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Fractal Architecture Permits Incredibly Tight Packing of Cellular DNA

Using a new technique called Hi-C, scientists have deciphered the three-dimensional structure of the human genome, paving the way for new insights into genomic function. The researchers reported two striking findings. First, the human genome is organized into two separate compartments, keeping active genes separate and accessible while sequestering unused DNA in a denser storage compartment. Chromosomes snake in and out of the two compartments repeatedly as their DNA alternates between active, gene-rich and inactive, gene-poor stretches. Second, at a finer scale, the genome adopts an unusual organization known in mathematics as a "fractal." The specific architecture the scientists found, called a "fractal globule," enables the cell to pack DNA incredibly tightly--the information density in the nucleus is trillions of times higher than on a computer chip--while avoiding the knots and tangles that might interfere with the cell's ability to read its own genome. Moreover, the DNA can easily unfold and refold during gene activation, gene repression, and cell replication. The fractal globule architecture, while proposed as a theoretical possibility more than 20 years ago, has never previously been observed. "Nature's devised a stunningly elegant solution to storing information--a super-dense, knot-free structure," said senior author Dr. Eric Lander, director of the Broad Institute. This paper is featured on the cover of the October 9 issue of Science. [Press release]

Bacterium May Aid Formation of Gold

Scientists in Australia, together with collaborators, have shown that a particular bacterium (Cupriavidus metallidurans) catalyzes the biomineralization of gold by transforming toxic gold compounds to their metallic form using an active cellular mechanism. “A number of years ago we discovered that the metal-resistant bacterium C. metallidurans occurred on gold grains from two sites in Australia. The sites are 3,500 km apart, in southern New South Wales and northern Queensland, so when we found the same organism on grains from both sites we thought we were onto something. It made us wonder why these organisms live in this particular environment. The results of this study point to their involvement in the active detoxification of Au complexes leading to formation of gold biominerals,” explained Dr. Frank Reith, first author of the research report. The experiments showed that C. metallidurans rapidly accumulates toxic gold complexes from a solution prepared in the lab. This process promotes gold toxicity, which pushes the bacterium to induce oxidative stress and metal resistance clusters, as well as an as yet uncharacterized Au-specific gene cluster in order to defend its cellular integrity. This leads to active biochemically-mediated reduction of gold complexes to nano-particulate, metallic gold, which may contribute to the growth of gold nuggets. This is the first direct evidence that bacteria are actively involved in the cycling of rare and precious metals, such as gold. These results open the doors to the production of biosensors that may help mineral explorers find new gold deposits. This work was published on October 7 in the online edition of PNAS.

Beta Cell Growth, Insulin Production Increased in Diabetic Mice

By “knocking out” the Lkb1 gene in the beta cells of diabetic laboratory mice, scientists have been able to increase the size and number of beta cells and also to increase the amount of insulin stored in and released by these cells. “We were surprised by the impressive accumulation of Lkb1 in beta cells of diabetic mice, which suggested that Lkb1 might contribute to their impaired function. After removal of the Lkb1 gene, the beta cells grow larger, proliferate more, and secrete more insulin. It's a one-stop shop for the much needed insulin", said Dr. Robert Screaton, senior author of the research report. Importantly, the improved beta cell function lasted for at least five months, even in mice fed a high-fat diet designed to mimic the high caloric intake associated with metabolic syndrome and type 2 diabetes in humans. "The knockout mice on a high-fat diet have lower blood glucose. If this observation is confirmed in humans, it may give us another clue into the development of type 2 diabetes, and perhaps new treatment options,” Dr. Screaton said. This work was published in the October 7 issue of Cell Metabolism. [Press release] [Cell Metabolism abstract]

Telomere Researchers Awarded Nobel Prize

Three scientists who combined to identify the end structures of chromosomes and the enzyme that maintains these structures have been awarded the 2009 Nobel Prize in Physiology or Medicine. The prestigious award went to Dr. Elizabeth Blackburn (photo) of the University of California-San Francisoc, Dr. Carol Greider of Johns Hopkins University, and Dr. Jack Szostak of Harvard Medical School. Blackburn, Greider, and Szostak performed their groundbreaking investigations in the late 1970s and the 1980s. Blackburn showed that simple, repeated DNA sequences make up chromosome ends and, with Szostak, established that these repeated sequences stabilize chromosomes and prevent them from becoming damaged. Szostak and Blackburn predicted the existence of an enzyme that would add the sequences to chromosome ends. While a graduate student with Blackburn, who was then a member of the faculty at the University of California-Berkeley, Greider tracked down the enzyme telomerase. She later determined that each organism's telomerase contains an RNA component that serves as a template for the creature’s particular telomere DNA repeat sequence. In addition to providing insight into how chromosome ends are maintained, Blackburn, Greider, and Szostak’s work laid the foundation for studies that have linked telomerase and telomeres to human cancer and age-related conditions. Subsequent research has shown that telomerase and telomeres play key roles in cell aging and death and also play a part in the aging of the entire organism. Research has also shown that cancer cells have increased telomerase activity, protecting them from death. The award was announced on October 5.

Small Body Size, High Mortality Rate, and Early Sexual Maturity in Pygmies

A new study suggests that high mortality rates in small-bodied people, commonly known as pygmies, may be part of the reason for their small stature. The study, by Dr. Jay Stock and Dr. Andrea Migliano, both of the University of Cambridge, may help unravel the mystery of how small-bodied people got that way. Adult males in small-bodied populations found in Africa, Asia, and Australia are less than four feet, 11 inches tall, which is about one foot shorter than the average adult male in the U.S. Why people in these populations are so small remains a mystery, but several hypotheses have been proposed. Some scientists think that small bodies provide an evolutionary advantage under certain circumstances. For example, a smaller body needs less food—a good thing in places where food supplies are inconsistent. Small bodies also may provide an advantage in getting around in thickly forested environments. Recently, however, a new hypothesis has come to the fore suggesting that reproductive consequences of high mortality rates may explain small body size. If death comes at an early age, then natural selection would favor those who are able to reproduce at an early age. But early sexual maturity comes with a cost. When the body matures early, it diverts resources to reproduction that otherwise would have gone to growth. So small body size could be essentially a side effect of early sexual maturity. Stock's and Migliano's study provides the first long-term evidence for the mortality hypothesis. The article appears in the October issue of Current Anthropology. [Press release] [Current Anthropology abstract]

New Clue to Tuberculosis

Scientists have discovered a potential chink in the armor of the organism that causes tuberculosis in humans. They have shown that the organism (Mycobacterium tuberculosis) produces a compound (edaxadiene) that provides a defense mechanism against the killing power of macrophages that normally engulf and destroy harmful bacteria. The scientists have, in addition, identified molecules that inhibit the edaxadiene-producing enzyme and therefore have the potential to reduce the tuberculosis organism’s resistance to macrophage attack. The researchers cautioned, however, that finding an inhibitor that works outside of the test tube, and in humans, and is stable, and can be ingested safely by humans, and can help kill tuberculosis is a process that may take a decade. Nevertheless, Dr. Reuben Peters, senior author of the study, said, "This is the project where I tell my students, 'If we can make even just a 1 percent impact, we can save 15,000 - 20,000 lives a year.' That is really a significant contribution towards alleviating human suffering.” Tuberculosis is a contagious disease that is on the rise, killing 1.5 to 2 million people worldwide annually. Portions of this new work are reported in the August 28 issue of the Journal of Biological Chemistry and are slated to be the cover subject of an upcoming issue of the Journal of the American Chemical Society. [Press release] [JBC abstract]

Hormone May Help Plants Rid Themselves of Pesticides

Scientists in China have discovered that a natural plant hormone, applied to crops, can help plants eliminate residues of certain pesticides. The researchers noted that pesticides are essential for sustaining food production for the world's growing population. Farmers worldwide use about 2.5 million tons of pesticides each year. Scientists have been seeking new ways of minimizing pesticide residues that remain in food crops after harvest — with little success. Previous research suggested that plant hormones called brassinosteroids (BRs) might be an answer to the problem. In the current work, the researchers treated cucumber plants with one type of BR, and then treated the plants with various pesticides, including chloropyrifos (CPF), a broad-spectrum commercial insecticide. The BR significantly reduced the pesticides’ toxicity and residues in the plants, the scientists said. BRs may be "promising, environmentally friendly, natural substances suitable for wide application to reduce the risks of human and environmental exposure to pesticides," the scientists noted. The substances do not appear to be harmful to people or other animals, they added. This work was reported in the September 23 issue of the Journal of Agricultural and Food Chemistry published by the American Chemical Society. [Press release] [JAFC abstract]

Olive Oil Compound May Aid Treatment/Prevention of Alzheimer’s

Scientists have discovered that a naturally-occurring compound (oleocanthal) found in extra-virgin olive oil alters the structure of neurotoxic proteins (ADDLs or beta-amyloid oligomers) believed to contribute to the debilitating effects of Alzheimer's disease. The structural change impedes the proteins' ability to damage brain nerve cells. "Binding of ADDLs to nerve cell synapses is thought to be a crucial first step in the initiation of Alzheimer's disease. Oleocanthal alters ADDL structure in a way that deters their binding to synapses," said Dr. William L. Klein, a co-leader of the research team. "Translational studies are needed to link these laboratory findings to clinical interventions." An unexpected finding was that oleocanthal makes ADDLs into stronger targets for antibodies. This action establishes an opportunity for creating more effective immunotherapy treatments, which use antibodies to bind to and attack ADDLs. Future studies to identify more precisely how oleocanthal changes ADDL structure may increase understanding of the pharmacological actions of oleocanthal and such pharmacological insights could provide discovery pathways related to disease prevention and treatment. This work was reported in the October 15 issue of Toxicology and Applied Pharmacology. [Press release] [TAP abstract]

Prion Proteins Appear to Share Evolutionary Origin with ZIP Proteins

Suggestive evidence as to the evolutionary ancestry of prion proteins has been obtained by researchers at the University of Toronto and collaborating institutions. Prions are responsible for such devastating diseases as “mad cow disease” (bovine spongiform encephalopathy) and Creutzfeldt-Jakob disease. The researchers’ analysis suggests that the prion gene is descended from the more ancient ZIP family of metal ion transporters. Members of the ZIP protein family are well known for their ability to transport zinc and other metals across cell membranes. The researchers initially demonstrated the physical proximity of two metal ion transporters, ZIP6 and ZIP10, to mammalian prion proteins in living cells. As with the normal cellular prion protein, ZIP6 and ZIP10 exhibit widespread expression in biological tissues with high transcript levels in the brain. The scientists then made the startling discovery that prion and ZIP proteins contain extensive stretches of similar amino acid sequence. The researchers next documented that the respective segments within ZIP and prion proteins are computationally predicted to acquire a highly similar three-dimensional structure. Finally, the team uncovered multiple additional commonalities between ZIP and prion proteins, which led them to conclude that these molecules are evolutionarily related. Overall, this work holds promise for efforts to reveal the physiological function of members of the prion protein family and may provide insights into the origins and underlying constraints of the conformational changes associated with prion diseases. This work was published on September 28 in PLoS ONE. [Press release] [PLoS ONE article]

Chemicals Prevent Premature Termination of Protein Synthesis in Genetic Disease

Using high-throughput screening of 35,000 compounds, scientists at UCLA have identified two compounds (nonaminoglycosides) that may have the potential to correct certain genetic diseases that are caused by the premature termination of protein synthesis due to nonsense mutations in the coding DNA. "When DNA changes, such as nonsense mutations, occur in the middle rather than the end of a protein-producing signal, they act like a stop sign that tells the cell to prematurely interrupt protein synthesis," explained Dr. Richard Gatti, senior author of the study. "These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders." Dr. Gatti's lab specializes in studying ataxia-telangiectasia (A-T), a progressive neurological disease that strikes young children, often killing them by their late teens or early 20s. "Of the dozens of active chemicals we discovered, only two were linked to the appearance and function of ATM, the protein missing from the cells of children with A-T," said Dr. Liutao Du, the first author of the study, in speaking about cellular studies that were conducted. "These two chemicals also induced the production of dystrophin, a protein that is missing in the cells of mice with a nonsense mutation in the muscular dystrophy gene." The UCLA team is optimistic that its discovery will aid pharmaceutical companies in creating drugs that correct genetic disorders caused by nonsense mutations. This could potentially affect one in five patients with most genetic diseases, including hundreds of thousands of people suffering from incurable diseases. Because nonsense mutations can lead to cancer, such drugs may also find uses in cancer treatment. This study was published in the September 28 issue of the Journal of Experimental Medicine.

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