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Archive - Jan 2014

January 26th

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.

Shortening Guide RNA Markedly Improves Specificity of CRISPR-Cas Nucleases

A simple adjustment to a powerful gene-editing tool may be able to improve its specificity. In a report published online on January 26, 2014 in Nature Biotechnology, Massachusetts General Hospital (MGH) investigators describe how adjusting the length of the the guide RNA (gRNA) component of the synthetic enzymes called CRISPR-Cas RNA-guided nucleases (RGNs) can substantially reduce the occurrence of DNA mutations at sites other than the intended target, a limitation the team had previously described just last year. "Simply by shortening the length of the gRNA targeting region, we saw reductions in the frequencies of unwanted mutations at all of the previously known off-target sites we examined," says J. Keith Joung, MD, PhD, associate chief for Research in the MGH Department of Pathology and senior author of the report. "Some sites showed decreases in mutation frequency of 5,000-fold or more, compared with full-length gRNAs, and importantly, these truncated gRNAs - which we call tru-gRNAs - are just as efficient as full-length gRNAs at reaching their intended target DNA segments." CRISPR-Cas RGNs combine a gene-cutting enzyme called Cas9 with a short RNA segment and are used to induce breaks in a complementary DNA segment in order to introduce genetic changes. Last year, r. Joung's team reported finding that, in human cells, CRISPR-Cas RGNs could also cause mutations in DNA sequences with differences of up to five nucleotides from the target, which could seriously limit the proteins' clinical usefulness. The team followed up those findings by investigating a hypothesis that could seem counterintuitive, that shortening the gRNA segment might reduce off-target mutations.

Breast Stem Cells Have Much Longer Lifespan Than Previously Thought, Implications for Breast Cancer

Researchers from Melbourne's Walter and Eliza Hall Institute in Australia have discovered that breast stem cells and their 'daughters' have a much longer lifespan than previously thought, and are active in puberty and throughout life. The longevity of breast stem cells and their daughters means that they could harbor genetic defects or damage that can progress to cancer decades later, potentially shifting back the timeline of breast cancer development. The finding is also integral to identifying the 'cells of origin' of breast cancer and the ongoing quest to develop new treatments and diagnostics for breast cancer. Breast stem cells were isolated in 2006 by Professors Jane Visvader and Geoff Lindeman and their colleagues at the Walter and Eliza Hall Institute. Now, in a project led by Dr. Anne Rios and Dr. Nai Yang Fu that tracked normal breast stem cells and their development, the team has discovered that breast stem cells actively maintain breast tissue for most of the life of the individual and contribute to all major stages of breast development. The research was published online on January 26, 2014 in Nature. Professor Lindeman, who is also an oncologist at The Royal Melbourne Hospital, said discovering the long lifespan and programming of breast stem cells would have implications for identifying the cells of origin of breast cancers. Professor Visvader said understanding the hierarchy and development of breast cells was critical to identifying the cells that give rise to breast cancer, and to understanding how and why these cells become cancerous. "Without knowing the precise cell types in which breast cancer originates, we will continue to struggle in our efforts to develop new diagnostics and treatments for breast cancer, or developing preventive strategies," Professor Visvader said.

January 25th

New Computer Model May Aid Personalized Cancer Care

Dana-Farber Cancer Institute scientists in Boston and colleagues have developed a mathematical model to predict how a patient's tumor is likely to behave and which of several possible treatments is most likely to be effective. Reporting online on January 23, 2014 in an open-access article in the journal Cell Reports, researchers combined several types of data from pre- and post-treatment biopsies of breast tumors to obtain a molecular picture of how the cancer evolved as a result of chemotherapy. "Better understanding of tumor evolution is key to improving the design of cancer therapies and for truly individualized cancer treatment," said Kornelia Polyak, M.D., Ph.D., a breast cancer researcher in the Susan F. Smith Center for Women's Cancers at Dana-Farber. The model was developed by Dr. Polyak and Franziska Michor, Ph.D., a computational biologist at Dana-Farber. The study analyzed breast cancer samples from 47 patients who underwent pre-operative chemotherapy to shrink the tumor so it could be removed more easily. The biopsy samples, representing the major types of breast cancer, included specimens taken at diagnosis and again after the chemotherapy was completed. As has been increasingly recognized, a tumor contains a varied mix of cancer cells and the mix is constantly changing. This is known as tumor heterogeneity. The cells may have different sets of genes turned on and off – phenotypic heterogeneity – or have different numbers of genes and chromosomes – genetic heterogeneity. These characteristics, and the location of different types of cells with the tumor, shape how the cancer evolves and are a factor in the patient's outcome. In generating their predictive model, Drs.

Study Identifies New Potential Targets for Eczema Treatment

A recent study reports the development of a new mouse model for atopic dermatitis, an inflammatory skin disorder commonly known as eczema. The findings, published online on January 9, 2014 in an open-access article in Cell Reports, suggest that mast cells (image), a type of immune cell, are critical for both spontaneous and allergen-induced eczema. The study, led by researchers at the La Jolla Institute for Allergy and Immunology in the United States and including researchers from the Laboratory for Allergic Disease at the RIKEN Center for Integrative Medicine in Japan and other institutions, was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health. Eczema is estimated to affect approximately one in five infants and one in fifty adults in the United States. The causes underlying the disorder are unclear. Previous research has suggested a role for imbalanced immune responses and impaired skin defenses, as well as overproduction of thymic stromal lymphopoietin (TSLP), a protein that promotes inflammation. While different mouse models for eczema have been developed, research examining how they are linked to human disease is still ongoing. In the current study, researchers show that mice lacking phospholipase C-beta3 (PLC- beta3), an enzyme that helps regulate inflammation, develop a skin disorder similar to human eczema, with high levels of TSLP. In this model, disease progression depends on the accumulation of mast cells and the activity of a signaling protein called Stat5. This role for mast cells and Stat5 in eczema was not previously known. The researchers also examined skin lesions of eczema patients and found that some had accumulation of mast cells expressing active Stat5.

Large-Scale Analysis of Over 20 Tumor Types Increases Catalog of Cancer Genes by 25 Percent

A landmark study across many cancer types reveals that the universe of cancer mutations is much larger than previously thought. By analyzing the genomes of thousands of patients' tumors, a Broad Institute-led research team has discovered many new cancer genes — expanding the list of known genes tied to these cancers by 25 percent. Moreover, the study shows that many key cancer genes still remain to be discovered. The team's work, which lays a critical foundation for future cancer drug development, also shows that creating a comprehensive catalog of cancer genes for scores of cancer types is feasible with as few as 100,000 patient samples. "For the first time, we know what it will take to draw the complete genomic picture of human cancer," said Broad Institute founding director Dr. Eric Lander, a senior co-author of the paper. "That's tremendously exciting, because the knowledge of genes and their pathways will highlight new, potential drug targets and help lead the way to effective combination therapy." Over the past 30 years, scientists had found evidence for about 135 genes that play causal roles in one or more of the 21 tumor types analyzed in the study. The new report not only confirms these genes, but, in one fell swoop, increases the catalog of cancer genes by one-quarter. It uncovers 33 genes with biological roles in cell death, cell growth, genome stability, immune evasion, as well as other processes. The researchers' results appear in print in the January 23, 2014 issue of Nature. "One of the fundamental questions we need to ask ourselves is: Do we have a complete picture yet? Looking at cancer genomes tells us that the answer is no: there are more cancer genes out there to be discovered," said the paper's first author Dr. Mike Lawrence, a computational biologist at the Broad.

January 23rd

Fruit Flies Can Detect Cancer Cells and Differentiate Subgroups via Olfactory Sense; Related Fluorescent System May Provide Early Cancer Screening Tool

A research unit in an international cooperation project led by the University of Konstanz (Germany)-based neurobiologist and zoologist Professor Dr. Giovanni Galizia, has been the first to demonstrate that fruit flies are able to distinguish cancer cells from healthy cells via their olfactory sense. In an article, published on January 6, 2014 in an open-access article in the international scientific journal "Scientific Reports" by the Nature Publishing Group, researchers of the University of Konstanz and the University La Sapienza in Rome, Italy, describe how characteristic patterns in the olfactory receptors of transgenic Drosophilae can be recorded when activated by scent. Not only could a clear distinction be made between healthy cells and cancer cells; moreover, groupings could be identified among the different cancer cells. "What really is new and spectacular about this result is the combination of objective, specific, and quantifiable laboratory results and the extremely high sensitivity of a living being that cannot be matched by electronic noses or gas chromatography," explains Dr. Galizia. Natural olfactory systems are better suited to detecting the very small differences in scent between healthy cells and cancer cells. This fact has already been shown in experiments with dogs; however, these results are not objectifiable and are thus not applicable for a systematic medical diagnosis. The researchers from Konstanz and Rome used the fact that single odorant molecules dock to the receptor neurons of the flies' antenna and thus activate the neurons. In an imaging technique developed by the researchers, the different odorant molecules of the respective scent samples create different patterns of activated neurons, which fluoresce under the microscope when active, thanks to a genetic modification.

January 23rd

Genome of 11,000-Year-Old Transmissible Dog Cancer Reveals Its Secrets

A cancer normally lives and dies with a person, however this is not the case with a particular sexually transmitted cancer in dogs. In a study published in the January 24, 2014 issue of Science, a team of researchers led by Professor Sir Mike Stratton (image), Director of the Sanger Institute, has described the genome and evolution of this cancer that has continued living within the dog population for the past 11,000 years. A commentary on these results, written by canine genetics experts Dr. Heidi Parker and Dr. Elaine Ostrander, is also published in the same issue of Science. Scientists have sequenced the genome of the world’s oldest continuously surviving cancer, a transmissible genital cancer that affects dogs. This cancer, which causes grotesque genital tumors in dogs around the world, first arose in a single dog that lived about 11,000 years ago. The cancer survived after the death of this dog by the transfer of its cancer cells to other dogs during mating. The genome of this 11,000-year-old cancer carries about two million mutations – many more mutations than are found in most human cancers, the majority of which have between 1,000 and 5,000 mutations. The team used one type of mutation, known to accumulate steadily over time as a “molecular clock,” to estimate that the cancer first arose 11,000 years ago. “The genome of this remarkable long-lived cancer has demonstrated that, given the right conditions, cancers can continue to survive for more than 10,000 years despite the accumulation of millions of mutations,” says Dr. Elizabeth Murchison, first author of the Science article from the Wellcome Trust Sanger Institute and the University of Cambridge.

January 22nd

Beautiful Life Science Fashion Now Available through Link on BioQuick

BioQuick News has added an exciting new advertiser we would like you to know about. It is “A Slice of Life Scarves” (http://www.asliceoflifescarves.com/), which produces highly artistic fashion products such as scarves and ties that feature images of biological structures observed with light and electron microscopy by their creator, Eve Reaven, Ph.D. Images include such structures as mitochondria, Golgi bodies, the endoplasmic reticulum, hormone secretory granules, actin filaments, and centrioles, all rendered in beautiful artistic patterns by Dr. Reaven. Dr. Reaven earned her Ph.D. in anatomy at the University of Chicago, working in a lab that had one of the first electron microscopes in the United States. Her work over the last several decades has helped elucidate the scavenger receptor pathway responsible for the bulk uptake and utilization of lipoprotein cholesterol by cells. Until her retirement, Dr. Reaven was a career research scientist at the Veteran’s Administration Hospital in Palo Alto, California, and for many years had been a senior research associate in the department of medicine at Stanford University. You can find an ad for “A Slice of Life Scarves” in BioQuick’s right-hand column and if you click on the ad, you will be taken to Dr. Reaven’s site, where you can view her beautiful collection of life science fashion items that are for sale. Once you see these beautiful products we believe you will become a life-time fan of Dr. Reaven’s fabulous work. We also hope that you will be convinced to purchase some of her uniquely magnificent creations. [A Slice of Life Scarves web site]

Some Salamanders Have Unique Torso-Based Jumping Ability, Possible Clue to Engineering Advances

A small, secretive creature with unlikely qualifications for defying gravity may hold the answer to an entirely new way of getting off the ground. Salamanders—or at least several species of the Plethodontidae family—can jump, and humans would like to know a lot more about it. “This particular jump is unique in the world,” said graduate researcher Anthony Hessel, as quoted in a January 21, 2014 press release from Northern Arizona University (NAU). “That’s why I think a lot of people are finding this very interesting.” The NAU student calls the move a “hip-twist jump” that powers a “flat catapult,” describing the biomechanics in language the public can access. But the work has caught the attention of a highly technical crowd. Hessel, who studies muscle physiology and biomechanics, recalled the moment he fully grasped the reach of his findings. An email from a premier journal reached him over the holiday break with the subject line “Science is interested in your work.” The contact arose from his presentation at the Society for Integrative and Comparative Biology symposium. There will likely be more who are interested. “It’s a new way to get vertical lift for animals,” Hessel said. “Something that is flat on the ground, that is not pushing directly down on the ground, can still get up in the air. I’d say that hundreds of engineers will now toy with the idea and figure out what cool things can be built from it.” Hessel used high-speed film, a home-built cantilever beam apparatus, some well-established engineering equations, and biomechanical analysis to produce the details of how a slippery little amphibian with short legs can propel itself six to 10 times its body length into the air. The key is that the salamander’s legs don’t provide the push that most creatures would require.