Parasite uses the power of sexual attraction to trick rats into becoming cat food

Posted by Biomechanism 

When a male rat senses the presence of a fetching female rat, a certain region of his brain lights up with neural activity, in anticipation of romance. Now Stanford University researchers have discovered that in male rats infected with the parasite Toxoplasma, the same region responds just as strongly to the odor of cat urine.

Is it time to dim the lights and cue the Rachmaninoff for some cross-species canoodling?

Caption: Individual toxoplasma parasites (green) are shown invading neurons (red) grown in a petri dish in the lab. The blue areas are fluorescently tagged cell nuclei. Credit: I-Ping Lee.

“Well, we see activity in the pathway that normally controls how male rats respond to female rats, so it’s possible the behavior we are seeing in response to cat urine is sexual attraction behavior, but we don’t know that,” said Patrick House, a PhD candidate in neuroscience in the School of Medicine. “I would not say that they are definitively attracted, but they are certainly less afraid. Regardless, seeing activity in the attraction pathway is bizarre.”

For a rat, fear of cats is rational. But a cat’s small intestine is the only environment in which Toxoplasma can reproduce sexually, so it is critical for the parasite to get itself into a cat’s digestive system in order to complete its lifecycle.

Thus it benefits the parasite to trick its host rat into putting itself in position to get eaten by the cat. No fear, no flight – and kitty’s dinner is served.

House, the lead author of a paper about the research published in the Aug. 17 issue of PLoS ONE, works in the lab of Robert Sapolsky, a professor of biology and, at the medical school, of neurology and neurological sciences.

Scientists have known about Toxoplasma’s manipulation of rats for years and they knew that rats infected with Toxoplasma seemed to lose their fear of cats.

It is an example of what is called the “manipulation hypothesis,” which holds that some parasites alter the behavior of their host organism in a way that benefits the parasite. There are several known examples of the phenomenon in insects.

But the details of how the little single-celled protozoan Toxoplasma, about a hundredth of a millimeter long, exerts control over the far more sophisticated rat have been a mystery.

Sapolsky’s group previously determined that although the parasite infects the entire brain, it shows a preference for a region of the brain called the amygdala, which is associated with various emotional states. Once in the brain, the parasite forms cysts around itself, in which it essentially lies dormant.

House was interested in how the amygdala is affected by the parasite, so he ran a series of experiments with both healthy and Toxoplasma-infected rats. He exposed each male rat to either cat urine or a female rat in heat for 20 minutes before analyzing its brains for evidence of excitation in the amygdala.

For the experiments, he used cat urine he purchased in bulk from a wholesaler. No actual cats participated in the experiments.

House analyzed certain subregions of the amygdala that focus on innate fear and innate attraction.

In healthy male rats, cat urine activated the “fear” pathway.

But in the infected rats, although there was still activity in the fear pathway, the urine prompted quite a bit of activity in the “attraction” pathway as well. “Exactly what you would see in a normal rat exposed to a female,” House said.

“Toxoplasma is altering these circuits in the amygdala, muddling fear and attraction,” he said.

The findings confirmed observations House made during the experiments, when he noticed that the infected rats did not run when they smelled cat urine, but actually seemed drawn to it and spent more time investigating it than they would just by chance.

Although House doesn’t have the data yet to speculate on just how the cysts in the rats’ brains are causing the behavioral changes, he is impressed with what Toxoplasma can accomplish.

“There are not many organisms that can get into the brain, stay there and specifically perturb your behavior,” he said.

“In some ways, Toxoplasma knows more about the neurobiology of fear than we do, because it can specifically alter it,” Sapolsky said.

Because Toxoplasma reproduces in the small intestine of cats, the parasites are excreted in feces, which is presumably how rats get infected. Rats are known to be extremely curious, tasting almost everything they come in contact with. Toxoplasma is also frequently found in fertilizer and can infect virtually any mammal.

Approximately one third of the world’s human population is infected with Toxoplasma. For most people, it appears to present no danger, although it can be fatal in people with compromised immune systems. It also can cross the placental barrier in a pregnant woman and lead to many complications, which is why pregnant women are advised not to clean cat litter boxes.

House said humans acquire the parasite by eating undercooked meat or “eating little bits of cat poop, which I suspect happens more often than people want to admit.” Or know.

Although Toxoplasma has not been shown to have any ill effects in most people, one can’t help but wonder whether it truly has no effect in humans.

“There are a couple dozen studies in the last few years showing that if you have schizophrenia, you are more likely to have Toxoplasma. The studies haven’t shown cause and effect, but it’s possible,” House said. “Humans have amygdalae too. We are afraid of and attracted to things – it’s similar circuitry.”

Enzyme’s structure reveals basis for head, sex organ deformities

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“Data show therapy with vitamin B2 to reverse enzyme defects is worth attempting.”

For example, some babies may have a genetic defect that prevents their body from producing a substance called 21-hydroxylase. If a developing baby girl lacks this substance, she will be born with a uterus, ovaries, and fallopian tubes, but her external genitals will look like those found on boys. Photo: WebMD.

Scientists this month reported the molecular structural basis for severe head deformities and ambiguous sex organs in babies born with Antley-Bixler syndrome accompanied by an enzyme deficiency.

The team, composed of researchers from The University of Texas Health Science Center San Antonio, the Medical College of Wisconsin and Charles University in Prague, solved the atomic structure of this human enzyme with an impressive name — NADPH-cytochrome P450 reductase, abbreviated CYPOR.

The group is the first to visualize and depict the structure of the human version of CYPOR. The scientists also reported the structure of two mutations of human CYPOR that result in congenital deformities.

“Human syndromes are caused by the deficiency of this enzyme,” said Bettie Sue Masters, Ph.D., D.Sc., M.D. (Hon.), professor of biochemistry and the Robert A. Welch Foundation Distinguished Professor in Chemistry at the UT Health Science Center. “The two mutations that we characterized are responsible for severe craniofacial and steroid-production defects in humans, the latter leading to sexual ambiguities.”

In the body, steroids are produced for many important functions. In CYPOR deficiency, these steroidal malfunctions are related to deformed sexual organs and other defects.

The structural basis for human CYPOR deficiency is described in the Aug. 4 edition of Proceedings of the National Academy of Sciences.

In previously published research from Dr. Masters’ laboratory, addition of a riboflavin (vitamin B2) derivative reversed the defects in the mutated enzymes; this is because the vitamin makes this particular enzyme work, producing metabolites. Metabolites are the products of enzyme-generated reactions. This reversal of CYPOR defects by a riboflavin derivative is yet to be investigated in animals or humans. Foods such as liver, herbs, almonds, wheat bran, fish and cheese are rich in riboflavin.

Knowing the molecular structure of CYPOR has proved that riboflavin therapy is worth attempting, Dr. Masters said. As demonstrated by this structure, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy within the womb, if predicted before birth, or rescued after birth in less severe cases, the authors wrote in the Aug. 4 publication.

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Antley-Bixler syndrome is a rare genetic disorder characterized by a prominent forehead, underdeveloped regions in the mid-face, protruding eyes and other abnormalities. Dr. Masters and her colleagues are studying the origins of these bone development defects.

Radical overhaul of farming could be ‘game-changer’ for global food security

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According to the authors of new research released today at the World Water Week in Stockholm, a radical transformation in how farming and natural systems interact could simultaneously boost food production and protect the environment—two goals that often have been at odds. The authors warn, however, that the world must act quickly if the goal is to save the Earth’s main breadbasket areas—where resources are so depleted the situation threatens to decimate global supplies of fresh water and cripple agricultural systems worldwide.

A new analysis resulting from the joined forces of the International Water Management Institute (IWMI) and the United Nations Environment Programme (UNEP) outlines the urgent need to rethink current strategies for intensifying agriculture, given that food production already accounts for 70 to 90 per cent of withdrawals from available water resources in some areas. The report, An Ecosystem Services Approach to Water and Food Security, finds that in many breadbaskets, including the plains of northern China, India’s Punjab and the Western United States, water limits are close to being “reached or breached.” Meanwhile, 1.6 billion people live under water scarcity conditions, and the report warns that the number could soon grow to 2 billion. The current situation in the Horn of Africa is a timely reminder of how vulnerable some regions are to famine“Agriculture is both a major cause and victim of ecosystem degradation,” said Eline Boelee of IWMI, the lead scientific editor of the report. “And whether we can continue increasing yields with the present practices is unclear. Sustainable intensification of agriculture is a priority for future food security, but we need to take a more holistic ‘landscape’ approach.”

Meanwhile, a separate report by IWMI, Wetlands, Agriculture and Poverty Reduction, warns against seeking to protect wetlands by simply excluding agriculture. It argues that policies focused entirely on wetland preservation and ignore the potential of ‘wetland agriculture’ to increase food production and contribute to reducing poverty.

“Blanket prohibitions against cultivation do not always reduce ecosystem destruction and can make things worse,” said Matthew McCartney of IWMI, who co-authored the report. “For example, sub-Saharan Africa's grassy ‘dambo’ wetlands often provide vital farmland to the rural poor. However, banning farming in these areas has exacerbated rather than reduced ecosystem destruction. It has prompted deforestation upstream and led to a shift from farming to grazing in the wetlands themselves, so there has been a much greater impact on these natural systems. A balance is needed: appropriate farming practices that support sustainable food production and protect ecosystems.”

New Alliance Between Agriculture and Environment Groups

The two reports seek a new path toward achieving food security and environmental health. They focus on radically reorienting practices and policies so that farming occurs in ‘agroecosystems’ that exist as part of the broader landscape, where they help maintain and supplement clean water, clean air and biodiversity.

“We are seeing a growing trend of alliances between traditionally conservationist groups and those concerned with agriculture,” said David Molden, Deputy Director General for Research at IWMI. UNEP is the United Nations' voice of the environment, and IWMI is part of the world’s largest consortium of agricultural researchers, the Consultative Group on International Agricultural Research (CGIAR).

“For instance,” Molden continued, “UNEP has adopted food security as a new strategic concern. IWMI and its partners in the CGIAR are developing a multi-million dollar research program that will look at water as an integral part of ecosystems to help solve issues of water scarcity and land and environmental degradation. IWMI has also recently become a key partner with the Ramsar Convention on the relationship between wetlands and agriculture.”

“The various political, research and community alliances now emerging are challenging the notion that we have to choose between food security and ecosystem health by making it clear that you can’t have one without the other,” he added.

Examples of Successful Integration in the Field

UNEP IWMI and collaborators have identified multiple opportunities to use trees on dryland farms that will intensify the amount of food produced per hectare of land area while helping to improve the surrounding ecosystem. Farmers can prevent runoff and soil erosion by integrating trees and hedgerows and retaining more water to nourish their crops.

Another example of innovative thinking includes better water and soil management in rainfed systems in sub-Saharan Africa, which have demonstrated the ability to reverse land degradation while increasing crop yields twofold or threefold at the same time.

Overall, the authors say it’s time for decision-makers at the international, national and local levels to embrace an agroecosystem approach to food production. These changes could include incentivising more farmers to adopt improved practices through ‘payments for environmental services (PES)’.

One example being explored by the CGIAR’s Challenge Program on Water and Food (CPWF) is the potential for benefit sharing in river basin areas of Peru, Ecuador and Colombia. Upstream users value the water for irrigation and ecotourism and have a spiritual affiliation with the ecosystem. The hydropower companies need a steady stream to support the downstream electrification of the growing urban population. Large-scale farms and agro-industry also need increasing supplies of water.

“More and more agriculture needs to be brought into the ‘green economy’,” said Alain Vidal of the CPWF. “We need to value farming practices that protect our precious water resources in the same way we are beginning to value forest management that helps reduce greenhouse gas emissions, especially because those natural resources support the livelihoods of the most vulnerable.”

In the report, An Ecosystem Services Approach to Water and Food Security, experts from UNEP, IWMI and 19 other organisations acknowledge that one major impediment to adopting a more sustainable approach to food production is that it requires a new level of cooperation and coordination among officials and organisations involved in agriculture, environmental issues, water management, forestry, fisheries and wildlife management—individuals and groups who routinely operate in separated, disconnected worlds.

“It is essential that in the future we do things differently. There is a need for a seminal shift in the way modern societies view water and ecosystems and the way we, people, interact with them,” said David Molden. “Managing water for food and ecosystems will bring great benefits, but there is no escaping the urgency of this situation. We are heading for disaster if we don’t change our practices from business as usual.”

Painting a ‘bullseye’ on cancer cells

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“Targeting cancer cell metabolism can lead to more effective therapy, Tel Aviv University research finds.”

Scientists are constantly on the hunt for treatments that can selectively target cancer cells, leaving other cells in our bodies unharmed. Now, Prof. Eytan Ruppin of Tel Aviv University’s Blavatnik School of Computer Science and Sackler Faculty of Medicine and his colleagues Prof. Eyal Gottlieb of the Beatson Institute for Cancer Research in Glasgow, UK, and Dr. Tomer Shlomi of the Technion in Haifa have taken a big step forward. They have successfully created the first computerized genome-scale model of cancer cell metabolism, which can be used to predict which drugs are lethal to the function of a cancer cell’s metabolism.

By inhibiting their unique metabolic signatures, explains Prof. Ruppin, cancer cells can be killed off in a specific and selective manner. The efficacy of this method has been demonstrated in both computer and laboratory models pertaining to kidney cancer. Because the researchers’ new approach is generic, it holds promise for future investigations aimed at effective drug therapies for other types of cancer as well.

The results were recently published in the journal Nature.

Lethal to cancer, safe for other cells

The ability to specifically target cancer cells is the holy grail of cancer research. Currently, many cancer drugs are designed to target any proliferating cells in the body — and while cancer cells certainly proliferate, so do healthy cells, such as hair and gut lining cells, the growth of which are essential to the body’s overall health. This explains why many cancer treatments, including chemotherapy, have adverse side effects like nausea and hair loss.

Targeting the metabolism of the cancer cell itself may be one of the most effective ways forward. Cancer cells have a special way of metabolizing nutrients for growth and for energy. This makes cancer cell metabolism essentially different from that of a normal cell.

The researchers’ computer model is a reconstruction of the thousands of metabolic reactions that characterize cancer cells. By comparing it to a pre-existing model of a normal human cell’s metabolism, they could distinguish the differences between the two. They could then identify drug targets with the potential to affect the specific, special characteristics of cancer metabolism.

To test their predictions, the researchers chose to target cells from a specific type of renal cancer. “In this type of renal cancer, we predicted that using a drug that would specifically inhibit the enzyme HMOX, involved in Heme metabolism, would selectively and efficiently kill cancer cells, leaving normal cells intact,” explains Prof. Ruppin. Their computer model led them to hypothesize that the Heme pathway was essential for the cancer cell’s metabolism.

In an experimental study led by Prof. Gottlieb’s lab, the researchers were able to verify this prediction in both mouse and human cell models, and to study these metabolic alterations in depth.

An all-around treatment model

Metabolism is a large and complex network, built on thousands of reactions. It is beyond the human capability to fully understand, let alone predict how such a complicated system works, says Prof. Ruppin. Now, by allowing researchers to simulate the effects of a disorder, computer models are helping researchers to predict the efficacy of potential drugs and treatments. Though the predictions should always be verified in a lab or clinic, this method is highly cost effective and leads to exciting opportunities for accelerating future drug developments.

While the first model was built to characterize a specific type of cancer, this approach can be applied in the future for creating models for other types of cancer. “This is the next big challenge for us,” says Prof. Ruppin. “We are going to continue to build models for other types of cancer, and seek selective drug therapies to defeat them.” Their multidisciplinary approach requires both the predictions of a computer model and the findings of experimental clinical trials, and may lead to the faster development of more selective and effective cancer treatments.

At last, a reason why stress causes DNA damage

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For years, researchers have published papers that associate chronic stress with chromosomal damage.

Now, researchers at Duke University Medical Center have discovered a mechanism that helps explain the stress response regarding DNA damage.

“We believe this paper is the first to propose a specific mechanism through which a hallmark of chronic stress, elevated adrenaline, could eventually cause DNA damage that is detectable,” said senior author Robert J. Lefkowitz, M.D., James B. Duke Professor of Medicine and Biochemistry and a Howard Hughes Medical Institute (HHMI) investigator at Duke University Medical Center.

The paper was published in the Aug. 21 online issue of Nature.

In the study, mice were infused with an adrenaline-like compound that works through a receptor called the beta adrenergic receptor Lefkowitz has studied for many years. The scientists found that this model of chronic stress triggered certain biological pathways that ultimately resulted in the accumulation of DNA damage.

“This could give us a plausible explanation of how chronic stress may lead to a variety of human conditions and disorders, which range from merely cosmetic, like greying hair, to life-threatening disorders like malignancies,” Lefkowitz said.

P53 is a tumour suppressor protein and is considered a “guardian of the genome” that prevents genomic abnormalities.

“The study showed that chronic stress leads to prolonged lowering of p53 levels,” said Makoto Hara, Ph.D., a postdoctoral fellow in the Lefkowitz laboratory. “We hypothesise that this is the reason for the chromosomal irregularities we found in these chronically stressed mice.”

Lefkowitz earlier had proved the existence of isolated, and characterized the G-protein-coupled receptors (GPCRs) such as the beta adrenergic receptor. These receptors, which are located on the surface of the membranes that surround cells, are the targets of almost half of the drugs on the market today, including beta blockers for heart disease, antihistamines and ulcer medications.

Now he is continuing studies along another pathway, stemming from the GPCRs, discovered in his lab, known as the beta-arrestin pathway. At first, the theory was that beta-arrestin proteins turned off or desensitized the G-protein pathways. Still, evidence is accumulating that these proteins are also responsible for causing certain biochemical activities in their own right.

In the current study, the scientists found a molecular mechanism through which adrenaline-like compounds acted through both G-protein and the beta-arrestin pathways to trigger DNA damage.

The Nature publication showed that the infusion of an adrenaline-like compound for four weeks in the mice caused degradation of p53, which was present in lower levels over time.

The study also showed that the DNA damage was prevented in mice lacking beta-arrestin 1. Loss of beta-arrestin 1 stabilized cellular levels of p53 both in the thymus, an organ that strongly responds to acute or chronic stress, and in the testes, where paternal stress might affect an offspring’s genome.

Future studies planned by the Lefkowitz laboratory include studying mice that are placed under stress (restrained), thus creating their own adrenaline or stress reaction to learn whether the physical reactions of stress, rather than an influx of adrenaline in the lab as was done in the current study, also leads to accumulation of DNA damage.

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Other authors include Jeffrey J. Kovacs, Erin J. Whalen, Sudarshan Rajagopal, Ryan T. Strachan, Seungkirl Ahn, Barbara Williams, Christopher M. Lam, Kunhong Xiao, and Sudha K. Shenoy, all of the Duke Department of Medicine; Aaron J. Towers and Simon G. Gregory of the Department of Medicine and the Center for Human Genetics at Duke; and Wayne Grant and Derek R. Duckett of the Translational Research Institute, The Scripps Research Institute, Jupiter, Fla..

The study was supported by the Howard Hughes Medical Institute.