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March 20th, 2010

Differences in Transcription Factor Binding May Explain Many Human Differences

Differences in gene expression associated with differences in transcription factor binding may help explain many of the differences among individual humans, according to a team of Yale University researchers and collaborators. Transcription factors bind to DNA regions and set in motion programs of increased or decreased gene expression through their influence on the binding of RNA polymerase and the transcription of DNA to RNA. Using the technique of chromatin immunoprecipitation followed by sequencing (ChIP-Seq), the authors showed, on a genome wide basis, that the binding regions for RNA polymerase II and NF-kappa B differed by 25 percent and 7.5 percent, respectively, between any two human individuals in samples of lymphoblastoid cells from 10 individuals of various ancestries. RNA polymerase II, which is active in all cells, transcribes DNA into RNA, and its activity is dependent on the appropriate transcription factors being present at the DNA binding regions. NF-kappa B is a transcription factor that is activated by stress, plays a key role in immune responses to infections, and has been implicated in several diseases, including cancer. Approximately 19,000 and 15,500 binding regions were found for RNA polymerase II and NF-kappa B, respectively, in the study. The researchers found that differences in the binding of RNA polymerase II and NF-kappa B at DNA regions were frequently associated with SNPs and genomic structural variants (SVs), such as duplications, deletions, and inversions of long stretches of DNA, and were often correlated with differences in gene expression, suggesting functional consequences of binding variation.

Cough Medicine Ingredient Shows Promise for Prostate Cancer Treatment

Researchers have shown that, in mice, the cough medicine ingredient noscapine inhibits prostate tumor growth and also limits the spread of tumors without causing any side-effects. Noscapine, a non-addictive derivative of opium, has been used worldwide since the 1950s as an ingredient in over-the-counter cough medicines and was originally suggested as an anti-cancer agent in the early 1960s--but major studies of its anti-cancer properties have only taken place in recent years. The current research focused on pre-treating mice with noscapine before injecting them with prostate cancer cells. This resulted in the tumor growth rate being two-thirds lower in the noscapine group than in a non-noscapine group. The study also found that metastasis rates to the lung were 80 percent lower in the mice pre-treated with noscapine. The scientists further noted that the noscapine group suffered no cancer-related weight loss--compared with significant weight loss in the non-noscapine group. They concluded that noscapine administered as a preventive measure may offer significant benefits in the management of prostate cancer, a disease that kills more than 28,000 men in the U.S. each year. The research team is now hoping to further its efforts by examining the effects of noscapine as a prophylactic agent given to patients following prostate cancer surgery or radiation. "Based on our research so far, we believe that noscapine could be a very promising treatment to prevent recurrence in such cases due to its excellent safety record and oral bioavailability," said co-author Dr. Israel Barker, Founder and Medical Director of the Prostate Cancer Research and Education Foundation. This new pre-clinical research was reported in Volume 30(2) of Anticancer Research.

March 18th

Most Domesticated Dogs Originated in Middle East, Study Suggests

Most domesticated dogs likely originated from gray wolves in the Middle East, with only some possibly originating in Europe or Asia, according to a new genetic analysis by an international team of scientists led by UCLA biologists. The team reported genetic data from 912 dogs from 85 breeds (including all the major ones) and 225 wild gray wolves (the ancestor of domesticated dogs) worldwide, including populations from North America, Europe, the Middle East and East Asia. The scientists used molecular genetic techniques to analyze more than 48,000 genetic markers (SNPs) on a genome-wide basis in the dogs and wolves. The team has not yet pinpointed a specific location of origin in the Middle East. The new research results were published online on March 17, 2010 in Nature. In their work, the researchers found evidence for certain candidate genes that might have been important in the early domestication of dogs. There was evidence of positive selection for two SNPs located near genes associated with memory formation and/or behavioral sensitization in mouse or human studies. There was also evidence of positive selection for a third SNP that is located near the dog counterpart of the gene associated with Williams-Beuren syndrome in humans. This syndrome is characterized by social traits such as exceptional gregariousness. The current results were consistent with earlier analyses suggesting that three groups of ancient breeds (origins >500 years ago) are distinct from modern domestic dogs that are the products of the controlled breeding practices of the Victorian era (circa 1830-1900). These ancient breeds consist of an Asian group (dingo, New Guinea singing dog, chow chow, Akita, and Chinese Shar Pei), a Middle Eastern group (Afghan hound and saluki), and a northern group (Alaskan malamute and Siberian husky).

Molecular Basis of Detecting Noxious Chemicals Has Ancient Origin

Chemical nociception, the detection of painful, tissue-damaging chemicals like those found in wasabi, tear gas, and cigarette smoke, is triggered, in humans, by a protein receptor known as TRPA1, which is found in the nose, mouth, skin, lungs, and GI tract. Studying the chemical sensors of fruit flies, researchers at Brandeis University have discovered that flies use their ortholog of the human TRPA1 sensor for the same purpose. Using a combination of behavioral, physiological, and phylogenetic analyses, the scientists found evidence suggesting that this defensive response to noxious compounds has been present across an immense evolutionary time scale and links humans, insects, and many other organisms back to a common ancestor that lived approximately 500 million years ago, said senior author and biologist Dr. Paul Garrity. The ability to detect such noxious compounds, known as reactive electrophiles—a class of compounds that humans find pungent and irritating--is important for animal survival, prompting them to avoid potentially toxic food or dangerous situations. These receptors give animals an advantage in survival by acting as a biological warning system, as it were. In humans, chemical nociception can cause pain and inflammation. "What the study, spearheaded by Kyeongjin Kang in my lab, shows, is that this chemical sense is nearly as ancient as vision," said Dr. Garrity. "While many aspects of other chemical senses, like taste and smell, have been independently invented multiple times over the course of animal evolution, the chemical sense that detects these reactive compounds is different.

March 18th

Dietary Tryptophan Reduces Aggression in Pigs

Feeding the amino acid tryptophan to young female pigs as part of their regular diet makes them less aggressive and easier to manage, according to a study by Agricultural Research Service (ARS) scientists and collaborators at Purdue University. The tryptophan-enhanced diet reduced aggression and overall behavioral activity among young female pigs during the eight-month study. Tryptophan, which is only acquired through diet, is the precursor for the calming cerebral neurotransmitter serotonin. Keeping swine calm is important, because aggressive behavior can harm them and increase feed and medical costs for producers. The supplemented diet resulted in calmer animals, mainly at the younger age. Persistent aggression in pigs can cause chronic stress, leading to poorer welfare, increased disease susceptibility, and reduced growth and efficiency. To test aggression, researchers put an "intruder" pig in the pen until an aggressive interaction was triggered or for a maximum of five minutes. Pigs receiving the high-tryptophan diet showed less aggression--fewer attacked the intruder, and those that did attack were slower to do so--compared with the animals that didn't get the supplement. Pigs form social groups that, over time, develop into stable hierarchies or "pecking orders." However, when new individuals are introduced, aggression is used to re-establish a new hierarchical order. If repeated changes in group composition occur, persistent aggression may arise, sometimes leading to physical injury and acute stress. A tryptophan-enriched diet may help producers avoid these problems, especially when groups of pigs are mixed together. This research was published in the January 31, 2010 issue of Applied Animal Behaviour Science. [Press release]

March 17th

Hood Keynote Highlights Conference on Future of Genomic Medicine

In the keynote address to 300 attendees at the Future of Genomic Medicine III conference in La Jolla, California (March 5-6, 2010), Dr. Leroy Hood, President of the Institute for Systems Biology, sketched his optimistic vision of the future of personalized DNA-based medicine, and predicted that within five years it will be possible to sequence an entire human genome in under an hour for a cost of $500 or less. He emphasized the importance of taking a systems approach to biological investigations and described how such an approach had been applied to the analysis of prion disease in a mouse model. Dr. Hood also outlined the first-ever full genome sequencing of a complete family of two children and both parents, in which both children had inherited the same two rare recessive genetic diseases (Miller’s syndrome and primary ciliary dyskinesia), but both parents were unaffected. The analysis of the four complete sequences revealed the two disease genes that were inherited by both affected children. Dr. Hood noted that the ability to compare all four related sequences allowed for a significant increase in sequencing accuracy. Dr. Hood also envisioned a future of individual patients surrounded by clouds of data points that might prove key to their individual diagnoses and therapies, and he emphasized that biology is an informational science. He noted that the management and interpretation of data will be crucial going forward. He said that a critical goal for medical genetic tests is that they be both predictive and actionable. Dr. Hood was just one of many luminaries who took to the podium at this year’s conference, hosted by the Scripps Translational Science Institute and the J. Craig Venter Institute, and sponsored by a number of major biotech and pharmaceutical companies.

Leptin May Have Advantages Over Insulin in Type 1 Diabetes Treatment

In a mouse model, scientists at the University of Texas Southwestern Medical Center, and collaborators, have shown that administration of the hormone leptin may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes. The scientist showed that, although the two hormones are similar in certain of their anti-diabetic effects, they differ dramatically with respect to their effects on lipid metabolism: leptin suppresses lipogenesis, whereas insulin monotherapy enhances lipogenesis and factors involved in cholesterologenesis. The researchers said that their findings indicate that recombinant leptin, either alone or combined with low-dose insulin therapy, provides equivalent or superior glycemic stability without the increase in body fat and up-regulation of cholesterologenic and lipogenic transcription factors and enzymes observed with insulin monotherapy. According to the researchers, their results raise the possibility of a role for leptin supplementation in the treatment of human type 1 diabetes. This work was published as the cover story of the March 16, 2010 issue of PNAS. [PNAS article]

March 15th

Loss of Single Gene Restores Regenerative Ability in Mice

Scientists have identified a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice that was long thought to have been lost through evolution, and reserved today only for creatures like flatworms, sponges, and some species of salamander. Researchers from The Wistar Institute and collaborating institutions have now demonstrated that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue. Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a so-called “blastema,” a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and the findings provide solid evidence to link tissue regeneration to the control of cell division. "Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist Dr. Ellen Heber-Katz, a professor in Wistar's Molecular and Cellular Oncogenesis program. "While we are just beginning to understand the repercussions of these findings, perhaps one day we'll be able to accelerate healing in humans by temporarily inactivating the p21 gene." This research was published online on March 15, 2010 in PNAS. [Press release] [PNAS abstract]

New Genetic Test for Autism Found Superior to Current Tests

A large study from Children's Hospital Boston and the Boston-based Autism Consortium, and collaborating institutions, has found that a genetic test known as chromosomal microarray analysis (CMA), which samples the entire genome, has about three times the detection rate for genetic changes related to autism spectrum disorders (ASDs) than standard tests. The authors urged that CMA become part of the first-line genetic work-up for ASDs. Because of the dramatic increase in variations identified using CMA, the Autism Consortium recommends that CMA should be included in the first tier of diagnostic testing for children with ASD symptoms that have no clear genetic cause. Expectant parents who have family members with ASDs, as well as families who already have an affected child, often request genetic testing. However, there is still only limited knowledge about actual causative genes. The currently recommended tests (karyotyping to look for chromosomal abnormalities and testing for Fragile X syndrome, the single most frequent known genetic cause of ASDs), often come up negative. CMA is a genome-wide assay that examines the chromosomes for tiny, sub-microscopic deletions or duplications of DNA sequences, known as copy-number variants. CMA offers about 100-fold greater resolution than standard karyotyping. However, because it is new, it is often considered a second-tier test. Depending on where a person lives, or what insurance he or she has, CMA may not be covered by health insurance. "Based on our findings, CMA should be considered as part of the initial clinical diagnostic evaluation of patients with ASDs," said Dr. Bai-Lin Wu, co-senior author of the report and Director of Children's Hospital Boston’s DNA Diagnostic Lab, which has offered CMA to families since 2006.

Banana Compound Blocks HIV

A potent new inhibitor of HIV infection, derived from bananas, may open the door to new treatments to prevent sexual transmission of HIV, according to a University of Michigan Medical School study. The research team discovered that BanLec, a lectin in bananas, can inhibit HIV infection by binding to the sugar-rich HIV-1 envelope protein, gp120, and blocking the virus’s entry to the body. In laboratory tests, BanLec was as potent as two current anti-HIV drugs. Based on their findings, the researchers believe that BanLec may become a less expensive new component of applied vaginal microbicides. New ways of stopping the spread of the HIV are vitally needed. The rate of new infections of HIV is outpacing the rate of new individuals getting anti-retroviral drugs by 2.5 to1, and, at present, it appears an effective vaccine is years away. "HIV is still rampant in the U.S. and the explosion in poorer countries continues to be a bad problem because of tremendous human suffering and the cost of treating it," said the study’s senior author Dr. David Markovitz, professor of internal medicine at the medical school. Although condom use is quite effective, condoms are most successful in preventing infection if used consistently and correctly, which is often not the case. "That's particularly true in developing countries where women have little control over sexual encounters, so development of a long-lasting, self-applied microbicide is very attractive," Dr. Markovitz said. Co-author Michael Swanson, a doctoral student at the medical school, is developing a process to molecularly alter BanLec to enhance its potential clinical utility. Clinical use is considered years away, but researchers say even modest success could save millions of lives.