#Tracking subtle brain mutations systematically DNA sequences were thought once to be identical from cell to cell,
but it's increasingly understood that mutations can arise during brain development that affect only certain groups of brain cells.
A technique developed at Boston Children's Hospital allows these subtle mutation patterns to be traced
and mapped spatially for the first time. This capability is a significant advance for genetics research and provides a new way to study both the normal brain and brain disorders such as epilepsy and autism.
Described in the January 7th issue ofneuron, the technique uses"deep""highly sensitive whole-genome sequencing of single neurons
and a new technology that identifies inserted bits of DNA caused by retrotransposons, one of several kinds of so-called somatic mutations that can arise as the brain develops.
The technique picks up somatic mutations that affect just a fraction of the brain's cells, in a"mosaic"pattern.
It also allows"lineage tracing, "showing when during brain development the mutations arise and how they spread through brain tissue as the mutated cells grow,
replicate and migrate, carrying the mutation with them.""There is a lot of genetic diversity from one neuron to the other,
and this work gets at how somatic mutations are distributed in the brain, "says Christopher Walsh, MD, Phd, chief of Genetics and Genomics at Boston Children's and co-senior author on the paper."
"Some mutations may occur on one side of the brain and not the other. Some may be clumped,'affecting just one gyrus fold of the brain,
disrupting just a little part of the cortex at a time.""The study examined brain tissue from a deceased 17-year-old who had been neurologically normal,
sampling in more than 30 brain locations. It builds on work published by the Walsh lab in 2012,
which developed methods to sequence the genomes of single neurons, and represents the first time single neurons have been sequenced in their entirety.
The single-cell technique is better at detecting subtle mosaicism than usual DNA sequencing methods,
which sequence many thousands or millions of cells mixed together and read out an average for the sample.
Somatic brain mutations, affecting just pockets of cells can be harmful, and have been suggested as a possible cause of neurodevelopmental disorders such as autism,
epilepsy or intellectual disability (see this review article for further background). But they also can be completely benign
or have just a subtle effect.""Our findings are intriguing because they suggest that every normal brain may in fact be a mosaic patchwork of focal somatic mutations,
though in normal individuals most are likely silent or harmless,"says Gilad Evrony, Phd, in the Walsh Lab, co-first author on the Neuronpaper."
"These same technologies can now be used to study the brains of people who died from unexplained neuropsychiatric diseases to determine
whether somatic mutations may be the cause.""Finally, says Evrony, the findings provide a proof-of-principle for a systematic way of studying how brain cells disperse
Co-first author Alice Eunjung Lee, Phd, from the lab of Peter Park, Phd, at the Center for Biomedical Informatics at Harvard Medical school, developed the study's retrotransposon analysis tool,
which detects somatic retrotransposon mutations in single-cell sequencing data. Mirroring these findings, study published by Walsh's lab in 2014 used single-neuron sequencing to detect copy number variants--another type of mutation affecting the number of copies of chromosomes or chromosome fragments.
The study found that these mutations can occur in both normal and neurologically diseased brains s
#Brain imaging may help predict future behavior Noninvasive brain scans, such as functional magnetic resonance imaging, have led to basic science discoveries about the human brain,
but they've had limited only impacts on people's day-to-day lives. A review article published in the January 7 issue of the Cell Press journalneuron,
however, highlights a number of recent studies showing that brain imaging can help predict an individual's future learning, criminality, health-related behaviors,
and response to drug or behavioral treatments. The technology may offer opportunities to personalize educational and clinical practices.
Dr. John Gabrieli of the Massachusetts institute of technology in Cambridge and his colleagues describe the predictive power of brain imaging across a variety of different future behaviors
including infants'later performance in reading, students'later performance in math, criminals'likelihood of becoming repeat offenders, adolescents'future drug and alcohol use,
"Presently, we often wait for failure, in school or in mental health, to prompt attempts to help,
"If we can use neuroimaging to identify individuals at high risk for future failure, we may be able to help those individuals avoid such failure altogether."
"We will need to make sure that knowledge of future behavior is used to personalize educational and medical practices,
"For example, rather than simply identifying individuals to be more or less likely to succeed in a program of education,
such information could be used to promote differentiated education for those less likely to succeed with the standard education program
#Genome wide expression changes in vascular tissue identified due to infection/diet Source: Boston University Medical Centeralthough it has been shown that a diet high in fat
and exposure to certain bacteria can cause atherosclerosis (the buildup of fats cholesterol and other substances on artery walls which can restrict blood flow) researchers have identified for the first time distinct gene pathways that are altered by these different stimuli.
These findings which currently appear inbmc Genomics suggest that future therapies for this disease may need to be individualized.
Atherosclerosis is a common human disease associated with heart attack and stroke. Certain bacteria as well as high fat diet are associated with an increased risk for atherosclerosis.
One of these bacteria Porphyromonas gingivalis is found in the mouth of humans with periodontal disease; another Chlamydia pneumoniae causes pneumonia.
In this study the researchers used four experimental groups to compare genome-wide expression changes in vascular tissue.
The first group was subjected to Porphyromonas gingivalis while the second group received Chlamydia pneumoniae. The third group was placed on a high-fat diet
while the fourth group was the control. In collaboration with the Clinical and Translational Science Institute (CTSI) at Boston University the researchers performed genome-wide microarray profiling
and analysis of vascular tissue from all groups to reveal gene pathways altered in the atherosclerotic plaque by each treatment group.
and infection with Porphyromonas gingivalis andchlamydia pneumoniae in the general population and the likelihood of co-morbidity of obesity with chronic or recurring infection with these common pathogens these findings suggest that the development of atherosclerosis in humans is likely more complex
and multifactorial than previously appreciated explained senior author Caroline Attardo Genco Phd professor of medicine and microbiology at BUSM.
These findings may explain how specific infections or a high-fat diet may cause atherosclerotic plaques to undergo changes which affect their size
and stability and may ultimately lead to a heart attack she added d
#Vanderbilt-led team studies blood test for prostate cancer Vanderbilt University researcher William Mitchell, M d.,Ph d,
. and colleagues in Germany and Canada have demonstrated a method for detecting"cell-free"tumor DNA in the bloodstream.
Mitchell believes the technique will be transformative in providing improved cancer diagnostics that can both predict treatment outcomes and monitor patient responses to therapy.
In a large retrospective study of blood samples, the researchers showed that the method, called a"liquid biopsy,
"could accurately distinguish prostate cancer from normal controls without prior knowledge of the genetic"signature"of the tumors,
and with over three times the sensitivity of current prostate specific-antigen antigen (PSA) screening. The study appears in the January issue of Clinical Chemistry (volume 61, page 239),
which is dedicated to"Molecular Diagnostics: A Revolution In progress.""""Based on the reported data and work in progress, I believe the'liquid biopsy'will revolutionize cancer diagnostics,
not only before a patient begins therapy but also following patient responses to therapy,"said Mitchell, the paper's corresponding author and professor of Pathology, Microbiology and Immunology.
The study collected serum from more than 200 patients with prostate cancer and more than 200 controls.
The samples included PSA levels and prostate tissue biopsy grading, called the Gleason score. The researchers reported that the technique distinguished prostate cancer from normal controls with 84-percent accuracy,
and cancer from benign hyperplasia and prostatitis with an accuracy of 91 percent. Because the method quantifies the inherent chromosomal instability of cancer
and can be followed as a function of time without having to do an invasive tissue biopsy,
it is called a"liquid biopsy.""It's been known for many years that dying cells, including tumor cells, shed DNA into the bloodstream.
But only recently has technology, notably"next-generation sequencing, "made it possible to reliably distinguish
and quantify cancer-specific DNA from normal controls by the identification and chromosomal location of billions of specific DNA fragments present in blood as cell-free DNA.
The prostate cancer study identified 20"hotspots"of greatest chromosomal instability as additions or deletions in less than 0. 5 percent of the total DNA present in human chromosomes.
While researchers around the world are working on their own"liquid biopsies""Mitchell said the group's technique takes a broader approach.
It examines the entire genome rather than known specific gene point mutations. Robust mutation panels vastly improve monitoring
since cancer cells are constantly deleting chromosomal DNA and liquid biopsies with only one or two mutations will allow cancer cell escape variants to go undetected,
he said. Since the entire genome was surveyed, the researchers were able to identify a non-coding region of the genome as a"hotspot,
"which may be generating previously unrecognized chromosomal control elements in prostate cancer. The other 19"hotspots"were involved rich in genes in replication
and cell control processes that are highly relevant to cancer.""Since cell-free DNA has a relatively short half-life in the circulation,
sequencing of cell-free DNA soon after therapy may be used to detect minimal residual disease in solid tumors,
"Mitchell said. The researchers reported similar results in a study of breast cancer at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
Mitchell further predicted that liquid biopsies will quantify immediate tumor responses to therapy y
#CWRU researchers discover byproducts from bacteria awaken dormant T-cells and HIV viruses Dental and medical researchers from Case Western Reserve University found another reason to treat periodontal disease as soon as possible.
They discovered that byproducts of bacteria in gum disease, called metabolic small chain fatty acid (SCFA),
can work together to wake up HIV in dormant T-cells and cause the virus to replicate.
Their findings help explain why people with the HIV-infections and periodontal disease have higher levels of the virus in their saliva than HIV patients with healthy gums.
The researchers speculate that byproducts from other bacteria infections in other diseases might change gene expression using similar mechanisms.
For dental patients with HIV their findings further support how important it is to treat bacterial infections in gum disease early.
This interaction by SCFA and T-cells surprised co-investigators Fengchun Ye, assistant professor of biological sciences at the Case Western Reserve University School of dental medicine,
and Jonathan Karn, director of the Center for Aids Research and professor and chair of the Department of Molecular biology and Microbiology at Case Western Reserve's medical school.
Their findings are described in the article, "Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFB and multiple histone modifications,"
"published in January 2015 in the journal Virology (Das B, et al. Virology. 2015 Jan 1; 474: 65-81. doi:
10.1016/j. virol. 2014.10.033. Epub 2014 Nov 14. In the interaction between gum disease and HIV, five SCFA byproducts from two prevalent oral bacteria--Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn)--are involved in activating resting immune T-cells carrying latent (inactive
) HIV-1 virus. The process acts much like the jumper cables attached to a live battery recharging a dead one to get it running again,
according the researchers. Ye explained that all humans have a reservoir of resting T-cells that wake up
and respond to inflammation to ward off an infection in the body.""As long as someone is healthy,
the reservoir remains untapped, "he said. But for people with HIV, these T-cells can also have the sleeper HIV-1 virus,
which remains in a dormant state until awakened, Karn said. Last year, Ye and Karn discovered that one SCFA--butyric acid--induced a chain of events that reactivate the virus associated with Kaposi's sarcoma, the most common malignancy in HIV patients.
Following that discovery, the researchers expanded their investigation to all SCFAS. They found that a high quantity of butyric acid activates the T-cell
and incites virus replication. But smaller amounts of the five SCFA working together, have the same impact."
"Looking at only butyric acid was said misleading Karn, the Reinberger Professor of Molecular biology.""It surprised us to find they all work as an aggregate."
"The impact on waking up T-cells and activating HIV replication was a"double whammy"find that contributes to understanding the little-known microbiome in HIV disease,
Karn said. That prompted the researchers to investigate the mechanism that drives the replication of the virus in gum disease.
HIV antiviral therapy prevents active HIV cells from replicating and doesn't affect the quiet viruses in sleeping T-cells.
As long as the patient is free of gum disease, the virus sleeps and remains in check, Karn said d
#UCSD Study Shows Why Protein Mutations Lead to Familial Form of Parkinson Disease Researchers at the San diego Supercomputer Center (SDSC) at the University of California, San diego, have shown for the first time why protein mutations
lead to the familial form of Parkinson disease. The study, available online in prepublication in ACS Chemical Neuroscience and partially funded by the National institutes of health, focuses specifically on alpha-synuclein (asyn), a protein
whose function in healthy tissue is unknown but which represents the major structural component of Lewy bodies protein clumps found in the brains of individuals with Parkinson disease and other neurological disorders.
Parkinson disease is characterized by impairment or deterioration of neurons in an area of the brain known as the substantia nigra In the familial form of the disorder,
a set of mutations in asyn had been identified but what was unknown was the molecular mechanism by
which these mutations caused disease. s an unstructured protein, asyn is called sometimes hameleonbecause it has no stable configuration
and constantly changes its shape, said lead author Igor F. Tsigelny, a research scientist with SDSC as well as the UC San diego Moores Cancer Center and the Department of Neurosciences. evertheless when these changes seem to be random on first glance,
they have specific intrinsic rules that control the evolution of the asyn shape. Using SDSC data-intensive Gordon supercomputer to find hidden rules of the conformational changes of asyn
researchers conducted extensive calculations of the possible evolution of the protein structure. Through computer modeling, researchers showed that asyn mostly can bind the membrane with four main sites, or zones.
While binding was shown to be superficial by three of the sites, one site Zone 2 had a particular affinity for the membrane.
Researchers found that asyn contacting the neuron membrane in that site immediately and deeply penetrated it,
which led to the creation of ring oligomers in the membrane, and eventually opened pores that allowed an uncontrolled influx of ions that ultimately killed the cell.
Most of the mutations changed the shape of the protein in a way that increased binding of asyn to the membrane by this zone.
These theoretical predications were confirmed by a set of experimental methods conducted in the laboratory of Eliezer Masliah, a professor in UC San diego Department of Neurosciences. revious to this study,
researchers could not say why these mutations caused Parkinson disease, said Tsigelny. he discovery of Zone 2 as the distinguishing feature of the membrane-penetrating configurations of asyn paves the road to possible prevention of such a binding.
Now we can affect this region with rational drug design, for example by creating compounds that would change its electrostatic profile.
In addition to Tsigelny and Masliah, researchers involved in the study include Yuriy Sharikov Valentina L. Kouznetsova,
and Jerry P. Greenberg from SDSC; Wolf Wrasidlo from the Moores Cancer Center; and Cassia Overk, Tania Gonzalez, Margarita Trejo, Brian Spencer,
and Kori Kosberg, from the Department of Neurosciences at UC San diego e
#Promising drug candidate protects against radiation exposure from nuclear fallout The 2011 Fukushima disaster was a stark reminder of the continuing dangers posed by nuclear fallout,
highlighting the need for an approved drug that can be taken after radiation exposure to protect against organ injury and death.
A study published by Cell Press on January 22nd in Chemistry & Biology identifies a drug candidate called DBIBB that increases the survival of mice suffering from radiation syndrome,
even when treatment started three days after radiation exposure. The findings suggest that DBIBB shows promise for becoming the first drug capable of treating acute radiation syndrome caused by the high levels of radiation released by nuclear explosions."
"The 21st Century has presented humankind with unforeseen challenges, including the possibility of radiation terrorism, "said senior study author Gábor Tigyi, a professor of physiology at the University of Tennessee Health Science Center (UTHSC)."
"We hope that the scientific community and our efforts will provide protection through medical countermeasures against the harmful effects of ionizing radiation
and also help humans to benefit from the useful effects of nuclear technology.""Nuclear explosions can expose humans to high levels of ionizing radiation,
which can cause cell death and organ injury due to DNA damage. Although some agents tested by the military can provide some protection against radiation sickness when taken prior to radiation exposure,
no approved drug is taken effective when after radiation exposure. In previous studies, Tigyi and his collaborators found that a molecule called lysophosphatidic acid (LPA),
The resulting compound, called DBIBB, protected mouse embryonic skin cells from radiation-induced DNA damage and enhanced the survival of radiation-exposed blood cells, intestinal cells,
This promising compound will soon join the regulatory pipeline of a biotech company called Rxbio Inc,
. which was cofounded by Tigyi and other UTHSC faculty.""Humankind might soon have a defense against unintended radiation exposure,
"This technology can potentially also help cancer patients from the side effects of radiation therapy and astronauts from chronic exposure to cosmic rays on their journey to Mars. s
#Reducing Myc gene activity extends healthy lifespan in mice A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice,
the first such finding regarding this gene in a mammalian species. Myc is found in the genomes of all animals,
It is a major topic of biomedical research and has been shown to be a central regulator of cell proliferation, growth, and death.
too much expression of the protein that Myc encodes has been linked closely to cancer, making it a well-known but elusive target of drug developers.
said senior author John Sedivy, the Hermon C. Bumpus Professor of Biology and professor of medical science at Brown."
The researchers conducted these experiments to try to understand the longevity difference between the two groups.
a medical and doctoral student, led the studies of the health of the mice, including various bodily systems.
because in many other longevity models like caloric restriction or treatment with rapamycin, the animals live longer
They did not develop osteoporosis, they maintained a healthier balance of immune system T cells, had less cardiac fibrosis,
were experienced more active less age-related slowing of their metabolic rate, produced less cholesterol, and exhibited better coordination.
Graduate student and co-lead author Xiaoai Zhao, meanwhile, led the molecular analysis of several pathways known to be involved in regulating longevity to find out how they might be different.
Sure enough, heterozygous mice exhibited changes in IGF-1 signaling and nutrient and energy-sensing pathways,
but how Myc engages those mechanisms is still not clear. Of particular interest, heterozygous mice showed less protein synthesis in several tissues.
Genome-wide patterns of gene expression showed that Myc heterozygotes had significant differences in pathways related to metabolism and the immune system.
Zhao and Hoffman's studies also argue against a role for Myc in an oft-cited paradigm of greater longevity:
upregulation of a variety of stress defense mechanisms. Their experimental mice seemed to suffer from as much stress and consequences of stress as normal mice.
The different benefits of Myc reduction compared to other laboratory longevity extenders shows that just as there are many ways the body can break down with aging,
Sedivy said, there may be many ways to forestall that.""There is more than one way to become long-lived,
if it can reduce osteoporosis in people the way it does in mice. In particular, Sedivy said,
any drug that can target Myc directly is likely to find many applications beyond cancer r
#Wearable sensor clears path to long-term EKG EMG monitoring Researchers from North carolina State university have developed a new, wearable sensor that uses silver nanowires to monitor electrophysiological signals, such as electrocardiography
(EKG) or electromyography (EMG. The new sensor is as accurate as the"wet electrode"sensors used in hospitals,
but can be used for long-term monitoring and is more accurate than existing sensors when a patient is moving.
Long-term monitoring of electrophysiological signals can be used to track patient health or assist in medical research,
and may also be used in the development of new powered prosthetics that respond to a patient's muscular signals.
Electrophysiological sensors used in hospitals, such as EKGS, use wet electrodes that rely on an electrolytic gel between the sensor
and the patient's skin to improve the sensor's ability to pick up the body's electrical signals.
However this technology poses problems for long-term monitoring, because the gel dries up-irritating the patient's skin and making the sensor less accurate.
The new nanowire sensor is comparable to the wet sensors in terms of signal quality, but is a"dry"electrode-it doesn't use a gel layer,
so doesn't pose the same problems that wet sensors do.""People have developed other dry electrodes in the past few years,
and some have demonstrated the potential to rival the wet electrodes, but our new electrode has better signal quality than most-if not all of the existing dry electrodes.
It is more accurate, "says Dr. Yong Zhu, an associate professor of mechanical and aerospace engineering at NC State and senior author of a paper describing the work."
"In addition, our electrode is mechanically robust, because the nanowires are inlaid in the polymer.""The sensors stem from Zhu's earlier work to create highly conductive and elastic conductors made from silver nanowires,
and consist of one layer of nanowires in a stretchable polymer. The new sensor is also more accurate than existing technologies at monitoring electrophysiological signals
when a patient is in motion.""The silver nanowire sensors conform to a patient's skin, creating close contact,
"Zhu says.""And, because the nanowires are so flexible, the sensor maintains that close contact even when the patient moves.
The nanowires are also highly conductive, which is key to the high signal quality.""The new sensors are also compatible with standard EKG
-and EMG-reading devices.""I think these sensors are essentially ready for use, "Zhu says"The raw materials of the sensor are comparable in cost to existing wet sensors,
but we are still exploring ways of improving the manufacturing process to reduce the overall cost
#New high-speed 3-D microscope--SCAPE--gives deeper view of living things Source: Columbia University School of engineering and Applied science-Opening new doors for biomedical and neuroscience research, Elizabeth Hillman, associate professor of biomedical engineering at Columbia Engineering and of radiology at Columbia University Medical center
(CUMC), has developed a new microscope that can image living things in 3d at very high speeds.
In doing so, she has overcome some of the major hurdles faced by existing technologies, delivering 10 to 100 times faster 3d imaging speeds than laser scanning confocal, two-photon,
and light-sheet microscopy. Hillman's new approach uses a simple, single-objective imaging geometry that requires no sample mounting or translation,
making it possible to image freely moving living samples. She calls the technique SCAPE, for swept confocally aligned planar excitation microscopy.
Her study is published in the Advance Online Publication (AOP) on Nature Photonics's website on January 19, 2015."
"The ability to perform real-time 3d imaging at cellular resolution in behaving organisms is a new frontier for biomedical
and neuroscience research,"says Hillman, who is also a member of Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute."
"With SCAPE, we can now image complex, living things, such as neurons firing in the rodent brain, crawling fruit fly larvae,
and single cells in the zebrafish heart while the heart is actually beating spontaneously--this has not been possible until now."
"Highly aligned with the goals of President Obama's BRAIN INITIATIVE, SCAPE is a variation on light-sheet imaging,
but,"It breaks all the rules, "says Hillman. While conventional light-sheet microscopes use two awkwardly positioned objective lenses,
The emergence of fluorescent proteins and transgenic techniques over the past 20 years has transformed biomedical research,
even delivering neurons that flash as they fire in the living brain. Yet imaging techniques that can capture these dizzying dynamic processes have lagged behind.
acquiring enough of these layers to form a 3d image at fast enough rates to capture events like neurons actually firing has become a frustrating road-block.
Hillman and her collaborators have used already the system to observe firing in 3d neuronal dendritic trees in superficial layers of the mouse brain.
SCAPE can also be combined with optogenetics and other tissue manipulations during imaging because, unlike other systems,
Hillman and her students built their first SCAPE system using inexpensive off-the-shelf components. Her"aha"moment came when
After several years of trial and error, Hillman and graduate student Matthew Bouchard came up with a configuration that worked,
including Randy Bruno (associate professor of neuroscience, Department of Neuroscience), Richard Mann (Higgins Professor of Biochemistry and Molecular Biophysics, Department of Biochemistry & Molecular Biophysics), Wesley Grueber (associate professor
of physiology and cellular biophysics and of neuroscience, Department of Physiology & Cell Biophysics), and Kimara Targoff (assistant professor of pediatrics, Department of Pediatrics), all of whom are starting to use the SCAPE system in their research."
"Deciphering the functions of brain and mind demands improved methods for visualizing, monitoring, and manipulating the activity of neural circuits in natural settings,
"says Thomas M. Jessell, co-director of the Zuckerman Institute and Claire Tow Professor of Motor neuron Disorders, the Department of Neuroscience and the Department of Biochemistry and Molecular Biophysics at Columbia."
"Hillman's sophistication in optical physics has led her to develop a new imaging technique that permits large-scale detection of neuronal firing in three-dimensional brain tissues.
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