Genes Help Decide When To Look For New Food

For worms, choosing when to search for a new dinner spot depends on many factors, both internal and external: how hungry they are, for example, how much oxygen is in the air, and how many other worms are around. A new study demonstrates this all-important decision is also influenced by the worm's genetic make-up.



In the simple Caenorhabditis elegans nematode, the researchers found that natural variations in several genes influence how quickly a worm will leave a lawn of bacteria on which it's feeding. One of the genes, called tyra-3, produces a receptor activated by adrenaline - a chemical messenger involved in the 'fight-or-flight' response. The findings appeared online March 16, 2011, in the journal Nature.



"What's encouraging to us about this story is that molecules related to adrenaline are implicated in arousal systems and in decision-making across a lot of different animals, including humans," says Howard Hughes Medical Institute investigator Cornelia Bargmann of Rockefeller University in New York, who mentored the work of graduate student Andres Bendesky. These parallels between diverse species suggest that aspects of our decision-making abilities have ancient evolutionary roots.



Six worms on a small lawn of bacterial food (circle). Occasionally, a worm leaves the food to explore the surrounding environment. Video: Bendesky et al. Nature



C. elegans thrive in agricultural settings, such as orchards and crop lands, feeding on bacteria from rotting fruits and vegetables. But eating in this environment is tricky: the worms encounter many bacterial species that are difficult to digest or even toxic. "The worms need to somehow evaluate a whole spectrum of conditions to decide whether they want to try this food source or go out and look for a better one," Bargmann says.



The great scientific advantage of using C. elegans to study complicated behavioral processes such as decision-making is that the worms have only 302 neurons, and the connections between all those neurons have all been precisely mapped. In contrast, the human brain has billions of neurons. What's more, most of the worm's 20,000 genes have equivalents in the human genome. "Behavior includes the action of genes, their function in neurons, and the neurons' assembly into circuits," Bargmann says. "Studying C. elegans gives you an exceptional ability to make connections between those levels."



Over the past decade, her lab has probed several of these levels. In 2004, they reported that C. elegans sense precise oxygen concentrations in soil, which helps steer them toward their favorite meal: oxygen-consuming bacteria. Three years later, they investigated what neurons do with chemosensory information, finding that odor-sensing neurons can switch on other cells that control crawling and turning behaviors.



In the new study, Bendesky and Bargmann went one level deeper, investigating how genetic tweaks can change a worm's behavior in particular circumstances. To do their experiments, the researchers placed hundreds of different strains of C. C. elegans onto Petri dishes lined with a circular "lawn" of bacteria and calculated the rate at which worms left the lawn. "Lawn-leaving is something that occurs abruptly, in an all-or-none way. It's very striking," Bargmann says.
















To find the genes that affect the behavior, they collaborated with HHMI investigator Leonid Kruglyak and his postdoc Matt Rockman to use a technique called quantitative trait locus analysis, they then analyzed the precise genetic make-up of each strain and correlated it with how frequently each strain left its lawn. In the end, the researchers could pinpoint particular genetic blips associated with moving away from a food source.



One of those blips crops up in a gene called npr-1, which had already been associated with foraging behaviors and immunity in the worm. The npr-1 variant is a special case, however, because it evolved in laboratory strains of C. elegans and is not known to exist in the wild.



In a more exciting development, the researchers also found a natural genetic variation in tyra-3 that is associated with lawn-leaving. This gene encodes a receptor protein that responds to tyramine, an adrenaline-like hormones derived from the amino acid tyrosine. Like adrenaline, tyramine is an internal signal that regulates the function of neurons expressing its various receptors.



To find out where in the brain the tyra-3 gene is turned on, the researchers engineered strains of worms in which they could observe production of tyra-3. By attaching a fluorescent green marker to the tyra-3 protein, they could easily observe whenever the protein was made. They then traced where the green fluorescence appeared inside the worms and discovered that the tyra-3 receptor is produced in a place that makes intuitive sense: sensory neurons. In these neurons, external cues, such as oxygen levels, can be integrated with internal states, such as hunger. "It's the result you would have gotten if you made it up," Bargmann says, laughing.



The findings show that particular genetic variants lead to specific behaviors in the real world - but how, exactly, they do this is still mysterious. "We don't have a fix on when tyramine is being made, where it's released, and how it's working to change behavior," Bargmann says.



Figuring that out is the obvious next step. The trouble is, the tools for tracking the brain's chemical messengers in real time don't exist yet. "We'll just have to put our heads down and develop some," she says.



Source:

Jim Keeley

Howard Hughes Medical Institute

Discovery Of Missing Link Between Fructose, Insulin Resistance

A new study in mice sheds light on the insulin resistance that can come from diets loaded with high-fructose corn syrup, a sweetener found in most sodas and many other processed foods. The report in the March issue of Cell Metabolism, a Cell Press publication, also suggests a way to prevent those ill effects.



The researchers showed that mice on a high-fructose diet were protected from insulin resistance when a gene known as transcriptional coactivator PPARg coactivator-1b (PGC-1b) was "knocked down" in the animals' liver and fat tissue. PGC-1b coactivates a number of transcription factors that control the activity of other genes, including one responsible for building fat in the liver.



"There has been a remarkable increase in consumption of high-fructose corn syrup," said Gerald Shulman of Yale University School of Medicine. "Fructose is much more readily metabolized to fat in the liver than glucose is and in the process can lead to nonalcoholic fatty liver disease," he continued. NAFLD in turn leads to hepatic insulin resistance and type II diabetes.



Metabolic syndrome and type 2 diabetes have both reached epidemic proportions worldwide with the global adoption of the westernized diet along with increased consumption of fructose, stemming from the wide and increasing use of high-fructose corn syrup sweeteners, the researchers noted.



High-fructose corn syrup, which is a mixture of the simple sugars fructose and glucose, came into use in the 1970s and by 2005 the average American was consuming about 60 pounds of it per year. Overall, dietary intake of fructose, which is also a component of table sugar, has increased by an estimated 20 to 40 percent in the last thirty years.



Earlier studies had established that fructose is more readily converted to fatty acids than glucose and had also linked high-fructose diets to high blood levels of triglycerides (a condition known as hypertriglyceridemia), NAFLD and insulin resistance. While researchers had implicated a gene known as SREBP-1, a master regulator of lipids' manufacture in the liver, much about the underlying molecular connections between fructose and those metabolic disorders remained mysterious.



In the new study, the researchers zeroed in on PGC-1b, a gene known for boosting SREBP-1 levels. To test its role in the effects of fructose, they blocked its activity in mice fed a diet high in that sugar for four weeks.



Those treatments improved the animals' metabolic profiles by lowering levels of SREBP-1 and other fat-building genes in their livers. The mice also showed a reversal of their fructose-induced insulin resistance and a threefold increase in glucose uptake in their fat tissue.



"These data support an important role for PGC-1b in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1b inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis," the researchers concluded.
















The new study has "revealed the transcriptional coactivator PGC-1b as a missing link between fructose intake and metabolic disorders," wrote Carlos Hernandez and Jiandie Lin of the University of Michigan Medical Center, Ann Arbor in an accompanying commentary. "The findings …support the emerging role of gene/environment interaction in modulating the metabolic phenotype and disease pathogenesis. Thus, perturbations of the same regulatory motif may produce vastly different metabolic responses, depending on the specific combinations of dietary nutrients," they continued.







The researchers include Yoshio Nagai, Yale University School of Medicine, New Haven, CT , Howard Hughes Medical InstituteShin Yonemitsu, Yale University School of Medicine, New Haven, CT , Howard Hughes Medical Institute; Derek M. Erion, Yale University School of Medicine, New Haven, CT, Howard Hughes Medical Institute; Takanori Iwasaki, Yale University School of Medicine, New Haven, CT; Romana Stark, Yale University School of Medicine, New Haven, CT; Dirk Weismann, Yale University School of Medicine, New Haven, CT Jianying Dong, Yale University School of Medicine, New Haven, CT; Dongyan Zhang, Yale University School of Medicine, New Haven, CT , Howard Hughes Medical Institute; Michael J. Jurczak, Yale University School of Medicine, New Haven, CT, Howard Hughes Medical Institute; Michael G. Loffler, Yale University School of Medicine, New Haven, CT; James Cresswell, Yale University School of Medicine, New Haven, CT; Xing Xian Yu, ISIS Pharmaceuticals, Carlsbad, CA; Susan F. Murray, ISIS Pharmaceuticals, Carlsbad, CA; Sanjay Bhanot, ISIS Pharmaceuticals, Carlsbad, CA; Brett P. Monia, ISIS Pharmaceuticals, Carlsbad, CA; Jonathan S. Bogan, Yale University School of Medicine, New Haven, CT; Varman Samuel, Yale University School of Medicine, New Haven, CT and Gerald I. Shulman, Yale University School of Medicine, New Haven, CT , Yale University School of Medicine, New Haven, CT, Howard Hughes Medical Institute.



Source: Cathleen Genova


Cell Press

BGI Researchers Sequenced The Human Methylome At Single Base-Pair Resolution

DNA methylation plays an important role in many processes such as animal development, X-chromosome inactivation, and carcinogenesis. Understanding the mechanisms and functions of DNA methylation and how it varies from tissue to tissue and between individuals will have profound implications for human health and disease. A team of Chinese researchers decoded the essentially complete methylome (an inventory of all the bases that are methylated) of the human genome using peripheral blood mononuclear cells (PBMCs). The results will be published in the online, open access journal PLoS Biology next week.


The research is part of YanHuang (YH) Project, which has been launched by BGI (previous known as Beijing Genomics Institute) at Shenzhen, which aims to sequence 100 Chinese individuals in 3 years to accelerate the discovery of disease genes and mutations in an Asian population. The methylome was generated from the same donor whose genome was deciphered in the YH project. The methylome was examined at 20 distinct features including regulatory, protein-coding, non-coding, and repeat sequences. The integration of the data with the previously determined genome sequence of the same Asian individual allowed the identification of allele-specific methylation (ASM) differences between the methylomes of the genomes inherited from either parent. This revealed that ASM was highly correlated with allele-specific gene expression (ASE) which indicated that parental gene imprinting (that is the favored expression of the genes inherited from one parent) may be more common than previously thought.


The research not only provides a comprehensive resource for future epigenomic research but also demonstrates a paradigm for epigenetic studies through new sequencing technology. The PBMC methylome data has been deposited to NCBI . It is expected to form a lasting resource as part of the International Human Epigenome Project.


Funding: This project was supported by the National Natural Science Foundation of China (30725008; 30890032;30811130531), the Chinese 863 program (2006AA02Z177), the Chinese Academy of Science (GJHZ0701-6), the Shenzhen Municipal Government of China (grants JC200903190772A, CXB200903110066A, ZYC200903240077A, ZYC200903240076A and ZYC200903240080A), the Danish Platform for Integrative Biology and the Ole Romer grant from the Danish Natural Science Research Council. This project was also funded by the Yantian District local government of Shenzhen. SB was supported by The Wellcome Trust (grant 084071) and is recipient of a Royal Society Wolfson Research Merit Award. JZ is supported by the funds from National Science Foundation(90919024, and 30921140312) , National Research Program for Basic Research(2009CB825606, 2009CB825607 and 2010CB912802), and Shanghai Science Foundation(09JC141300). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Competing interests statement: The authors declare that no competing interests exist.


Citation: Li Y, Zhu J, Tian G, Li N, Li Q, et al. (2010) The DNA Methylome of Human Peripheral Blood Mononuclear Cells. PLoS Biol 8(11): e1000533. doi:10.1371/journal.pbio.1000533


Source:

PLoS Biology

Paralysis In Animals Triggered By New On-Off 'Switch' - Reversed With A Beam Of Light

In an advance with overtones of Star Trek phasers and other sci-fi ray guns, scientists in Canada are reporting development of an internal on-off "switch" that paralyzes animals when exposed to a beam of ultraviolet light. The animals stay paralyzed even when the light is turned off. When exposed to ordinary light, the animals become unparalyzed and wake up. Their study appears in the Journal of the American Chemical Society (JACS). It reports the first demonstration of such a light-activated switch in animals.



Neil Branda and colleagues point out that such "photoswitches" -- light-sensitive materials that undergo photoreactions -- have been available for years. Scientists use them in research. Doctors use light-sensitive materials and photoreactions in medicine in photodynamic therapy to treat certain forms of cancer. Those light-sensitive materials, however, do not have the reversibility that exists in photoswitching.



The JACS report describes development and successful testing of a photoswitch composed of the light-sensitive material, dithienylethene. The scientists grew transparent, pinhead-sized worms (C. elegans) and fed them a dithienylethene. When exposed to ultraviolet light, the worms turned blue and became paralyzed. When exposed to visible light, the dithienylethene became colorless again and the worms' paralysis ended. Many of the worms lived through the paralyze-unparalyze cycle. Scientists were not sure how the switch causes paralysis. The study demonstrates that photoswitches may have great potential in turning photodynamic therapy on and off, and for other applications in medicine and research, they indicate.



Article: "A Photocontrolled Molecular Switch Regulates Paralysis in a Living Organism" pubs.acs/stoken/presspac/presspac/full/10.1021/ja903070u



Click here for video. (18.9 MB)



Source: Michael Bernstein


American Chemical Society


View drug information on Photodynamic Therapy.

New Designer Lipid-Lke Peptide With Lipid Nanostructures For Drug Delivery Systems

Scientists from the Institute of Biophysics and Nanosystems Research (IBN), Austrian Academy of Sciences and of Centre for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, USA report the study of "Tuning Curvature and Stability of Monoolein Bilayers by Designer Lipid-Like Peptide Surfactants" in the online, open-access journal PLoS ONE. Their findings not only help us to understand the basic science of how lipid-like peptides interact with lipid molecules, but also may provide new strategies for the encapsulation and the delivery of biological active materials. They detailed their findings in the report on the impact of integrating short surfactant-like designer peptides in lipidic nanostructures.



Anan Yaghmur, Michael Rappolt, Peter Laggner and Shuguang Zhang reported the formations of dynamic nanostructures of lipid-like peptides that are like two-headed Janus, both water-loving and water-hating, which represent a new class of designer materials using common amino acids, the same basic molecules from meat, beans and fruits. These lipid-like peptides have excellent potential to solubilize membrane proteins and enzymes, and - as now demonstrated - can also be utilized to stabilize different self-assembled liquid crystalline nanostructures. Moreover, the surface charge density of lipidic nanostructures can be varied in a simple manner.



Dr. Anan Yaghmur, first author of the study, comments on the study, "the addition of small amounts of designer lipid-like peptides is sufficient to form systems with excellent potential for various biotechnological applications such as the encapsulation of water-insoluble drugs and the delivery of biological active materials."



Currently, many anticancer drugs are difficult to deliver to patients due to their difficulty to be soluble in water. "This is a systematic study to combine with lipid molecules," Shuguang Zhang of MIT, a co-author said, "people have been curious about if these similar molecules can interact. This study provided the first answer". "Since these lipid-like peptides can be designed, just like to design an elegant watch, an art object, a music instrument, a ski, or a pair of sunglasses, we have the ultimate control to the outcome of the structure and their properties" Zhang added.



This study stemmed from a scientific visit by Peter Laggner to Shuguang Zhang at MIT in Cambridge, USA in May 2006. They shared some ideas and decided to collaborate since Laggner is a world-expert on nanostructure using small angle X-ray scattering and Zhang can provide the designer lipid-like peptides that he has been studied since 2000.



In the near future, many colloidal aqueous dispersions, which are similar to milk and some paints, with confined inner nanostructures, will offer unique characteristics like high drug load capacities and low viscosity. Here these designer lipid-like peptides may play a key role in improving effective drug delivery systems.






Disclaimer



The following press release refers to an upcoming article in PLoS ONE. The release has been provided by the article authors and/or their institutions. Any opinions expressed in this are the personal views of the contributors, and do not necessarily represent the views or policies of PLoS. PLoS expressly disclaims any and all warranties and liability in connection with the information found in the release and article and your use of such information.



Citation: Yaghmur A, Laggner P, Zhang S, Rappolt M (2007) Tuning Curvature and Stability of Monoolein Bilayers by Designer Lipid-Like Peptide Surfactants. PLoS ONE 2(5): e479. doi:10.1371/journal.pone.0000479



LINK TO THE PUBLISHED ARTICLE: plosone/doi/pone.0000479



Contact: Anan Yaghmur


Public Library of Science

Bioeffects Consensus Report Featured In Journal Of Ultrasound In Medicine

The April 2008 issue of the Journal of Ultrasound in Medicine (JUM) includes an important special feature, the "AIUM Consensus Report on Potential Bioeffects of Diagnostic Ultrasound," which addresses issues related to the bioeffects of diagnostic ultrasound and is intended for use in assessing its risks and benefits.



The report includes 5 articles that provide extensive evaluations of 5 bioeffects categories: postnatal thermal effects, fetal thermal effects, postnatal mechanical effects, fetal mechanical effects, and bioeffects considerations for ultrasound contrast agents. Each article provides an in-depth analysis, conclusions, and recommendations for use.



This work is the culmination of a 2005 conference organized by the American Institute of Ultrasound in Medicine (AIUM) Bioeffects Committee. At the 3-day conference, 37 ultrasound experts assembled to examine issues involving the potential bioeffects of diagnostic ultrasound. The results of the conference, including background and supporting materials, were then extensively reviewed and approved by the Bioeffects Committee and the AIUM Board of Governors before publication.



The Bioeffects Committee held a previous consensus conference in 1998, the results of which were published as a special issue of the JUM in February 2000.



In the "Foreword" to the current report, AIUM Immediate Past President Lennard D. Greenbaum, MD, states, "For several decades, the AIUM has been active in the evaluation of ultrasound safety through its Bioeffects Committee and special panels convened periodically to review issues related to diagnostic ultrasound . . . . The publications associated with all of these activities have provided important guidance to the medical ultrasound community."







The official journal of the AIUM, the Journal of Ultrasound in Medicine is dedicated to the rapid, accurate publication of original articles dealing with all aspects of diagnostic ultrasound, particularly its direct application to patient care but also relevant basic science, advances in instrumentation, and biological effects.



The American Institute of Ultrasound in Medicine is a multidisciplinary association dedicated to advancing the safe and effective use of ultrasound in medicine through professional and public education, research, development of guidelines, and accreditation. For more information, visit aium/.



Source: Jennifer Hilderbrand


American Institute of Ultrasound in Medicine

Another Tumor Suppressor Discovered That Leads To Accelerated Lung Tumor Growth When Mutated

Cancer causing mutations occur in our bodies every day -- but luckily, we have specific genes that recognize these malignant events and keep cells from growing out of control. Only a few of these genes -- called tumor suppressors -- are currently known.



Now scientists at the University of North Carolina at Chapel Hill School of Medicine and Harvard Medical School have added to the list another powerful tumor suppressor, a gene called LKB1. Their research indicates that this gene is mutated in almost a quarter of all human lung cancers. In mice, these mutations result in tumors that are more aggressive and more likely to spread throughout the body.



"Defects in this gene appear to result in a much nastier form of lung cancer, a disease that is bad to begin with," said Dr. Norman Sharpless, an assistant professor of medicine and genetics in the UNC School of Medicine, a member of the UNC Lineberger Comprehensive Cancer Center and a senior author of the study. This finding is expected to help doctors better assign a prognosis to their patients, as well as giving them a new target for future therapies, Sharpless said.



The study, published online in the journal Nature, also presents the first mouse model of the most lethal malignancy in man, a form of lung cancer called squamous cell carcinoma. Lung cancer kills more Americans each year than breast, prostate and colorectal cancers combined. Of the different types of lung cancer, squamous is strongly associated with tobacco use and is the most common worldwide.



Mice genetically engineered to have defects in the LKB1 gene in the lung develop cancer at a much faster rate than those with defects in other tumor suppressors commonly mutated in lung cancer. These mice develop cancers of not just one lung cancer subtype, but exhibit all three forms of non-small cell lung cancer: adenocarcinomas, squamous cell carcinomas and large cell carcinomas. In addition, these cancers are more likely to metastasize, or spread to other organs.



"Clearly mice with lung cancers harboring LKB1 mutations do much worse than those with other types of cancers; however, we still do not know what this gene does," Sharpless said. "This mouse model will enable us to determine how this gene is important for lung cancer and to develop therapies targeted in a way that can help human patients."



To determine whether the model mirrors the genetic events of human lung cancer, the researchers analyzed DNA from 144 non-small cell lung cancer patients treated at UNC and affiliated hospitals. Defects in LKB1 appeared in 34 percent of human lung adenocarcinomas, 19 percent of squamous cell carcinomas and 10 percent of large cell carcinomas.



"Based on this study and ones like it we should be able to sort patients into groups based on exactly what genetic lesion is causing their cancer," said Dr. Neil Hayes, an assistant professor of medicine in UNC's School of Medicine, a member of UNC Lineberger and co-author of the study. "Then we can make better treatment decisions depending on which therapy is most likely to target that defect."



Currently, Hayes and his colleagues are looking at cancer progression in patients from this study to see how specific LKB1 mutations correlate with clinical outcomes.







The research was funded in part by grants from the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the Joan Scarangello Foundation to Conquer Lung Cancer, the Flight Attendant Medical Research Institute, Waxman Foundation and Harvard Stem Cell Institute.



Study co-authors at UNC include Matthew Ramsey, Cheng Fan, Chad Torrice and Janakiraman Krishnamurthy.



Drs. Kwok-Kin Wong of Dana-Farber Cancer Institute and Nabeel Bardeesy at Massachusetts General Hospital contributed equally to this work.



School of Medicine contacts: Les Lang and Stephanie Crayton

Lineberger Center contact: Dianne Shaw



Source: L. H. Lang


University of North Carolina School of Medicine