Sunday, August 11, 2013

Fruit flies help Yale scientists sniff out new insect repellents

Research published in the journal Genetics identifies pieces of control DNA that turn on or off genes that allow fruit flies to differentiate between smells, paving the way for better insect repellents


By following the "nose" of fruit flies, Yale scientists are on the trail of new insect repellents that may reduce the spread of infectious disease and damage to agricultural crops. That's because they've learned for the first time how a group of genes used to differentiate smells is turned on and off, opening new possibilities for insect control. Just as in new drug development, researchers can target these or similar genes in other insects to create substances that make crops and people "invisible" to insect antennae. Without the ability to smell correctly, the insects are far less likely to attack a person or plant, as is the case with mosquitoes whose ability to smell lactic acid is disrupted by the active ingredient in insect repellents, DEET. This finding is reported in the September 2010 issue of the journal GENETICS (http://www.genetics.org).

According to Carson Miller, a researcher involved in the work from the Department of Molecular, Cellular and Developmental Biology at Yale University, "One of the fundamental questions in biology is, 'how does a cell choose which genes it should turn on and which genes it should turn off?' By studying this question in odor-sensitive neurons of fruit flies, we hope to learn how cells make these choices, as well as to develop more effective odor-based insect repellents."

The scientists studied four genes from a group of odor receptor genes in the fruit fly. These genes afford flies the ability to detect different scents. Pieces of DNA in front of these genes contained enough information to tell the fly to turn on these genes in specific cells of the antenna. Miller made an artificial reporter gene that used the regulatory DNA in front of an Odor receptor gene to control a test gene that could be easily monitored for expression. An entire set of such reporter genes were created, each containing less of the regulatory DNA. The goal was to determine how short the regulatory region could be and yet still control the test gene normally. This helped Miller to identify where the important control elements lie in the regulatory DNA, and whether they serve to turn the gene on in cells where it is needed or to turn the gene off where it doesn't belong.

"The sense of smell is an Achilles heel for many insects," said Mark Johnston, Editor-in-Chief of the journal GENETICS, "and the more we learn about odor receptors the easier it will be to interfere with them to battle insect-borne disease and crop devastation. This study is a step forward in doing that by identifying the mechanism that results in the highly selective expression of 'smell genes'."


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Family Members of Children with Cancer May Also Be at Risk

When a child is diagnosed with cancer, one of the first questions the parents ask is “Will my other children get cancer?” A new study from Huntsman Cancer Institute (HCI) at the University of Utah suggests the answer to that question depends on whether a family history of cancer exists. The research results were published online in the International Journal of Cancer and will appear in the November 15 print issue.

The study, led by Joshua Schiffman, M.D., medical director of HCI’s High Risk Pediatric Cancer Clinic and a pediatric hematologist/oncologist in in the Department of Pediatrics at the University of Utah, examined the family medical history of 4,482 children diagnosed with cancer over a 43-year period to determine the cancer risk in their relatives.
The research team found that when children were diagnosed with any kind of cancer at age 18 or younger, the risk to their parents, siblings, or children for childhood cancer doubled compared to families with no childhood cancer patients. If the cancer diagnosis came when the child was ag4 or less, the risk to close relatives for childhood cancer increased almost four times.
“No one had previously studied the question, so we simply told parents there was no evidence of increased risk to the other children,” said Schiffman. “Now we can give an evidence-based answer—the risk depends on your family history of cancer.”
This is the first study that uses the Utah Population Database (UPDB) to broadly examine the risk of all types of cancer in relatives of children with cancer. This unique resource at the University of Utah links genealogies and cancer registry data from Utah to medical records and vital records, including Utah death certificates.
“Because our data came from the UPDB, the assessment of family history in our study does not rely on self- or family-reported medical history,” said lead author Karen Curtin, Ph.D., a genetic epidemiologist and UPDB assistant director. “Self-reporting of family medical history depends on an individual’s memory, while our data comes from the statewide Utah Cancer Registry that records nearly all cancer cases, which reduces possible errors in reporting family cancers.”
The team also assessed known inherited genetic syndromes in adult relatives of pediatric cancer patients. They found cancers associated with Li-Fraumeni Syndrome (LFS) seemed to be driving the increased risk to relatives in families with a history of cancer.
“Not all children’s cancers are hereditary,” said Schiffman. “But the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5-10% generally cited in adult hereditary cancers, and likely even more than 20%.
“LFS is one of the most devastating cancer syndromes,” said Schiffman. “It causes a variety of cancers in both children and adults. For people with LFS, the lifetime risk of getting cancer is 80% to 90%, but with increased and early screening for tumors, there’s early indication of a very high survival rate, perhaps even approaching100%. In a previous study, LFS patients who did not receive early screening only had a 20% survival rate.”
Although childhood cancer rarely occurs in the population, based on their findings, the authors recommended collection of three generations of family medical history for all newly diagnosed pediatric cancer patients and referral of families with a history of early-onset cancers in children or adults for genetic counseling. In addition, parents of children diagnosed with cancer before age five with a family history of cancer should be advised of the potential for increased risk to other children in the family.
“We want to encourage the taking of a family history as part of routine care. With all cancers, but perhaps especially with childhood cancers, so many other questions seem so urgent, a family history may not seem to be the most pressing issue,” said co-author Wendy Kohlmann, director of HCI’s Genetic Counseling Program. “When families are referred into genetic counseling, we can provide them with more information about the risks and actions they can take.”
“For families with previously unidentified LFS, following these recommendations could actually save the lives of multiple family members if at risk individuals are identified and early cancer surveillance programs implemented,” Schiffman said.
The data analyzed in this study indicated that outcomes for pediatric cancer patients are worse in families with a history of cancer. Schiffman said that further studies are planned to learn the clinical implications of this observation.

Other co-authors of the article include Ken R. Smith, Ph.D., an HCI investigator, director of the UPDB and a professor in Human Development and Family Studies at the University of Utah; Alison Fraser; and Richard Pimentel, both of HCI’s UPDB resource. The study was funded by an Alex’s Lemonade Stand Foundation Epidemiology Award, the Utah State Department of Health, Huntsman Cancer Foundation, the National Institutes of Health grant number P30 CA042014, and the National Cancer Institute’s SEER program HHSN261201000026C.

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The Temperature Tastes - Thermal Sensor in Insects Linked to Taste, Smell

Call it the Goldilocks Principle — animals can survive and reproduce only if the temperature is just right. Too hot and they will overheat. Too cold and they will freeze. To stay in their comfort zone, animals have evolved very sensitive temperature sensors to detect the relatively narrow margin in which they can survive. Until recently, scientists knew little about how these sensors operated.

 Now, a team of Brandeis University scientists has discovered a previously unknown molecular temperature sensor in fruit flies belonging to a protein family responsible for sensing tastes and smells. These types of sensors are present in disease-spreading insects like mosquitoes and tsetse flies and may help scientists better understand how insects target warm-blooded prey — like humans — and spread disease. 
The discovery is published in the advance online edition of the journal Nature.
Biting insects, such as mosquitoes, are attracted to carbon dioxide and heat. Notice how mosquitoes always seem to bite where there is the most blood? That is because those areas are the warmest, says Paul Garrity, a professor of biology in the National Center for Behavioral Genomics at Brandeis who co-authored the paper.
“If you can find a mosquito’s temperature receptor, you can potentially produce a more effective repellent or trap,” Garrity says. “The discovery of this new temperature receptor in the fruit fly gives scientists an idea of where to look for similar receptors in the mosquito and in other insects.”
Professor of Biology Leslie Griffith and Associate Professor of Biochemistry Douglas Theobald assisted with the research, which was led by postdoctoral fellows Lina Ni and Peter Bronk.
The newly discovered sensor belongs to a family of proteins, called gustatory receptors, that have been studied for over a decade but never linked to thermosensation, Garrity says. In previous studies, other gustatory receptors have been found to allow insects to smell carbon dioxide and to taste sugar and bitter chemicals like caffeine.
But in fruit flies, one type of gustatory receptor senses heat rather than smell or taste. This receptor, known as Gr28b, is responsible for sensing external temperatures and triggering a quick response if temperatures exceed the fly’s Goldilocks zone, Garrity and his team discovered.
The research also reconciles previously conflicting views of how a fruit fly senses warmth, by showing that the insect has distinct external and internal systems for thermal detection.
Related systems are likely present in other insects, including those that spread diseases like malaria and sleeping sickness that kill hundreds of thousands annually. The more scientists understand about how insects respond to and sense heat, the better they can understand insect migration in response to rising global temperatures and the spread of disease through insect bites.
“This research reveals a new way in which animals detect temperature,” Garrity says. “It’s important because heat detection is critical for the behavior of insects that spread disease, kill crops and impact the environment.”

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Children and Magnets Have a Dangerous Attraction, End Up in the ER


Cases involving children ingesting magnets quintupled between 2002 and 2011, with ingestion of multiple magnets generally resulting in more serious outcomes, including emergency surgery.  The results of a study documenting a rapid rise in pediatric injuries was published online yesterday in Annals of Emergency Medicine ("Rise in Pediatric Magnet-Related Foreign Bodies Requiring Emergency Care")
"It is common for children to put things in their mouth and nose, but the risk of intestinal damage increases dramatically when multiple magnets are swallowed," said lead study author Jonathan Silverman, MD, of the Department of Pediatrics at the University of Washington in Seattle, Wash. "The ingestion of multiple magnets can severely damage intestinal walls to the point that some kids need surgery. The magnets in question were typically those found in kitchen gadgets or desk toys marketed to adults but irresistible to children."
Over a 10-year period, 22,581 magnetic foreign body injuries were reported among children. Between 2002 and 2003, incidence of injury was 0.57 cases per 100,000 children; between 2010 and 2011, that jumped to 3.06 cases per year out of 100,000 children. The majority of the cases occurred in 2007 or later.
In cases where children ingested multiple magnets, 15.7 percent were admitted to the hospital (versus 2.3 percent of single magnet ingestions). Nearly three-quarters (74 percent) of magnets were swallowed; twenty-one percent were ingested through the nose.  Nearly one-quarter (23.4 percent) of the case reports described the magnets as "tiny," or other variants on the word "small."
"The injuries were not restricted to small children either," said Dr. Silverman. "There were proportionally more nasal injuries involving older children, possibly because strong, attractive magnets are being used to imitate nose, tongue, lip or cheek piercings.  Parents need to be aware of the serious risk these rare-earth magnets pose if swallowed."

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Saturday, August 10, 2013

Scientists Isolate New Antifreeze Molecule in Alaska Beetle

Scientists have identified a novel antifreeze molecule in a freeze-tolerant Alaska beetle able to survive temperatures below minus 100 degrees Fahrenheit. Unlike all previously described biological antifreezes that contain protein, this new molecule, called xylomannan, has little or no protein. It is composed of a sugar and a fatty acid and may exist in new places within the cells of organisms.
"Scientists have identified a novel 
antifreeze molecule in a freeze-tolerant
 Alaska beetle, Upis ceramboides, 
able to survive temperatures 
below minus 100 degrees Fahrenheit. 
Unlike all previously described biological 
antifreezes that contain protein, this 
new molecule, called xylomannan, has little 
or no protein. It is composed of a 
sugar and a fatty acid and may exist in 
new places within the cells of organisms."
(Credit: Todd Sformo and Franziska Kohl)
"The most exciting part of this discovery is that this molecule is a whole new kind of antifreeze that may work in a different location of the cell and in a different way," said zoophysiologist Brian Barnes, director of the University of Alaska Fairbanks Institute of Arctic Biology and one of five scientists who participated in the Alaska Upis ceramboides beetle project.
Just as ice crystals form over ice cream left too long in a freezer, ice crystals in an insect or other organism can draw so much water out of the organism's cells that those cells die. Antifreeze molecules function to keep small ice crystals small or to prevent ice crystals from forming at all. They may help freeze-tolerant organisms survive by preventing freezing from penetrating into cells, a lethal condition. Other insects use these molecules to resist freezing by supercooling when they lower their body temperature below the freezing point without becoming solid.
UAF graduate student and project collaborator Todd Sformo found that the Alaska Upis beetle, which has no common name, first freezes at about minus 18.5 degrees Fahrenheit in the lab and survives temperatures down to about 104 degrees below zero Fahrenheit.
"It seems paradoxical that we find an antifreeze molecule in an organism that wants to freeze and that's adapted to freezing," said Barnes, whose research group is involved in locating insects, determining their strategies of overwintering and identifying the mechanisms that help them get through the winter
A possible advantage of this novel molecule comes from it having the same fatty acid that cells membranes do. This similarity, says Barnes, may allow the molecule to become part of a cell wall and protect the cell from internal ice crystal formation. Antifreeze molecules made of proteins may not fit into cell membranes.
"There are many difficult studies ahead," said Barnes. "To find out how common this biologic antifreeze is and how it actually prevents freezing and where exactly it's located."
This project was led by Kent Walters at the University of Notre Dame with collaborators Anthony Serianni and John H. Duman of UND and Barnes and Sformo of UAF and was published in the Dec. 1 issue of the journal Proceedings of the National Academy of Sciences.
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Ice Ages Only thanks to Feedback

Science struggled to explain fully why an ice age occurs every 100,000 years. As researchers now demonstrate based on a computer simulation, not only do variations in insolation play a key role, but also the mutual influence of glaciated continents and climate.
Ice ages and warm periods have alternated fairly regularly in the Earth’s history: the Earth’s climate cools roughly every 100,000 years, with vast areas of North America, Europe and Asia being buried under thick ice sheets. Eventually, the pendulum swings back: it gets warmer and the ice masses melt. While geologists and climate physicists found solid evidence of this 100,000-year cycle in glacial moraines, marine sediments and arctic ice, until now they were unable to find a plausible explanation for it.
Using computer simulations, a Japanese, Swiss and American team including Heinz Blatter, an emeritus professor of physical climatology at ETH Zurich, has now managed to demonstrate that the ice-age/warm-period interchange depends heavily on the alternating influence of continental ice sheets and climate.
“If an entire continent is covered in a layer of ice that is 2,000 to 3,000 metres thick, the topography is completely different,” says Blatter, explaining this feedback effect. “This and the different albedo of glacial ice compared to ice-free earth lead to considerable changes in the surface temperature and the air circulation in the atmosphere.” Moreover, large-scale glaciation also alters the sea level and therefore the ocean currents, which also affects the climate.
Weak effect with a strong impact
As the scientists from Tokyo University, ETH Zurich and Columbia University demonstrated in their paper published in the journal Nature, these feedback effects between the Earth and the climate occur on top of other known mechanisms. It has long been clear that the climate is greatly influenced by insolation on long-term time scales. Because the Earth’s rotation and its orbit around the sun periodically change slightly, the insolation also varies. If you examine this variation in detail, different overlapping cycles of around 20,000, 40,000 and 100,000 years are recognisable (see box).
Given the fact that the 100,000-year insolation cycle is comparatively weak, scientists could not easily explain the prominent 100,000-year-cycle of the ice ages with this information alone. With the aid of the feedback effects, however, this is now possible.
Simulating the ice and climate
The researchers obtained their results from a comprehensive computer model, where they combined an ice-sheet simulation with an existing climate model, which enabled them to calculate the glaciation of the northern hemisphere for the last 400,000 years. The model not only takes the astronomical parameter values, ground topography and the physical flow properties of glacial ice into account but also especially the climate and feedback effects. “It’s the first time that the glaciation of the entire northern hemisphere has been simulated with a climate model that includes all the major aspects,” says Blatter.
Using the model, the researchers were also able to explain why ice ages always begin slowly and end relatively quickly. The ice-age ice masses accumulate over tens of thousands of years and recede within the space of a few thousand years. Now we know why: it is not only the surface temperature and precipitation that determine whether an ice sheet grows or shrinks. Due to the aforementioned feedback effects, its fate also depends on its size. “The larger the ice sheet, the colder the climate has to be to preserve it,” says Blatter. In the case of smaller continental ice sheets that are still forming, periods with a warmer climate are less likely to melt them. It is a different story with a large ice sheet that stretches into lower geographic latitudes: a comparatively brief warm spell of a few thousand years can be enough to cause an ice sheet to melt and herald the end of an ice age.
The Milankovitch cycles
The explanation for the cyclical alternation of ice and warm periods stems from Serbian mathematician Milutin Milankovitch (1879-1958), who calculated the changes in the Earth’s orbit and the resulting insolation on Earth, thus becoming the first to describe that the cyclical changes in insolation are the result of an overlapping of a whole series of cycles: the tilt of the Earth’s axis fluctuates by around two degrees in a 41,000-year cycle. Moreover, the Earth’s axis gyrates in a cycle of 26,000 years, much like a spinning top. Finally, the Earth’s elliptical orbit around the sun changes in a cycle of around 100,000 years in two respects: on the one hand, it changes from a weaker elliptical (circular) form into a stronger one. On the other hand, the axis of this ellipsis turns in the plane of the Earth’s orbit. The spinning of the Earth’s axis and the elliptical rotation of the axes cause the day on which the Earth is closest to the sun (perihelion) to migrate through the calendar year in a cycle of around 20,000 years: currently, it is at the beginning of January; in around 10,000 years, however, it will be at the beginning of July.
Based on his calculations, in 1941 Milankovitch postulated that insolation in the summer characterises the ice and warm periods at sixty-five degrees north, a theory that was rejected by the science community during his lifetime. From the 1970s, however, it gradually became clearer that it essentially coincides with the climate archives in marine sediments and ice cores. Nowadays, Milankovitch’s theory is widely accepted. “Milankovitch’s idea that insolation determines the ice ages was right in principle,” says Blatter. “However, science soon recognised that additional feedback effects in the climate system were necessary to explain ice ages. We are now able to name and identify these effects accurately.”
Literature reference
Abe-Ouchi A, Saito F, Kawamura K, Raymo ME, Okuno J, Takahashi K, Blatter H: Insolation-driven 100,000-year glacial cycles and hysteresis of ice-sheet volume. Nature, 2013, 500: 190-193, doi: 10.1038/nature12374

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Scientists Use Genome Sequencing To Prove Herbal Remedy Causes Upper Urinary Tract Cancers

Genomic sequencing experts at Johns Hopkins partnered with pharmacologists at Stony Brook University to reveal a striking mutational signature of upper urinary tract cancers caused by aristolochic acid, a plant compound contained in herbal remedies used for thousands of years to treat a variety of ailments such as arthritis, gout and inflammation. Their discovery is described in the Aug. 7 issue of Science Translational Medicine.
Aristolochic [pronounced a-ris-to-lo-kik] acid is found in the plant family “Aristolochia,” a vine known widely as birthwort, and while the U.S. Food and Drug Administration first warned of its cancer-causing potential in 2001, botanical products and herbal remedies containing it can still be purchased online. Moreover, the vine has been found to be an environmental carcinogen through the contamination of food supplies of farming villages in the Balkans, where Aristolochia grows wildly in the local wheat fields. For years, scientists have known of some mutations in upper urinary tract cancer patients exposed to the plant toxin. But the genome-wide spectrum of mutations associated with aristolochic acid exposure remained largely unknown.
For the current study, the Johns Hopkins and Stony Brook team used whole-exome sequencing on 19 Taiwanese upper urinary tract cancer patients exposed to aristolochic acid, and seven patients with no suspected exposure to the toxin. The technique scours the exome, part of the human genome that contains codes for functional proteins and can reveal particular mutations, in this case, those associated with cancer.
“Genome-wide sequencing has allowed us to tie aristolochic acid exposure directly to an individual getting cancer,” Kenneth Kinzler, Ph.D., professor of oncology in the Johns Hopkins Kimmel Cancer Center’s Ludwig Center for Cancer Genetics and Therapeutics. “The technology gives us the recognizable mutational signature to say with certainty that a specific toxin is responsible for causing a specific cancer. Our hope is that using the more targeted whole-exome-sequencing process will provide the necessary data to guide public health decisions related to cancer prevention.”
Specifically, Kinzler says they found an average of 753 mutations in each tumor from the toxin-exposed group compared with 91 in tumors from the non-exposed group. This level of mutation is more than that found in melanomas caused by ultraviolet radiation and lung cancer caused by smoking.
The toxin-exposed group had a large number of a particular, rare type of mistake (a mutational signature) in the ATCG chemical code of their DNA. The predominant mutation type in the toxin-exposed tumors (72 percent) was an A substituted with a T. In one instance, the scientists used the mutational signature to uncover an artistolochic-related tumor in a patient who was unaware of prior exposure.
This study illustrates how genomic sequencing could also be used to pinpoint a culprit carcinogen in some cancer clusters, says Margaret L. Hoang, Ph.D., lead author of the study. Cancer clusters are defined as an unusually large number of similar cancers occurring within a specific group of people, geographic area or period of time.
The research was funded by the Virginia and DK Ludwig Fund for Cancer Research, the Commonwealth Foundation and the Howard Hughes Medical Institute.
Scientists contributing to the work include: Margaret L. Hoang, Chung-Hsin Chen, Viktoriya S. Sidorenko, Jian He, Kathleen G. Dickman, Byeong Hwa Yun, Masaaki Moriya, Noushin Niknafs, Christopher Douville, Rachel Karchin, Robert J. Turesky, Yeong-Shiau Pu, Bert Vogelstein, Nickolas Papadopoulos, Arthur P. Grollman and Thomas A. Rosenquist.
Institutions are: the Johns Hopkins Kimmel Cancer Center’s Ludwig Center for Cancer Genetics and Therapeutics, National Taiwan University Hospital and College of Medicine, Stony Brook University, New York State Department of Health and the Division of Computational Medicine at The Johns Hopkins University.

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