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Archive - Nov 2014

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November 28th

Bitter Food, but Posssibly Sweet Medicine, from Cucumber Genetics

High-tech genomics and traditional Chinese medicine come together as researchers identify the genes responsible for the intense bitter taste of wild cucumbers. Taming this bitterness made cucumber, pumpkin, and their relatives into popular foods, but the same compounds also have potential to treat cancer and diabetes. "You don't eat wild cucumber, unless you want to use it as a purgative," said Dr. William Lucas, professor of plant biology at the University of California, Davis, and coauthor on the article published in the November 28, 2014 issue of Science. That bitter flavor in wild cucurbits -- the family that includes cucumber, pumpkin, melon, watermelon, and squash -- is due to compounds called cucurbitacins. The bitter taste protects wild plants against predators. The fruit and leaves of wild cucurbits have been used in Indian and Chinese medicine for thousands of years, as emetics and purgatives, and to treat liver disease. More recently, researchers have shown that cucurbitacins can kill or suppress growth of cancer cells. Bitterness is known to be controlled by two genetic traits, "Bi" which confers bitterness on the whole plant and "Bt", which leads to bitter fruit. In the new work, Dr. Lucas, Dr. Sanwen Huang at the Chinese Academy of Agricultural Sciences, and colleagues employed the latest in DNA sequencing technology to identify the exact changes in DNA associated with bitterness. They also tasted a great many cucumbers. "Luckily this is an easy trait to test for," Dr. Lucas said.

November 27th

Pseudouridylation Found to Occur Naturally in mRNA

The so-called central dogma of molecular biology—that DNA makes RNA which makes protein—has long provided a simplified explanation for how genetic information is deciphered and translated in living organisms. In reality, of course, the process is vastly more complicated than the schema first articulated nearly 60 years ago by Nobel Laureate Francis Crick, co-discoverer of the DNA’s double-helix structure. For one, there are multiple types of RNA, three of which—messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)—are essential for proper protein production. Moreover, RNAs that are synthesized during the process known as transcription often undergo subsequent changes, which are referred to as “post-transcriptional modifications.” Multiple such RNA modifications have been documented over the years, although the precise functions and significance of many of these have been shrouded in mystery. Among the most common post-transcriptional modifications is pseudouridylation, during which the base nucleoside uridine—the ‘U’ of the four base RNA nucleosides abbreviated as A, C, G, and U—has its chemical structure altered to form a molecule known as pseudouridine (ψ) (see image). To date, ψ has been found in abundance in tRNA, rRNA, and small nuclear or snRNA, but was thought not to exist in mRNA. Deploying sophisticated high-throughput sequencing technology, dubbed ψ-seq, a team of Whitehead Institute and Broad Institute researchers collaborated on a comprehensive, high-resolution mapping of ψ sites that confirms that pseudouridylation does indeed occur naturally in mRNA. This somewhat surprising finding and the novel approach that led to it were revealed online on September 13, 2014 in Cell.

November 26th

Study Reveals Basis of Key Immune Protein's Two-Faced Role; Identification of TIM-3’s Partner May Stimulate Therapeutic Development

A Brigham and Women's Hospital (BWH)-led team has identified a long-sought-after partner for a key immune protein, called TIM-3 (image), that helps explain TIM-3’s two-faced role in the immune system -- sometimes dampening it, other times stimulating it. TIM-3 is T-cell immunoglobulin mucin-3. It negatively regulates Th1 responses and affects macrophage activation. This newly identified partner of TIM-3 not only sheds light on the inner workings of the immune system in diseases such as HIV, autoimmunity, and cancer, but also provides a critical path toward the development of novel treatments that target TIM-3. The research findings were publishe online on October 26, 2014 in Nature. "There has been a lot of confusion around TIM-3 -- how does it both inhibit and activate the immune system," said Dr. Richard Blumberg, chief of the Division of Gastroenterology, Hepatology, and Endoscopy at BWH and senior author of the paper. "This is a crucial question because TIM-3 has been recognized as an important drug target, but nobody really understands exactly how to approach it because of this Janus-like property." The interest in TIM-3 as a drug target stems largely from its inhibitory role, particularly in cancer. When immune cells are stimulated over long periods of time, they switch on signals, such as TIM-3, that help them dial down their own activity. This chronically activated state, termed "exhaustion," is an immunological hallmark of chronic viral infections, such as HIV. It is also common in cancer. If there were a way to block TIM-3 pharmacologically, it could unleash the immune system, freeing it to attack tumors. Despite this interest, the details of how TIM-3 works have been unclear -- until now. Dr.

November 25th

Link Found Between Transcription and Disease-Causing DNA Repeat Expansions

Researchers in human genetics have known that long nucleotide repeats in DNA lead to instability of the genome and ultimately to human hereditary diseases such as Freidreich's ataxia and Huntington's disease. Scientists have believed that the lengthening of those repeats occurs during DNA replication when cells divide or when the cellular DNA repair machinery gets activated. Recently, however, it became apparent that yet another process called transcription (see image), which is copying the information from DNA into RNA, could also been involved. A Tufts University study published online on November 20, 2014 in Cell Reports by a research team led by Dr. Sergei Mirkin, the White Family Professor of Biology at the Tufts School of Arts and Sciences, along with former graduate student Dr. Kartick Shah and graduate students Ryan McGuity and Vera Egorova, explores the relationship between transcription and the expansions of DNA repeats. It concludes that the active transcriptional state of a DNA segment containing a DNA repeat predisposes it for expansions. "There are a great many simple repetitive motifs in our DNA, such as GAAGAAGAA or CGGCGGCGG," says Dr. Mirkin. "They are stable and cause no harm if they stay short. Occasionally, however, they start lengthening compulsively, and these uncontrollable expansions lead to dramatic changes in genome stability, gene expression, which can lead to human disease." In their study, the researchers used baker's yeast to monitor the progress and the fundamental genetic machineries for transcription, replication, and repair in genome functioning. "The beauty of the yeast system is that it provides one with a practically unlimited arsenal of tools to study the mechanisms of genome functioning," says Dr.

How Environment and Oxidized Nucleotides Contribute to Several Human Diseases

Using a new imaging technique, NIH researchers have found that the biological machinery that builds DNA can insert molecules into the DNA strand that are damaged as a result of environmental exposures. These damaged molecules trigger cell death that produces some human diseases, according to the researchers. The work, published online on November 17, 2014 in Nature, provides a possible explanation for how one type of DNA damage may lead to cancer, diabetes, hypertension, cardiovascular and lung disease, and Alzheimer’s disease. Time-lapse crystallography was used by National Institute of Environmental Health Sciences (NIEHS) researchers to determine that DNA polymerase, the enzyme responsible for assembling the nucleotides or building blocks of DNA, incorporates nucleotides with a specific kind of damage into the DNA strand. Time-lapse crystallography is a technique that takes snapshots of biochemical reactions occurring in cells. Samuel Wilson, M.D., senior NIEHS researcher on the team, explained that the damage is caused by oxidative stress, or the generation of free oxygen molecules, in response to environmental factors, such as ultraviolet exposure, diet, and chemical compounds in paints, plastics, and other consumer products. He said scientists suspected that the DNA polymerase was inserting nucleotides that were damaged by carrying an additional oxygen atom. After the DNA polymerase inserts a damaged nucleotide into DNA, the damaged nucleotide is unable to bond with its undamaged partner. As a result, the damaged nucleotide swings freely within the DNA, interfering with the repair function or causing double-strand breaks. These steps may ultimately lead to several human diseases.

November 24th

Babies Remember Good Feeling-Associated Images, Study Shows

Parents who spend their time playing with and talking to their five-month-old baby may wonder whether their child remembers any of it a day later. Thanks to a new Brigham Young University (BYU) study, we now know that they at least remember the good times. The study, published in the November 2014 issue of Infant Behavior and Development, shows that babies are more likely to remember something if there is a positive emotion, or affect, that accompanies it. “People study memory in infants, they study discrimination in emotional affect, but we are the first ones to study how these emotions influence memory,” said BYU psychology professor Dr. Ross Flom, lead author of the study. Although the five-month-olds can’t talk, there are a number of different ways that researchers can analyze how the babies respond to testing treatments. In this particular study, the scientists monitored the infants’ eye movements and how long they looked at a test image. The babies were set in front of a flat paneled monitor in a closed-off partition and then exposed to a person on screen speaking to them with either a happy, neutral, or angry voice. Immediately following the emotional exposure, they were shown a geometric shape. To test their memory, the researchers did follow-up tests five minutes later and again one day later. In the follow-up tests, babies were shown two side-by-side geometric shapes: a brand new one, and the original one from the study. The researchers then were able to record how many times the baby looked from one image to the next and how long they spent looking at each image. Babies’ memories didn’t improve if the shape had been paired with a negative voice, but they performed significantly better at remembering shapes attached to positive voices.

Long-Term Survivors of Retinoblastoma Fare Well Cognitively and Socially; Diagnosis in First Year of Life Leads to Better Scores in Many Tests

Most long-term survivors of retinoblastoma, particularly those who had been diagnosed with tumors by their first birthdays, have normal cognitive function as adults, according to a St. Jude Children’s Research Hospital study. The research, which was published online on November 24, 2014 in the journal Cancer, found that the vast majority of survivors work full time, live independently, and fulfill other milestones of adult life. The study is the first to examine how adult survivors of retinoblastoma fare cognitively and socially decades after their diagnosis. The findings contrast with research involving survivors of other childhood cancers that suggest a younger age at cancer diagnosis may put survivors at risk for reduced cognitive functioning later in life. “As a group, adult survivors of retinoblastoma are doing quite well based on their cognitive functioning and attainment of adult social milestones,” said the study’s first and corresponding author Tara Brinkman, Ph.D., an assistant member of the St. Jude Department of Epidemiology and Cancer Control and the Department of Psychology. “This suggests that for children whose visual system is damaged very early in life, the brain may compensate by reorganizing areas responsible for processing visual information to enhance processing of verbal and auditory information,” Dr. Brinkman said. “This highlights the importance of early intervention and rehabilitation for these patients.” Retinoblastoma is diagnosed in about 350 children annually in the U.S., and 95 percent of patients are younger than 5 years old when their tumor is identified. Today, more than 95 percent of retinoblastoma patients become long-term survivors. Previous research with retinoblastoma survivors focused on cognitive functioning in childhood. The results of those studies were mixed.

Landmark Evolution Research Groups Turtles Closest to Birds, Crocodiles, & Dinosaurs; Not Lizards & Snakes

A team of scientists, including researchers from the California Academy of Sciences, has reconstructed a detailed "tree of life" for turtles. The specifics of how turtles are related--to one another, to other reptiles, and even to dinosaurs--have been hotly debated for decades. Next-generation sequencing technologies in Academy labs have generated unprecedented amounts of genetic information for a thrilling new look at turtles' evolutionary history. These high-tech lab methods have revolutionized the way scientists explore species origins and evolutionary relationships, and provide a strong foundation for future looks into Earth's fossil record. Research results, which were published online on November 4, 2014 in an open-access article in Molecular Phylogenetics and Evolution, describe how a new genetic sequencing technique called Ultra Conserved Elements (UCE) reveals turtles' closest relatives across the animal kingdom. The new genetic tree uses an enormous amount of data to refute the notion that turtles are most closely related to lizards and snakes. Instead, authors place turtles in the newly named group "Archelosauria" with their closest relatives being birds, crocodiles, and dinosaurs. Scientists suspect the new group will be the largest group of vertebrates to ever receive a new scientific name. The UCE technique used in high-tech labs allowed scientists to move beyond years of speculation and place the Archelosauria group in its rightful place on the reptile tree of life. UCE has been available since 2012, yet scientists are just beginning to tap its potential for generating enormous amounts of genetic data across vertebrates.

ASU & IBM Make Progress Toward Ultra Low-Cost DNA Sequencing with Fixed-Gap Tunnel Junction Device

A team of scientists from Arizona State University's Biodesign Institute and IBM's T.J. Watson Research Center has developed a prototype DNA reader that could make whole-genome profiling an everyday practice in medicine. "Our goal is to put cheap, simple, and powerful DNA and protein diagnostic devices into every single doctor's office," said Dr. Stuart Lindsay (photo), an ASU physics professor and director of Biodesign's Center for Single Molecule Biophysics. Such technology could help usher in the age of personalized medicine, where information from an individual's complete DNA and protein profiles could be used to design treatments specific to their individual makeup. The report was published online on November 7, 2014 in ACS Nano. Such game-changing technology is needed to make genome sequencing a reality. The current hurdle is to do so for less than $1,000, an amount for which insurance companies are more likely to provide reimbursement. In their latest research breakthrough, the team fashioned a tiny, DNA reading device a thousands of times smaller than the width of a single human hair. The device is sensitive enough to distinguish the individual chemical bases of DNA when they are pumped past the reading head. Proof-of-concept was demonstrated, by using solutions of the individual DNA bases, which gave clear signals sensitive enough to detect tiny amounts of DNA (nanomolar concentrations), even better than today's state-of-the-art, so-called next-generation DNA sequencing technology. Making the solid-state device is similar to making a sandwich, just with ultra-high-tech semiconductor tools used to slice and stack the atomic-sized layers of meats and cheeses like the butcher shop's block.

November 23rd

Four Gene Loci Newly Identified for Severe Food Allergy

Scientists have identified four gene loci newly associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the findings may point toward potential new treatments for EoE. "This research adds to the evidence that genetic factors play key roles in EoE, and broadens our knowledge of biological networks that may offer attractive targets for therapy," said study leader Hakon Hakonarson (image), M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). Dr. Hakonarson and colleagues from other hospitals and academic centers published the study online on November 19, 2014 in Nature Communications. The research builds on a 2010 study by Dr. Hakonarson and colleagues that identified TSLP (thymic stromal lymphopoietin ) as the first major gene associated with EoE. Only recently recognized as a distinct condition, EoE has been rapidly increasing in prevalence over the past 20 years. Its hallmark is inflammation and painful swelling in the esophagus, along with high levels of immune cells called eosinophils. It can affect people of any age, but is more common among young men who have a history of other allergic diseases such as asthma and eczema. EoE is often first discovered in children with feeding difficulties and failure to thrive. Because children with EoE are often allergic to many foods, they may be placed on a highly-restricted diet containing no large food proteins, to allow time for their symptoms to resolve. Physicians then perform tests to determine which foods a child can or cannot eat.