A fortuitous collaboration at Rice University has led to the total synthesis of a recently discovered natural antibiotic. The laboratory recreation of a fungus-derived antibiotic, viridicatumtoxin B, may someday help bolster the fight against bacteria that evolve resistance to treatments in hospitals and clinics around the world. As part of the process, Rice organic chemist Dr. K.C. Nicolaou and structural biologist Dr. Yousif Shamoo and their colleagues created and tested a number of variants of viridicatumtoxin B that could lead to the simplified synthesis of a new generation of more effective antibiotics. The work, reported online on August 15, 2014 in the Journal of the American Chemical Society (JACS), focused on a tetracycline discovered in 2008 by scientists who isolated small amounts from penicillium fungi. The yield wasn’t nearly enough for extensive testing, but it provided a basis for the discoverers to analyze its structure through magnetic resonance imaging, Dr. Nicolaou said. “We’re inspired by molecules that are biologically active and have the potential to become medicines one day,” he said. The new discovery belongs to a class of antibiotics known as tetracyclines for their distinctive molecular structure. They proved potent in initial tests on Gram-positive bacteria, so named for a staining technique to mark bacteria that are more susceptible to antibiotics than their Gram-negative counterparts. The first tetracyclines, discovered in the late 1940s, ushered in a new class of powerful antibacterial agents to treat high-mortality diseases, among them anthrax and plague, as well as such bacterial infections as chlamydia, syphilis, and Lyme disease.
Dyslexia, the most commonly diagnosed learning disability in the United States, is a neurological reading disability that occurs when the regions of the brain that process written language don't function normally. The use of non-invasive functional neuroimaging tools has helped characterize how brain activity is disrupted in dyslexia. However, most prior work has focused on only a small number of brain regions, leaving a gap in our understanding of how multiple brain regions communicate with one another through networks, called functional connectivity, in persons with dyslexia. This led neuroscience Ph.D. student Emily Finn and her colleagues at the Yale University School of Medicine to conduct a whole-brain functional connectivity analysis of dyslexia using functional magnetic resonance imaging (fMRI). They report their findings in the September 1, 2014 issue of Biological Psychiatry. "In this study, we compared fMRI scans from a large number of both children and young adults with dyslexia to scans of typical readers in the same age groups. Rather than activity in isolated brain regions, we looked at functional connectivity, or coordinated fluctuations between pairs of brain regions over time," explained Ms. Finn. In total, the team recruited and scanned 75 children and 104 adults. Ms. Finn and her colleagues then compared the whole-brain connectivity profiles of the dyslexic readers to the non-impaired readers, which revealed widespread differences. Dyslexic readers showed decreased connectivity within the visual pathway as well as between visual and prefrontal regions, increased right-hemisphere connectivity, reduced connectivity in the visual word-form area, and persistent connectivity to anterior language regions around the inferior frontal gyrus. This altered connectivity profile is consistent with dyslexia-related reading difficulties. Dr.
Oxidized lipids are known to play a key role in inflaming blood vessels and hardening arteries, which causes diseases such as atherosclerosis. A new study at UCLA demonstrates that these oxidized lipids may also contribute to pulmonary hypertension, a serious lung disease that narrows the small blood vessels in the lungs. Using a rodent model, the researchers showed that a peptide mimicking part of the main protein in high-density lipoprotein (HDL), the so-called "good" cholesterol, may help reduce the production of oxidized lipids in pulmonary hypertension. They also found that reducing the amount of oxidized lipids improved the rodents' heart and lung function. The study is published in the August 26, 2014 issue of Circulation. A rare progressive condition, pulmonary hypertension can affect people of all ages. The disease makes it harder for the heart to pump blood through these vital organs, which can lead to heart failure. "Our research helps unravel the mechanisms involved in the development of pulmonary hypertension," said Dr. Mansoureh Eghbali, the study's senior author and an associate professor of anesthesiology at the David Geffen School of Medicine at UCLA. "A key peptide related to HDL cholesterol that can help reduce these oxidized lipids may provide a new target for treatment development." Lipids such as fatty acids become oxidized when they are exposed to free radicals — tiny particles that are produced when the body converts food into energy -- or when they are exposed to pollution, and in numerous other ways. Although researchers have known that oxidized lipids played a role in the development of atherosclerosis and other vascular diseases, the UCLA team discovered higher-than-normal levels of oxidized proteins in rodents with pulmonary hypertension.
The mechanical force that a single fungal cell or bacterial colony exerts on a plant cell may seem vanishingly small, but it plays a key role in setting up some of the most fundamental symbiotic relationships in biology. In fact, it may not be too much of a stretch to say that plants may have never moved onto land without the ability to respond to the touch of beneficial fungi, according to a new study led by Dr. Jean-Michel Ané, a professor of agronomy at the University of Wisconsin-Madison. "Many people have studied how roots progress through the soil, when fairly strong stimuli are applied to the entire growing root," says Dr. Ané, who just published a review of touch in the interaction between plants and microbes in the August 2014 issue of Current Opinion in Plant Biology. "We are looking at much more localized, tiny stimuli on a single cell that is applied by microbes." Specifically, Dr. Ané, Dr. Dhileepkumar Jayaraman, a postdoctoral researcher in agronomy, and Dr. Simon Gilroy, a professor of botany, studied how such a slight mechanical stimulus starts round one of a symbiotic relationship — that is, a win-win relationship between two organisms. It's known that disease-causing fungi build a structure to break through the plant cell wall, "but there is growing evidence that fungi and also bacteria in symbiotic associations use a mechanical stimulation to indicate their presence," says Dr. Ané. "They are knocking on the door, but not breaking it down." After the fungus announces its arrival, the plant builds a tube in which the fungus can grow. "There is clearly a mutual exchange of signals between the plant and the fungus," says Dr. Ané.
A big step in understanding the mysteries of the human genome was unveiled today (August 28, 2014) in the form of three analyses that provide the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function. The research, published in the August 28, 2014 issue of Nature, compares how the information encoded in the three species’ genomes is “read out,” and how their DNA and proteins are organized into chromosomes. The results add billions of entries to a publicly available archive of functional genomic data. Scientists can use this resource to discover common features that apply to all organisms. These fundamental principles will likely offer insights into how the information in the human genome regulates development, and how it is responsible for diseases. The analyses were conducted by two consortia of scientists that include researchers from the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab). Both efforts were funded by the National Institutes of Health’s National Human Genome Research Institute (NHGRI). One of the consortia, the “model organism Encyclopedia of DNA Elements” (modENCODE) project, catalogued the functional genomic elements in the fruit fly and roundworm. Dr. Susan Celniker and Dr. Gary Karpen of Berkeley Lab’s Life Sciences Division led two fruit fly research groups in this consortium. Dr. Ben Brown, also with the Life Sciences Division, participated in another consortium, ENCODE, to identify the functional elements in the human genome. The consortia are addressing one of the big questions in biology today: now that the human genome and many other genomes have been sequenced, how does the information encoded in an organism’s genome make an organism what it is?
Scientists at The Scripps Research Institute (TSRI) have solved the mystery of why a specific signaling pathway can be associated with alcohol dependence. This signaling pathway is regulated by a gene called neurofibromatosis type 1 (Nf1), which TSRI scientists found is linked with excessive drinking in mice. The new research shows Nf1 regulates gamma-aminobutyric acid (GABA), a neurotransmitter that lowers anxiety and increases feelings of relaxation. “This novel and seminal study provides insights into the cellular mechanisms of alcohol dependence,” said TSRI Associate Professor Marisa Roberto, a co-author of the paper. “Importantly, the study also offers a correlation between rodent and human data.” In addition to showing that Nf1 is key to the regulation of the GABA, the research, which was published online on August 18, 2014 in Biological Psychiatry, shows that variations in the human version of the Nf1 gene are linked to alcohol-dependence risk and severity in patients. Dr. Pietro Paolo Sanna, associate professor at TSRI and the study’s corresponding author, was optimistic about the long-term clinical implications of the work. “A better understanding of the molecular processes involved in the transition to alcohol dependence will foster novel strategies for prevention and therapy,” he said. Researchers have long sought a gene or genes that might be responsible for risk and severity of alcohol dependence. “Despite a significant genetic contribution to alcohol dependence, few risk genes have been identified to date, and their mechanisms of action are generally poorly understood,” said TSRI Staff Scientist Dr. Vez Repunte-Canonigo, co-first author of the paper with TSRI Research Associate Dr. Melissa Herman.
Scientists at Cancer Research UK have discovered that acral melanomas – the rare type of skin cancer that caused reggae musician Bob Marley’s death – are genetically distinct from other more common types of skin cancer, according to a study published online on June 30, 2014 in the journal Pigment Cell & Melanoma Research. Acral melanoma most often affects the palms of the hands, soles of the feet, nail-beds, and other hairless parts of the skin. Unlike other more common types of melanoma, it’s not caused by UV damage from the sun. The scientific team, from the Cancer Research UK Manchester Institute at The University of Manchester, sequenced the tumors of five patients with acral melanoma and combined this information with data from three other patients. The researchers then compared the pattern of genetic faults found in these eight tumors with that of more common types of skin cancer. This comparison revealed that the type of DNA damage found in acral melanoma is very different from other types of skin cancer. For example, in acral melanomas, it was much more common to find large chunks of the DNA that had broken off and reattached elsewhere, as opposed to the smaller DNA changes typically found in more common types of skin cancer. Study leader Professor Richard Marais, director of the Cancer Research UK Manchester Institute, at The University of Manchester, said: “Too much UV radiation from the sun or sunbeds can lead to a build-up of DNA damage that increases skin cancer risk. But acral skin cancer is different because the gene faults that drive it aren’t caused by UV damage.
Bay Area Lyme Foundation, which aims to make Lyme disease easy to diagnose and simple to cure, applauds new research published online on August 10, 2014 in the Elsevier peer-reviewed journal Ticks and Tick-borne Diseases. The findings show that ticks that carry Lyme disease in Northwest California are active throughout the year, making the threat of Lyme disease year-round. The research was conducted by researchers at California Department of Public Health (CDPH) Vector-borne Disease Section and University of California, Berkeley (UC-B). "These results are critical as they offer proof that it is possible to become infected with Lyme disease in the Bay Area at any time of the year," said Linda Giampa, Executive Director, Bay Area Lyme Foundation. "It underscores the need for residents to take precautions year-round and know the symptoms of the disease. While the threat in Northwest California is lower, it's more constant than the Northeast USA." The findings suggest that the timing of peak tick activity of Western Black-legged ticks (Ixodes pacificus) (image), which are the ticks most commonly known to carry Lyme disease in Northwest California is largely predictable and year-round. In general, tick larvae (young ticks) are active April to June, and sometimes activity extends into October, while adult ticks are active from October to May. From January to October, nymphal ticks (which are younger and smaller than adult ticks, but older than larvae) become active. Interestingly, the highest reported incidence of Lyme disease in humans in Northwest California correlate to the times when the younger, smaller ticks (nymphal I. pacificus), which are smaller than a poppy seed, are most active.
In many parts of the world, leprosy and tuberculosis live side-by-side. Worldwide there are approximately 233,000 new cases of leprosy per year, with nearly all of them occurring where tuberculosis is endemic. The currently available century-old vaccine Bacille Calmette-Guerin, or BCG, provides only partial protection against both tuberculosis and leprosy, so a more potent vaccine is needed to combat both diseases. UCLA-led research may have found a stronger weapon against both diseases. In a study published in the September 2014 issue of Infection and Immunity, the researchers found that rBCG30, a recombinant variant of BCG that overexpresses a highly abundant 30 kDa protein of the tuberculosis bacterium known as Antigen 85B, is superior to BCG in protecting against tuberculosis in animal models, and also cross protects against leprosy. In addition, they found that boosting rBCG30 with the Antigen 85B protein, a protein also expressed by the leprosy bacillus, provides considerably stronger protection against leprosy. "This is the first study demonstrating that an improved vaccine against tuberculosis also offers cross-protection against Mycobacterium leprae (image), the causative agent of leprosy," said Dr. Marcus A. Horwitz, professor of medicine and microbiology, immunology and molecular genetics, and the study's senior author. "That means that this vaccine has promise for better protecting against both major diseases at the same time. It is also the first study demonstrating that boosting a recombinant BCG vaccine further improves cross-protection against leprosy," he added. In one experiment, mice were immunized with either rBCG30 or the old BCG vaccine, or they were given a salt solution.
The Progeria Research Foundation (PRF) is thrilled to announce that Life According To Sam won the Emmy last week for "Exceptional Merit in Documentary Filmmaking." Congratulations to HBO Documentary Films, Sean Fine, and Andrea Nix Fine, and the entire talented, passionate team of people who have helped raise awareness of Progeria and PRF's work through this exceptional film. Sam continues to impact viewers every day with his lasting legacy of hope, determination and love. Watch the awards on Sunday, August 24 at 8 pm ET/PT on FXM; Click here (http://www.emmys.com/awards/primetime-emmys/2014/creative-arts-emmys) and choose "Where to Watch" for local listings. Obtain a copy of the film Life According to Sam here (http://store.hbo.com/detail.php?p=546129&SESSID=e7c169cae575e7da507c7b9b...) and share it with a friend! As depicted in the film, one of Sam's greatest passions was music, and he realized his lifelong dream of being in his school's marching band. Keep Moving Forward (http://keepmovingforwardmusic.com/) was commissioned by the Foxborough Music Association in Sam's memory. It is based on Sam's life philosophy (https://www.youtube.com/watch?v=36m1o-tM05g), his enthusiasm, and the spirit of inclusion and solidarity his classmates showed him. "Keep Moving Forward" was part of Sam's philosophy for a happy life, and thanks to composer Mark Miller and other supporters, PRF is proud to provide the sheet music and full score for "Keep Moving Forward" at no cost to band directors. Visit KeepMovingForward.com (http://keepmovingforwardmusic.com/) for details.