionary step between proto-RNA and current RNA is a ‘pre-RNA.’

“There have been many proposals for possible pre-RNA structures,” he said. “While it may not be possible to determine the exact structure of any of the molecules that served as the ancestors of RNA, researchers generally agree that the ability to form a duplex with RNA is an important criterion that must be met for a molecule to be considered a possible ancestor of RNA.”



Back in 2000 Hud and his collaborator Frank Anet proposed that small molecules might have helped the synthesis of RNA, or the original ancestor of RNA, if RNA came later. They called these hypothetical small molecules ‘molecular midwives,’ to reflect that these molecules would have helped give birth to RNA. They proposed that molecular midwives would have been similar to molecules that are currently known to bind DNA and RNA, such as fluorescent dye molecule known as “intercalators” that are used to visualize DNA in the laboratory.

Most recently, Hud and his collaborators have discovered that proflavine, a particular intercalator, is able to cause the formation of a double helix, like that formed by two DNAmolecules, but between RNA and a non-natural RNA-like molecule that has a “backbone” structure distinct from RNA and DNA. In the absence of proflavine these molecules do not form double helixes.

This result has important implications regarding the origin of the first RNA-like molecules of life. In particular, the number of molecules that could have served as the first genetic molecules of life might have been much greater than previously expected if intercalator molecules we present on the early Earth. Hud notes that proflavine is not a potentially prebiotic molecule, but was used in their study as a model for the type of intercalator molecules that may have been available on early Earth.

Hud has spent years studying the potential role of intercalators in the origin of RNA. Very few studies have investigated the ability of intercalators to bind non-natural RNA-like molecules, and no previous studies had investigated the possibility that intercalators might allow RNA to pair with polymers that would otherwise be “incompatible” with RNA.

Connections made within the Center for Chemicals Evolution (or CCE) allowed these studies to move to a whole new level. Ram Krishnamurthy, a fellow member of the CCE who is at The Scripps Research Institute in La Jolla, Calif., was synthesizing with his co-workers a polymer called ISO-GNA that is in some ways simpler than RNA, and they thought this polymer might shed light on the structural requirements for the simplest informational system RNA.

Their observation that ISO-GNA has limited base-pairing with RNA made them question the currently accepted requirements for ancestors of RNA. Conversations within the CCE resulted in Hud’s group testing the ability of an intercalator to facilitate the pairing of Krishnamurthy’s molecule (ISO-GNA) with RNA.



“In our earlier work on iso-GNA revealed that this molecule did not form duplexes that are stable as those of DNA or RNA,” Krishnamurthy said. “We proposed that this limitation of ISO-GNA could be overcome by the use of intercalators since they are known to stabilize base-pairing within a duplex structure by enhancing base-stacking. What is fascinating in this study is that the increase we observed for the stability of iso-GNA duplexes in the presence of proflavine is much larger than the increased stability those observed when proflavine binds DNA or RNA, far exceeding our expectations. This study should allow for a greater flexibility when searching for possible prebiotic polymers that are able to interact with RNA (or DNA).”

These latest results have caused Hud and Krishnamurthy to broaden their view of which molecules might have come before RNA. These two researchers and their co-workers are currently trying to find a possible ancestor of RNA that is able to spontaneously form from molecules that were present on the early Earth. They remain more open than ever to the idea that some molecules not seen in life today may have been necessary to get life started, perhaps molecules that we could view as the “midwives” that helped give “birth” to RNA.



Funding for the research was provided by the National Science Foundation (which funds CCE more generally) and support from the NASA Astrobiology Program at NASA.

Source: Aaron Gronstal, Astrobio.net

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