Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.
Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.
In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni’s lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called “nonsense” mutations in a mouse model of DMD.
The findings appear in the current online edition of the journal Human Molecular Genetics.
“We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans,” Bertoni said. “We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism.”
Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the “missing” protein is called dystrophin.
For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus’s California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.
The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.
The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans.
The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.
Other study authors included Jin-Mo Ku, Gregory Khitrov, Michael E. Jung and Olga Prikhodko, all from UCLA. The researchers report no conflicts of interest. The work has been supported in large part by the Muscular Dystrophy Association (MDA) and, more recently, by the National Institutes of Health.
UCLA researchers have discovered that a diet enriched with a popular omega-3 fatty acid and an ingredient in curry spice helps to preserve walking ability in rats that have experienced damage to their spinal cords.
The findings, published June 26 in the Journal of Neurosurgery: Spine, suggest that these dietary supplements help repair nerve cells and maintain neurological function after degenerative damage to the neck.
“Normal aging often narrows the spinal canal, putting pressure on the spinal cord and injuring tissue,” said principal investigator Dr. Langston Holly, associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. “While surgery can relieve the pressure and prevent further injury, it can’t repair damage to the cells and nerve fibers. We wanted to explore whether dietary supplementation could help the spinal cord heal itself.”
The UCLA team studied two groups of rats with a condition that simulated cervical myelopathy — a progressive disorder that often occurs in people with spine-weakening conditions like rheumatoid arthritis and osteoporosis. Cervical myelopathy can lead to disabling neurological symptoms, such as difficulty walking, neck and arm pain, hand numbness, and weakness of the limbs. It’s the most common cause of spine-related walking problems in people over 55.
The first group of animals was fed rat chow that replicated a Western diet high in saturated fats and sugar. The second group consumed a standard diet supplemented with docosahexaenoic acid (DHA) and curcumin, a compound in the Indian curry spice turmeric. A third set of rats received a standard rat diet and served as a control group.
Why these supplements? DHA is an omega-3 fatty acid shown to repair damage to cell membranes. Curcumin is a strong antioxidant that previous studies have linked to tissue repair. Both reduce inflammation.
“The brain and spinal cord work together, and years of research demonstrate that supplements like DHA and curcumin can positively influence the brain,” said study co-author Fernando Gomez-Pinilla, a professor of neurosurgery at UCLA. “We suspected that what works in the brain may also work in the spinal cord. When we were unable to find good data to support our hypothesis, we decided to study it ourselves.”
The researchers recorded a baseline of the rats walking and re-examined the animals’ gait on a weekly basis. As early as three weeks, the rats eating the Western diet demonstrated measurable walking problems that worsened as the study progressed. Rats fed a diet enriched with DHA and curcumin walked significantly better than the first group even six weeks after the study’s start.
Next, the scientists examined the rats’ spinal cords to evaluate how diet affected their injury on a molecular level. They measured levels of three markers respectively linked to cell-membrane damage, neural repair and cellular communication.
The rats that ate the Western diet showed higher levels of the marker linked to cell-membrane damage. In contrast, the DHA and curcumin appeared to offset the injury’s effect in the second group, which displayed marker levels that were equivalent to the control group.
Levels of the markers linked to neural repair and cellular communication were significantly lower in the rats raised on the Western diet. Again, levels in the animals fed the supplemented diet appeared similar to those of the control group.
“DHA and curcumin appear to invoke several molecular mechanisms that preserved neurological function in the rats,” said Gomez-Pinilla. “This is an exciting first step toward understanding the role that diet plays in protecting the body from degenerative disease.”
“Our findings suggest that diet can help minimize disease-related changes and repair damage to the spinal cord,” Holly said. “We next want to look at other mechanisms involved in the cascade of events leading up to chronic spinal-cord injury. Our goal is to identify which stages will respond best to medical intervention and identify effective steps for slowing the disease process.”
Other co-authors included Dr. Donald Blaskiewicz, Aiguo Wu, Cameron Feng and Zhe Ying, all of UCLA. Their research was supported by grants from the National Institutes of Health (RO1 NS056413) and the Craig H. Neilsen Foundation.
Psoriasis is an autoimmune disorder in which skin cells proliferate out of control. For some hard-to-heal wounds, the problem is just the opposite: Restorative skin cells don’t grow well or fast enough. In a paper published in the June 21, 2012 issue of Immunity, researchers at the University of California, San Diego School of Medicine describe a molecule that may lead to new treatments for both problems.
An international team of scientists led by principal investigator Richard L. Gallo, MD, PhD, professor of medicine and chief of UC San Diego’s Division of Dermatology, and first author Yuping Lai, PhD, professor of microbiology and immunity at East China Normal University in Shanghai, analyzed skin biopsies of patients with and without psoriasis, as well as the skin of mice with psoriasis and with wounds on their backs. They discovered that a molecule called regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in skin cells during psoriasis and wound-healing, but not under normal skin conditions.
In tests on mice, researchers found that inhibiting REG3A slowed wound-healing but cleared up psoriasis, which is commonly characterized by patches of inflammation and white, scaly skin.
The scientists also noted that REG3A acts in concert with interleukin-17 (IL-17), an immune system protein involved in the signaling cascade which prompts skin cells to multiply in excess numbers. “IL-17 binds to receptors on skin cells and causes REG3A to be expressed, which then binds to another protein inside the cells that promotes cell growth,” said Lai.
Gallo said the discovery of REG3A’s dual roles provides a new target for different therapies.
“A drug that inhibits the expression of REG3A could represent a more targeted way to treat psoriasis without the systemic immunosuppression problems of current treatments,” Lai. “Conversely, a drug that stimulates or mimics REG3A could boost cell growth and improve wound healing.”
Co-authors are Dongqing Li, Changwei Li, Ziwei Jiang, Zhiheng Li, Hu Lei, Yanchun Quan and Tian Zhang, all at the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; Beda Muhleisen, Paul Kotol and Tissa R. Hata, Division of Dermatology, Departments of Medicine and Pediatrics, UC San Diego; Katherine A. Radek, Department of Surgery, Burn and Shock Trauma Institute, Loyola University, Chicago; Hyun Jeong Park, Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul; Shin Morizane and Keiji Iwatsuki, Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan; Ge Tang, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo.
Funding for this research came, in part, from the National Institutes of Health (grants AR052728, AI052453, AI083358), the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality.
Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.
In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.
De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.
Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.
“Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,” said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.
The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.
“We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly,” said Gleeson. “These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.”
The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.
“Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere,” said Mathern. “Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere.”
But a less-invasive drug therapy would still be more appealing.
“We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly,” said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. “We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?”
Co-authors are My Huynh, department of Neurosurgery and Psychiatry and Biobehavioral Sciences, Mattel Children’s Hospital, Geffen School of Medicine, UCLA; Jennifer L. Silhavy, Tracy Dixon-Salazar, Andrew Heiberg, Eric Scott, Kiley J. Hill and Adrienne Collazo, Institute for Genomic Medicine, Rady Children’s Hospital, UC San Diego and Howard Hughes Medical Institute; Sangwoo Kim and Vineet Bafna, Department of Computer Sciences, Jacobs School of Engineering, UC San Diego; Vincent Furnari and Carsten Russ, Institute for Medical Genetics, Cedars-Sinai Medical Center, Los Angeles and Department of Pediatrics, Geffen School of Medicine, UCLA; and Stacey B. Gabriel, The Broad Institute of MIT and Harvard, Cambridge.
Funding for this research came, in part, from the Daland Fellowship from the American Philosophical Society, the National Institutes of Health (grants R01 NS038992, R01 NS048453, R01 NS052455, R01 NS41537 and P01 HD070494), the Simons Foundation Autism Research Initiative and the Howard Hughes Medical Institute.
Human Papilloma Virus (HPV), once almost exclusively associated with cancer of the cervix, is now linked to head and neck cancer. According to a new University at Buffalo study just published in the Archives of Otolaryngology — Head & Neck Surgery, a JAMA publication, gum disease is associated with increased odds of tumors being HPV-positive.
Mine Tezal, DDS, PhD, assistant professor of oral biology in the UB School of Dental Medicine who is the primary investigator on the study, and a team of scientists from UB evaluated data from 124 patients diagnosed with primary head and neck squamous cell carcinoma (HNSCC) between 1999 and 2007.
“The aim of the study was to test the presence of periodontitis, a persistent inflammatory process and HPV-status of HNSCC,” she said.
Of the 124 tumor samples Tezal and her team studied, 50 were positive for HPV-16 DNA and that subjects with HPV-positive tumors had a significantly higher severity of periodontitis when compared to subjects with HPV-negative tumors.
According to the National Cancer Institute, there has been a steady increase in the prevalence of oropharyngeal cancers in the U.S. since 1973 despite the significant decline in tobacco use since 1965.
Tezal notes that this increase has mainly been attributed to oral HPV infection.
Understanding the natural history of the oral HPV infection and targeting factors associated not only with its acquisition but also with its persistence, says Tezal, will lead to more effective strategies, not only for prevention, but also for treatment.
“While there is an effective vaccine for cervical HPV infection if given prior to the exposure of the virus (females 9-26; males 9-21), oral HPV infection can be transmitted at or any time after birth, and the target population for a vaccine to prevent oral HPV infection has not yet been defined,” said Tezal.
Tezal pointed out that though many previous studies combined periodontitis and dental decay as indicators of poor oral health, dental decay was not significantly linked to tumor-HPV status in the present study.
“The fact that only periodontitis was associated with tumor HPV status points to the potential association of inflammation with tumor HPV status,” she says.
When Tezal and colleagues started their research about eight years ago they were looking at the potential association between chronic inflammation and head and neck cancers because the importance of the local oral environment for malignant tumor growth was widely accepted. However there wasn’t research evaluating the role of local oral factors in the natural history of HNSCC, Tezal said.
“The next step in this research will be intervention studies to test whether treating the sources of inflammation, like gum disease, can reduce the acquisition and/or persistence of oral HPV infection and improve the prognosis of HPV-related diseases,” she said.
Researchers at the University of California, San Diego Jacobs School of Engineering have developed a technique that enables metallic nanocrystals to self-assemble into larger, complex materials for next-generation antennas and lenses. The metal nanocrystals are cube-shaped and, like bricks or Tetris blocks, spontaneously organize themselves into larger-scale structures with precise orientations relative to one another. Their findings were published online June 10 in the journal Nature Nanotechnology.
This research is in the new field of nanoplasmonics, where researchers are developing materials that can manipulate light using structures that are smaller than the wavelength of light itself. The nanocubes used in this study were less than 0.1 microns; by comparison, the breadth of a human hair is 100 microns. Precise orientation is necessary so that the cubes can confine light (for a nanoscale antenna) or focus light (for a nanoscale lens) at different wavelengths.
“Our findings could have important implications in developing new optical chemical and biological sensors, where light interacts with molecules, and in optical circuitry, where light can be used to deliver information,” said Andrea Tao, a professor in the Department of NanoEngineering at the Jacobs School. Tao collaborated with nanoengineering professor Gaurav Arya and post-doctoral researcher Bo Gao.
To construct objects like antennas and lenses, Tao’s team is using chemically synthesized metal nanocrystals. The nanocrystals can be synthesized into different shapes to build these structures; in this study, Tao’s team created tiny cubes composed of crystalline silver that can confine light when organized into multi-particle groupings. Confining light into ultra-small volumes could allow optical sensors that are extremely sensitive and that could allow researchers to monitor how a single molecule moves, reacts, and changes with time.
To control how the cubes organize, Tao and her colleagues developed a method to graft polymer chains to the silver cube surfaces that modify how the cubes interact with each other. Normally when objects like cubes stack, they pack side-by-side like Tetris blocks. Using simulations, Tao’s team predicted that placing short polymer chains on the cube surface would cause them to stack normally, while placing long polymer chains would cause the cubes to stack edge-to-edge. The approach is simple, robust, and versatile.
In demonstrating their technique, the researchers created macroscopic films of nanocubes with these two different orientations and showed that the films reflected and transmitted different wavelengths of light.
The research was supported by the National Science Foundation, the Hellman Foundation, and Jacobs School of Engineering at UC San Diego.
A grasshopper’s change in diet to high-energy carbohydrates while being hunted by spiders may affect the way soil releases carbon dioxide into the atmosphere, according to research results published this week in the journal Science.
Grasshoppers like to munch on nitrogen-rich grass because it stimulates their growth and reproduction.
But when spiders enter the picture, grasshoppers cope with the stress from fear of predation by shifting to carbohydrate-rich plants, setting in motion dynamic changes to the ecosystem they inhabit, scientists have found.
“Under stressful conditions they go to different parts of the ‘grocery store’ and choose different foods, changing the makeup of the plant community,” said Oswald Schmitz, a co-author of the paper and an ecologist at Yale University.
The high-energy, carbohydrate diet also tilts a grasshopper’s body chemistry toward carbon at the expense of nitrogen.
So when a grasshopper dies, its carcass breaks down more slowly, thus depriving the soil of high-quality fertilizer and slowing the decomposition of uneaten plants.
“This study casts a new light on the importance of predation in natural communities,” said Saran Twombly, program director in the National Science Foundation’s Division of Environmental Biology, which funded the research.
“A clever suite of experiments shows that the dark hand of predation extends all the way from altering what prey eat to the nutrients their decomposing bodies contribute to soil.”
Microbes in the soil require a lot of nitrogen to function and to produce the enzymes that break down organic matter.
“It only takes a slight change in the chemical composition of that animal biomass to fundamentally alter how much carbon dioxide the microbial pool is releasing to the atmosphere while it is decomposing plant organic matter,” said Schmitz.
“This shows that animals could potentially have huge effects on the global carbon balance because they’re changing the way microbes respire organic matter.”
The researchers found that the rate at which the organic matter of leaves decomposed increased between 60 percent and 200 percent in stress-free conditions relative to stressed conditions, which they consider “huge.”
“Climate and litter quality are considered the main controls on organic-matter decomposition, but we show that aboveground predators change how soil microbes break down organic matter,” said Mark Bradford, a co-author of the study and also an ecologist at Yale.
Schmitz added: “What it means is that we’re not paying enough attention to the control that animals have over what we view as a classically important process in ecosystem functioning.”
The researchers took soil from the field, put it in test tubes and ground up grasshopper carcasses obtained from environments either with or without grasshopper predators.
They then sprinkled the powder atop the soil, where the microbes digested it.
When the grasshopper carcasses were completely decomposed, the researchers added leaf litter and measured the rate of leaf-litter decomposition.
The experiment was then replicated in the field at the Yale Myers Forest in northeastern Connecticut.
“It was a two-stage process where the grasshoppers were used to prime the soil, then we measured the consequences of that priming,” said Schmitz.
The effect of animals on ecosystems is disproportionately larger than their biomass would suggest.
“Traditionally people thought that animals had no important role in recycling of organic matter, because their biomass is relatively small compared to the plant material that’s entering ecosystems,” Schmitz said.
“We need to pay more attention to the role of animals, however. In an era of biodiversity loss we’re losing many top predators and larger herbivores from ecosystems.”
Microorganisms in the human gastrointestinal tract form an intricate, living fabric made up of some 500 to 1000 distinct bacterial species, (in addition to other microbes). Recently, researchers have begun to untangle the subtle role these diverse life forms play in maintaining health and regulating weight.
In a new study appearing in the journal Nutrition in Clinical Practice, researcher Rosa Krajmalnik-Brown and her colleagues at the Swette Center for Environmental Biotechnology at Arizona State University’s Biodesign Institute in collaboration with John DiBaise from the Division of Gastroenterology at the Mayo Clinic, review the role of gut microbes in nutrient absorption and energy regulation.
According to Krajmalnik-Brown, “Malnutrition may manifest as either obesity or undernutrition, problems of epidemic proportion worldwide. Microorganisms have been shown to play an important role in nutrient and energy extraction and energy regulation although the specific roles that individual and groups/teams of gut microbes play remain uncertain.”
The study outlines the growth of varied microbial populations—from birth onwards— highlighting their role in extracting energy from the diet. The composition of microbial communities is shown to vary with age, body weight, and variety of food ingested; as well as in response to bariatric surgery for obesity, use of antibiotics and many other factors.
Based on current findings, the authors suggest that therapeutic modification of the gut microbiome may offer an attractive approach to future treatment of nutrition-related maladies, including obesity and a range of serious health consequences linked to under-nutrition.
The microbes in the human gut belong to three broad domains, defined by their molecular phylogeny: Eukarya, Bacteria, and Achaea. Of these, bacteria reign supreme, with two dominant divisions—known as Bacteroidetes and Firmicutes— making up over 90 percent of the gut’s microbial population. In contrast, the Achaea that exist in the gut are mostly comprised of methanogens (producers of methane) and specifically by Methanobrevibacter smithii— a hydrogen-consumer.
Within the bacterial categories however, enormous diversity exists. Each individual’s community of gut microbes is unique and profoundly sensitive to environmental conditions, beginning at birth. Indeed, the mode of delivery during the birthing process has been shown to affect an infant’s microbial profile.
Communities of vaginal microbes change during pregnancy in preparation for birth, delivering beneficial microbes to the newborn. At the time of delivery, the vagina is dominated by a pair of bacterial species, Lactobacillus and Prevotella. In contrast, infants delivered by caesarean section typically show microbial communities associated with the skin, including Staphylococcus, Corynebacterium, and Propionibacterium. While the full implications of these distinctions are still murky, evidence suggests they may affect an infant’s subsequent development and health, particularly in terms of susceptibility to pathogens.
Diet and destiny
After birth, diet becomes a critical determinant in microbial diversity within the gut. Recent research indicates that microbial populations vary geographically in a manner consistent with regional differences in diet. Children in rural areas of Burkina Faso for example showed much more abundant concentrations of Bacteroidetes compared with their cohorts in Italy, a finding consistent with the African children’s plant-rich diet.
While microbiomes appear to have adapted to local diets, changes in eating habits significantly alter composition of gut microbes. Variations in macronutrient composition can modify the structure of gut microbiota in a few days—in some cases, a single day. Studies in mice show that changing from a low fat, plant polysaccharide diet to a Western diet high in sugar and fat rapidly and profoundly reconfigures the composition of microbes in the gut.
Another modifier of gut microbe composition is gastric bypass surgery, used in certain cases to alleviate conditions of serious obesity. In earlier work, the authors found that the post-surgical microbial composition of patients who underwent so-called Roux-en-Y gastric bypass was distinct from both obese and normal weight individuals.
“Obesity affects more than a third of adults in the U.S. and is associated with a raft of health conditions including heart disease, stroke, type 2 diabetes and certain forms of cancer,” says Dr. John DiBaise. The authors further note that concentrations in the blood of lipopolysaccharides derived from gut bacteria increase in obese individuals, producing a condition known as metabolic endotoxemia. The disorder has been linked with chronic, systemic, low-level inflammation as well as insulin resistance.
In the current review, the cycle of microbial energy extraction from food, involving hydrogen-producing and consuming reactions in the human intestine, is described in detail. Short chain fatty acids (SCFAs) are a critical component in this system. During the digestive process, fermentation in the gut breaks down complex organic compounds, producing SCFA and hydrogen. The hydrogen is either excreted in breath or consumed by 3 groups of microorganisms inhabiting the colon: methanogens, acetogens and sulfate reducers.
Research conducted by the authors and others has demonstrated that hydrogen-consuming methanogens appear in greater abundance in obese as opposed to normal weight individuals. Further, the Firmicutes—a form of acetogen—also seem to be linked with obesity. Following fermentation, SCFAs persist in the colon. Greater concentration of SCFAs, especially propionate, were observed in fecal samples from obese as opposed to normal weight children. (SCFAs also behave as signaling molecules, triggering the expression of leptin, which acts as an appetite suppressor.)
While it now seems clear that certain microbial populations help the body process otherwise indigestible carbohydrates and proteins, leading to greater energy extraction and associated weight gain, experimental results have shown some inconsistency. For example, while a number of studies have indicated a greater prevalence of Bacteroidetes in lean individuals and have linked the prevalence of Firmicutes with obesity, the authors stress that many questions remain.
Alterations in gut microbiota are also of crucial concern for the one billion people worldwide who suffer from undernutrition. Illnesses resulting from undernutrition contribute to over half of the global fatalities in children under age 5. Those who do survive undernutrition often experience a range of serious, long-term mental and physical effects. The role of gut microbial diversity among the undernourished has yet to receive the kind of concentrated research effort applied to obesity—a disease which has reached epidemic proportions in the developed world.
Exploiting microbes affecting energy extraction may prove a useful tool for non-surgically addressing obesity as well as treating undernutrition, though more research is needed for a full understanding of regulatory mechanisms governing the delicate interplay between intestinal microbes and their human hosts.
Dr. Krajmalnik-Brown and colleagues at the Biodesign Institute and Mayo Clinic are currently in the second year of an NIH-funded study to better understand the role of the gut microbiome in the success or failure of surgical procedures performed to treat obesity including the Roux-en-Y gastric bypass, adjustable gastric band and vertical sleeve gastrectomy.
There’s a most unusual gym in ecologist Sonia Altizer’s lab at the University of Georgia in Athens. The athletes are monarch butterflies, and their workouts are carefully monitored to determine how parasites impact their flight performance.
With support from the National Science Foundation (NSF), Altizer and her team study how animal behavior, including long distance migration, affects the spread and evolution of infectious disease. In monarchs, the researchers study a protozoan parasite called Ophryocystis elektroscirrha, or “OE” for short.
In Altizer’s lab, the adult butterflies are tethered to a “flying treadmill” and the time and speed of each lap is recorded on a computer. They fly at between two and five miles per hour in this setting. Infected butterflies, on average, fly about 20 percent less well than healthy butterflies. “So, they actually fly shorter total distances, they’ve got slower flight speeds and they lose more weight per distance flown than healthy butterflies,” says Altizer.
Up to two billion monarchs migrate every year to central Mexico, where Altizer and her colleagues capture, sample and release hundreds of butterflies each day during the researchers’ field study. “The sound of the wings of the butterflies just whirring past your head is about as good as it gets for a terrestrial ecologist, I think!” says Altizer.
Altizer says even a tiny impact from infection on the monarchs’ migration ability could make the difference between survival and death. Her work is providing some details on the differences in how diseases spread in human and animal populations.
“General models for predicting the spread of infectious disease largely ignore behavioral changes,” says Alan Tessier, program director in the Division of Environmental Biology within the NSF Biological Sciences Directorate. “This research addresses a critical gap in understanding how infection changes the movement behavior of animals from the scale of individuals to the dynamics of populations spread across a landscape. Lessons learned from this work will be broadly relevant to disease spread in other species, including humans.”
“We know that for humans, travel and migration can help spread disease. With more and more air travel, a person can get on a plane and move a virus to the other side of the world in a matter of hours. But, many animal species have to undertake these really strenuous long-distance journeys on their own power. And, if these journeys are really costly, animals that are heavily infected are probably not going to make it,” explains Altizer. “So, we can think about it from our own perspective. If we had to run a marathon with the flu, we probably wouldn’t do very well. The animals that are the most heavily infected simply can’t make a long-distance journey.”
Take the migration away and what’s left are smaller remnant populations that don’t migrate. “We could actually see infections build up in those populations and that could possibly increase the risk of pathogens jumping over into people and their domesticated animals,” says Altizer.
Human activities, from logging and other habitat destruction to herbicide use, are disrupting longstanding migration patterns for monarchs and other animals, according to Altizer. Over a decade ago, around half of the monarch population that overwinters in Mexico originated from the corn belt of the United States, where their milkweed host plants commonly grew in agricultural fields and roadsides. Altizer says that today monarch populations in those same areas are declining, in large part due to transgenic crops that are tolerant of herbicides. This allows farmers to more effectively eliminate weeds, including milkweeds, thus removing a large fraction of the monarchs’ former habitat.
Another aspect of this research builds on the fascination many people have for these beautiful insects and their arduous migratory journey.
“Monarchs have this amazing annual lifecycle where they’ve got three or four short-lived generations that breed during the summer months, and then they’ve got one long-lived generation where butterflies that emerge at the end of the summer live for eight, nine, sometimes 10 months. It’s that generation that travels all the way to the overwintering sites and then re-migrates north in the spring to re-colonize the southern part of their breeding range. So, it’s the great, great, grand-progeny of that generation that will make the journey the following year,” explains Altizer.
Graduate student Dara Satterfield processes data sent in from volunteers who sample the butterflies in their backyards. She’s looking for OE infection.
“The Monarch Health Program is our citizen science project. People from the eastern part of the U.S. and Canada send us samples from monarchs in their own backyard,” says Satterfield. “The citizen scientists put a piece of clear tape on the monarch’s abdomen and that will pick up spores and scales from the monarch. Then they place those tape samples on index cards and mail them to us. We can tell from the samples whether or not the monarch in their yard has a parasite.”
“Monarchs, like a lot of other migratory species, face complex conservation challenges because they have very different habitats at different times of the year and they cross international boundaries. We need to identify the threats and protect them,” says Altizer.
“There’s also a need to study pathogen dynamics in other migratory species, as well as how human activities affect those dynamics,” she adds.
Vampire bats may not have the beauty factor that monarch butterflies do, but the bats are important in Altizer’s study of how the spread of infectious diseases by animals is affected by human activities.
In Peru, University of Georgia postdoctoral researcher Daniel Streicker focuses on these bats whose populations have exploded in recent years. Ranchers have introduced livestock into the Andes and the Amazon. More bloodthirsty bats might mean more rabies.
“One of the main goals we have is to try to understand what determines the frequency and intensity of rabies outbreaks and what we can do about it,” says Streicker.
That fieldwork involves capturing vampire bats to determine what’s on their menu.
“We’re catching bats in the Amazon jungle, particularly in areas where there aren’t a lot of livestock. These are usually areas where bats are reported to bite people, but we don’t know what else they’re feeding on,” continues Streicker. “So, we catch these bats after they’ve taken a blood meal and we extract the stomach contents in a way that’s fairly non-invasive, and then we can use genetic typing to figure out what species were actually being fed upon.”
While vampire bats have a hyped Hollywood reputation for danger, Streicker says there are things people can learn from them about rabies and other diseases. For example, some bats have antibodies against rabies, so they appear healthy even though they have been exposed. This runs counter to the common wisdom that rabies is universally fatal to all mammals. If antibodies protect these bats from future exposures, that could fundamentally change our view of how rabies persists in wild bat populations. Understanding how bats survive these exposures could also eventually help researchers develop a treatment. Vampire bat saliva has already been used to develop a medicine for treating stroke victims.
Streicker and Altizer say that the results of this study will improve rabies control efforts in Latin America, where vampire bats cause most human and livestock cases. More generally, because deforestation and livestock rearing are intensifying in much of the developing world, a better understanding of how wildlife-pathogen interactions will respond to such changes is urgently needed.
For the first time, researchers have produced a coherent, laser-like, directed beam of light that simultaneously streams ultraviolet light, X-rays and all wavelengths in between.
One of the few light sources to successfully produce a coherent beam that includes X-rays, this new technology is the first to do so using a setup that fits on a laboratory table.
An international team of researchers, led by engineers from the National Science Foundation’s Engineering Research Center (ERC) for EUV Science and Technology, reports its findings in the June 8, 2012, issue of Science.
By focusing intense pulses of infrared light–each just a few optical cycles in duration–into a high-pressure gas cell, the researchers converted part of the original laser energy into a coherent super-continuum of light that extends well into the X-ray region of the spectrum.
The X-ray burst that emerges has much shorter wavelengths than the original laser pulse, which will make it possible to follow the tiniest, fastest physical processes in nature, including the coupled dance of electrons and ions in molecules as they undergo chemical reactions, or the flow of charges and spins in materials.
“This is the broadest spectral, coherent-light source ever generated,” says engineering and physics professor Henry Kapteyn of JILA at the University of Colorado at Boulder, who led the study with fellow JILA professor Margaret Murnane and research scientist Tenio Popmintchev, in collaboration with researchers from the Vienna University of Technology, Cornell University and the University of Salamanca.
“It definitely opens up the possibility to probe the shortest space and time scales relevant to any process in our natural world other than nuclear or fundamental particle interactions,” Kapteyn adds. The breakthrough builds upon earlier discoveries from Murnane, Kapteyn and their colleagues to generate laser-like beams of light across a broad spectrum of wavelengths.
The researchers use a technique called high-harmonic generation (HHG). HHG was first discovered in the late 1980s, when researchers focused a powerful, ultra-short laser beam into a spray of gas. The researchers were surprised to find that the output beam contained a small amount of many different wavelengths in the ultraviolet region of the spectrum, as well as the original laser wavelength. The new ultraviolet wavelengths were created as the gas atoms were ionized by the laser.
“Just as a violin or guitar string will emit harmonics of its fundamental sound tone when plucked strongly, an atom can also emit harmonics of light when plucked violently by a laser pulse,” adds Murnane. “The laser pulse first plucks electrons from the atoms, before driving them back again where they can collide with the atoms from which they came. Any excess energy is emitted as high-energy ultraviolet photons.”
Like many phenomena, when HHG was first discovered, there was little science to explain it, and it was considered more a curious phenomenon than a potentially useful light source. After years of work, scientists eventually understood how very high harmonics were emitted. However, there was one major challenge that most researchers gave up on–for most wavelengths in the X-ray region, the output HHG beams were extremely weak.
Murnane, Kapteyn and their students realized that there might be a chance to overcome that challenge and turn HHG into a useful X-ray light source–the tabletop-scale X-ray laser that has been a goal for laser science since shortly after the laser was first demonstrated in 1960.
“This was not an easy task,” says Murnane. “Unlike a laser–which gets more intense as more energy is pumped into the system–in HHG, if the laser hits the atoms too hard, too many electrons are liberated from the gas atoms, and those electrons cause the laser light to speed up. If the speed of the laser and X-rays do not match, there is no way to combine the many X-ray waves together to create a bright output beam, since the X-ray waves from different gas atoms will interfere destructively.”
Popmintchev and JILA graduate student Ming-Chang Chen worked out conditions that enable X-ray waves from many atoms in the gas to interfere constructively. The key was to use a relatively long-wavelength, mid-infrared laser and a high pressure gas cell that also guides the laser light. The resulting bright, X-ray beams maintain the coherent, directed beam qualities of the laser that drives the process.
The HHG process is effective only when the atoms are hit “hard and fast” by the laser pulses, with durations nearing 10-14 seconds–a fundamental limit representing just a few oscillations of the electromagnetic fields. Murnane and Kapteyn pioneered the technology for generating such light pulses in the 1990s, and used those lasers to develop and utilize HHG-based light sources in the extreme-ultraviolet (EUV) region of the spectrum in the 2000s. However, while researchers were using those lasers and the HHG technique to measure ever-shorter duration light pulses, they were stymied in how to make coherent light at shorter wavelengths in the more penetrating X-ray region of the spectrum.
The new paper in Science, under lead author and senior research associate Popmintchev, demonstrates that breakthrough, showing that the understanding of the HHG process the researchers developed is broadly valid.
“We would have never found this if we hadn’t sat down and thought about what happens overall during HHG, when we change the wavelength of the laser driving it, what parameters have to be changed to make it work,” added Kapteyn. “The amazing thing is that the physics seem to be panning out even over a very broad range of parameters. Usually in science you find a scaling rule that prevents you from making a dramatic jump, but in this case, we were able to generate 1.6 keV – each X-ray photon was generated from more than 5,000 infrared photons.”
When the researchers first started to work with ultrafast, mid-infrared lasers just a few years ago, they actually made a step backwards and generated bright extreme-ultraviolet light of longer wavelengths than they used to achieve in the lab.
“However, we discovered a new regime that helped us to realize, just on paper, that we could make this giant step forward towards much shorter electromagnetic wavelengths and generate bright, laser-like, soft and hard X-rays,” adds Popmintchev. “What the experiments were suggesting back then looked too good to be true! It seemed that Mother Nature has combined together, in the most simple and beautiful way, all the microscopic and macroscopic physics. Now, we are already at X-ray wavelengths as short as roughly 7.7 angstroms, and we do not know the limit.”
To truly control the beam of photons, the researchers needed to understand the HHG process at the atomic level and how X-rays emitted from individual atoms combine to form a coherent beam of light.
That understanding combines microscopic and macroscopic models of the HHG process with the fact that those interactions occur at very high intensity in a dynamically changing medium. The development of such a conceptual understanding took the last decade to develop.
The result was the realization that there is no fundamental limit to the energy of the photons that can be generated using the HHG process. To obtain higher-energy photons, the system paradoxically begins with laser light using lower energy photons–specifically, mid-infrared lasers.
The JILA researchers demonstrated the validity of that principle in their labs in Colorado, but to achieve their breakthrough, the researchers traveled to Vienna with their beam-generating setup. There, they used a laser developed by co-author Andrius Baltuška and colleagues at the Vienna University of Technology–the world’s most-intense ultrashort-pulse laser operating in the mid-infrared, with a wavelength of four microns.
“Thirty years ago, people were saying we could make a coherent X-ray source, but it would have to be an X-ray laser, and we’d need an atomic bomb as the energy source to pump it,” said Deborah Jackson, the program officer who oversees the ERC’s grant. “Now, we have these guys who understand the science fundamentals well enough to introduce new tricks for efficiently extracting energetic photons, pulling them out at X-ray wavelengths … and it’s all done on a table-top!”
In addition to achieving the high energy, the increasingly broad spectrum opens a range of new applications.
“In an experiment using such a source, one energy region from the beam will correspond with one element, another with another element, and so on to simultaneously look at atoms across entire molecules, and that will allow us to see how charge moves from one part of a molecule to another as a chemical reaction is happening,” adds Kapteyn. “It’ll take us awhile to learn how to use this, but it’s very exciting.”