Syndicate content

Archive - Jan 2014 - Story

January 29th

MMP-9 Protein Presence or Absence Explains Differing Motor Neuron Susceptibility in ALS, Points to Potential Therapeutic Target

Columbia University Medical Center (CUMC) researchers have identified a gene, called matrix metalloproteinase-9 (MMP-9), that appears to play a major role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The findings, made in mice, explain why most, but not all, motor neurons are affected by the disease and identify a potential therapeutic target for this still-incurable neurodegenerative disease. The study was published online on January 22, 2014 in Neuron. “One of the most striking aspects of ALS is that some motor neurons—specifically, those that control eye movement and eliminative and sexual functions—remain relatively unimpaired in the disease,” said study leader Christopher E. Henderson, Ph.D., the Gurewitsch and Vidda Foundation Professor of Rehabilitation and Regenerative Medicine, professor of pathology & cell biology and neuroscience (in neurology), and co-director of Columbia’s Motor Neuron Center. “We thought that if we could find out why these neurons have a natural resistance to ALS, we might be able to exploit this property and develop new therapeutic options.” To understand why only some motor neurons are vulnerable to ALS, the researchers used DNA microarray profiling to compare the activity of tens of thousands of genes in neurons that resist ALS (oculomotor neurons/eye movement and Onuf’s nuclei/continence) with neurons affected by ALS (lumbar 5 spinal neurons/leg movement). The neurons were taken from normal mice. “We found a number of candidate ‘susceptibility’ genes—genes that were expressed only in vulnerable motor neurons. One of those genes, MMP-9, was strongly expressed into adulthood. That was significant, as ALS is an adult-onset disease,” said co-lead author Dr. Krista J. Spiller, a former graduate student in Dr.

Nanophotonic System of “Chameleon of the Sea” May Inspire Improved Paints, Cosmetics, Electronics, and Military Camouflage

Scientists at Harvard University in Boston and the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, hope new understanding of the natural nanoscale photonic device that enables a small marine animal to dynamically change its colors will inspire improved protective camouflage for soldiers on the battlefield. The cuttlefish, known as the "chameleon of the sea," can rapidly alter both the color and pattern of its skin, helping it blend in with its surroundings and avoid predators. In a paper published online on January 29, 2014 in the Journal of the Royal Society Interface, the Harvard-MBL team reports new details on the sophisticated biomolecular nanophotonic system underlying the cuttlefish’s color-changing ways. "Nature solved the riddle of adaptive camouflage a long time ago," said Dr. Kevin Kit Parker, Tarr Family Professor of Bioengineering and Applied Physics at the Harvard School of Engineering and Applied Sciences (SEAS) and core faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard. “Now the challenge is to reverse-engineer this system in a cost-efficient, synthetic system that is amenable to mass manufacturing." In addition to textiles for military camouflage, the findings could also have applications in materials for paints, cosmetics, and consumer electronics. The cuttlefish (Sepia officinalis) is a cephalopod, like squid and octopuses. Neurally controlled, pigmented organs called chromatophores allow it to change its appearance in response to visual clues, but scientists have had an incomplete understanding of the biological, chemical, and optical functions that make this adaptive coloration possible.

January 28th

Scientists ID Protein Crucial to the First Step of Cilium Formation, May Aid Understanding of Ciliopathies Like PKD

A team of researchers from Penn State University and the University of California-San Francisco has discovered a protein that is required for the growth of tiny, but critical, hair-like structures called cilia on cell surfaces. The discovery has important implications for human health because lack of cilia or problems with them can lead to serious diseases such as polycystic kidney disease PKD), blindness, and neurological disorders. "If we want to better understand and treat diseases related to cilium development, we need to identify important regulators of cilium growth and learn how those regulators function," said co-author Dr. Aimin Liu, Associate Professor of Biology at Penn State. "This work gives us significant insight into one of the earliest steps in cilium formation." The researchers describe their findings in a paper that was published online on January 27, 2014 in PNAS. In addition to Dr. Liu, article authors include Penn State cellular biologists Dr. Xuan Ye, Dr. Huiqing Zeng, and Dr. Gang Ning, as well as Dr. Jeremy F. Reiter, a biophysicist at the University of California-San Francisco. Cilia, which are present on the surface of almost all mammalian cells, are responsible for sending, receiving, and processing information within the body. "You could think of cilia as the cells' antennae," Dr. Liu said. "Without cilia, the cells can't sense what's going on around them, and they can't communicate." Cilia also perform important filtering and cleansing functions. For example, cilia inside the trachea, or windpipe, trap and prevent bacteria from entering the lungs. In a previous study, Dr. Liu and his colleagues learned that a protein called C2cd3 is important for cilium formation because mice that lacked this protein exhibited severe developmental problems typically associated with the lack of cilia.

Gone Today, Hair Tomorrow !

One potential approach to reversing hair loss uses stem cells to regenerate the missing or dying hair follicles. But it hasn't been possible to generate sufficient number of hair-follicle-generating stem cells – until now. Xiaowei "George" Xu, M.D., Ph.D., Associate Professor of Pathology and Laboratory Medicine and Dermatology at the Perelman School of Medicine, University of Pennsylvania (Penn), and colleagues published online on January 26, 2014 in Nature Communications a method for converting adult cells into epithelial stem cells (EpSCs), the first time anyone has achieved this in either humans or mice. The epithelial stem cells, when implanted into immunocompromised mice, regenerated the different cell types of human skin and hair follicles, and even produced structurally recognizable hair shaft, raising the possibility that they may eventually enable hair regeneration in people. Dr. Xu and his team, which includes researchers from Penn's Departments of Dermatology and Biology, as well as the New Jersey Institute of Technology, started with human skin cells called dermal fibroblasts. By adding three genes, they converted those cells into induced pluripotent stem cells (iPSCs), which have the capability to differentiate into any cell types in the body. They then converted the iPS cells into epithelial stem cells, normally found at the bulge of hair follicles. Starting with procedures other research teams had previously worked out to convert iPSCs into keratinocytes, Dr. Xu's team demonstrated that by carefully controlling the timing of the growth factors the cells received, they could force the iPSCs to generate large numbers of epithelial stem cells. In the Xu study, the team's protocol succeeded in turning over 25% of the iPSCs into epithelial stem cells in 18 days.

GWAS Study Identifies 11 New Genetic Associations for Asthma-with-Hay Fever

23andMe, a California-based personal genetics company, has participated in the first-ever genome-wide association study (GWAS) of the combined asthma-with-hay fever phenotype. Led by researchers at the QIMR Berghofer Medical Research Institute in Australia, the study identified 11 independent genetic markers associated with the development of asthma-with-hay fever, including two associations reaching a level of significance with allergic disease for the first time. Through these findings, 23andMe aims to substantially improve the ability to detect genetic risk factors shared between both diseases. Previous research has shown that both asthma and hay fever share 50-90 percent of their genetic susceptibility and 20-50 percent of their environmental susceptibility. 23andMe has collected information on both conditions through its asthma symptoms survey, and, in this analysis, used data contributed by 15,072 of its customers. Data was also collected from three additional studies conducted in Australia and the United Kingdom, with cases defined as persons who reported a physician diagnosis of asthma and also hay fever (total N=6,685). This group was compared to a control group of individuals who reported neither a diagnosis of asthma or hay fever (total N=14,091). “While previous analyses provided evidence of a stronger genetic association of this combined phenotype, there has not been a genome-wide association study exploring the connection in further detail,” said David Hinds, Ph.D., study author and 23andMe principal scientist in statistical genetics.

January 27th

Hopkins Study Suggests Non-CpG Methylation Is Reversible System of Gene Regulation That May Contribute to Rett Syndrome

In normal development, all cells turn off genes they don't need, often by attaching a chemical methyl group to the DNA, a process called methylation. Historically, scientists believed methyl groups could only stick to a particular DNA sequence: a cytosine followed by a guanine, called CpG. But in recent years, methyl groups have been found on other sequences, and so-called non-CpG methylation has been found in stem cells, and in neurons in the brain. Now, a team of researchers at Johns Hopkins has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation. In a study that was published online on December 23, 2013 in Nature Neuroscience, the Hopkins team describes this new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication. The research team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons, a finding that surprised the team, because this wasn't found in any other cells other than stem cells. By looking at what genes were being transcribed in neurons, he and his colleagues found that, like the form of methylation scientists had seen in stem cells, non-CpG methylation stops genes from being expressed. They also mapped the genome to find where non-CpG methylation happens, and found that it carves out its own niche, and the sites are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Dr. Song says.

Study Casts Doubt on Theory That Retired NFL Football Players Suffer Chronic Traumatic Encephalopathy (CTE)

The media have widely reported that a debilitating neurological condition called chronic traumatic encephalopathy (CTE) is a well-established disease in retired athletes who played football and other contact sports. But a study by a Loyola University Medical Center neuropsychologist has found little evidence that CTE actually exists. "There has not yet been one controlled epidemiological study looking at the risk of late-life cognitive impairment in any collision sport, including boxing, American football, or other sports involving repetitive head trauma," Christopher Randolph, Ph.D., reports in an open-access article in the January-February 2014 peer-reviewed journal Current Sports Medicine Reports. The author declares no conflict of interest and has no financial disclosures. CTE is said to be the cause of behavioral symptoms such as anger, aggression and suicidality, and cognitive symptoms such as impaired learning and memory problems. CTE is thought to be linked to concussions and characterized by the build-up of abnormal substances in the brain called tau proteins. A 2005 study, co-authored by Dr. Randolph, reported that rates of mild cognitive impairment among retired National Football League (NFL) players seemed to be higher than that of the general population, but Dr. Randolph noted there were no controls in this study, and results may have been subject to reporting biasb A more recent study of retired NFL players found that rates of Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) were higher than that of the general population. But this may be due to the fact that the NFL players had lower overall mortality rates from heart disease and other causes. Because they lived longer, the players naturally would be more likely to get age-related diseases such as Alzheimer's disease.

DNA-Glued Gold Nanostructures Safely Target and Image Cancerous Tumors

A team of researchers at the University of Toronto has discovered a method of assembling "building blocks" of gold nanoparticles as the vehicle to deliver cancer medications or cancer-identifying markers directly into cancerous tumors. The study, led by Dr. Warren Chan, Professor at the Institute of Biomaterials & Biomedical Engineering (IBBME) and the Donnelly Centre for Cellular & Biomolecular Research (CCBR), appears in an article published online on January 27, 2014 in Nature Nanotechnology. "To get materials into a tumor they need to be a certain size," explains Dr. Chan. "Tumors are characterized by leaky vessels with holes roughly 50 – 500 nanometers in size, depending on the tumor type and stage. The goal is to deliver particles small enough to get through the holes and 'hang out' in the tumor's space for the particles to treat or image the cancer. If a particle is too large, it can't get in, but if the particle is too small, it leaves the tumor very quickly." Dr. Chan and his fellow researchers solved this problem by creating modular structures 'glued' together with DNA. "We're using a 'molecular assembly' model - taking pieces of materials that we can now fabricate accurately and organizing them into precise architectures, like putting LEGO blocks together," comments Leo Chou, a 5th year Ph.D. student at IBBME and first author of the paper. Dr. Chou was awarded a 2012-13 Canadian Breast Cancer Foundation Ontario Region Fellowship for his work with nanotechnology. "The major advantage of this design strategy is that it is highly modular, which allows you to 'swap' components in and out. This makes it very easy to create systems with multiple functions, or screen a large library of nanostructures for desirable biological behaviors," he states.

January 26th

Computer Modeling Identifies Gene-Inhibiting Drug to Potentially Halt Breast Cancer Metastasis

Researchers at Cardiff University are developing a novel compound known to reverse the spread of malignant breast cancer cells. The vast majority of deaths from cancer result from its progressive spread to vital organs, known as metastasis. In breast cancer, up to 12,000 patients a year develop this form of the disease, often several years after initial diagnosis of a breast lump. In a recent series of studies, researchers identified a previously unknown critical role for a potential cancer-causing gene, Bcl3, in metastatic breast cancer. "We showed that suppressing this gene reduced the spread of cancer by more than 80%," said Dr Richard Clarkson from Cardiff University's European Cancer Stem Cell Research Institute. "Our next goal was to then find a way to suppress Bcl3 pharmacologically. Despite great improvements in therapy of early-stage breast cancer, the current therapeutic options for patients with late-stage metastatic disease are limited. There is therefore a clear unmet clinical need to identify new drugs to reverse or at least to slow down disease progression," he added. Dr. Clarkson and his team joined up with researchers Dr. Andrea Brancale and Dr. Andrew Westwell from the Cardiff University School of Pharmacy and Pharmaceutical Sciences, to develop small chemical inhibitors of the Bcl3 gene. Computer-aided modeling of how the Bcl3 gene functions inside the cell allowed the group to identify a pocket on the surface of Bcl3 essential for its function. By screening a virtual compound library for chemicals that could fit inside this pocket, using state-of-the-art computer software, they identified a drug candidate that potently inhibits Bcl3. The compound was then trialed on mice with metastatic disease.

Research Sheds Light on How Brain Creates Behavioral Sequences

When you learn how to play the piano, first you have to learn notes, scales, and chords, and only then will you be able to play a piece of music. The same principle applies to speech and to reading, where instead of scales you have to learn the alphabet and the rules of grammar. But how do separate small elements come together to become a unique and meaningful sequence. It has been shown that a specific area of the brain, the basal ganglia, is implicated in a mechanism called chunking, which allows the brain to efficiently organize memories and actions. Until now little was known about how this mechanism is implemented in the brain. In an article published online on January 26, 2014 in Nature Neuroscience, neuroscientist Dr. Rui Costa, and his postdoctoral fellow, Dr. Fatuel Tecuapetla, both working at the Champalimaud Neuroscience Programme (CNP) in Lisbon, Portugal, and Dr. Xin Jin, an investigator at the Salk Institute, in San Diego, California, reveal that neurons in the basal ganglia can signal the concatenation of individual elements into a behavioral sequence. "We trained mice to perform gradually faster sequences of lever presses, similar to a person who is learning to play a piano piece at an increasingly fast pace," explains Dr. Costa. "By recording the neural activity in the basal ganglia during this task, we found neurons that seem to treat a whole sequence of actions as a single behavior." The basal ganglia encompass two major pathways, the direct and the indirect pathways. The authors found that although activity in these pathways was similar during the initiation of movement, it was rather different during the execution of a behavioral sequence. "The basal ganglia and these pathways are absolutely crucial for the execution of actions.