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  • richardmitnick 12:45 pm on January 17, 2017 Permalink | Reply
    Tags: , , Medicine,   

    From Vanderbilt: “Softening tumor tissue could aid cancer treatments” 

    Vanderbilt U Bloc

    Vanderbilt University

    Jan. 16, 2017
    Liz Entman

    Softening tumors’ blood vessels may help more chemo reach the cancer

    Normally, the glue that holds cells together in the human body – what scientists call the extracellular matrix – is soft and pliable. But when a metastatic tumor forms it causes the matrix surrounding it to stiffen.

    According to a new study, this mechanical effect produces changes in the blood vessels that feed the tumor in a way that can reduce the effectiveness of chemotherapeutics and radiation treatments. The finding suggests that softening this protective layer could make existing cancer treatments more effective.

    2
    Cynthia Reinhart-King (Steve Green/Vanderbilt)

    The study was published Dec. 22 in the Proceedings of the National Academy of Sciences, by a team of researchers led by Vanderbilt Professor of Biomedical Engineering Cynthia Reinhart-King, which includes postdoctoral researcher François Bordeleau in the Reinhart-King group along with collaborators from Cornell University. The report is titled Matrix Stiffening Promotes a Tumor Vasculature Phenotype.

    For years, the idea has been that the way to treat tumors was to starve them by killing off their blood vessels. While that works in some cases, in others it only serves to make the tumor more aggressive, Reinhart-King said, adding: “There are ways tumors can grow in the absence of those nutrients, and they get more aggressive. At the same time, they may also stop responding to some chemotherapeutics and radiation treatments.”

    A metastatic tumor’s blood vessels tend to be malformed and more permeable than blood vessels in healthy tissue. For this reason, fluid tends to leak from the vessels, building up pressure inside the tumor that prevents drugs from getting to their target.

    “Basically, as fluid leaks out of the blood vessels, it causes high pressures to build up in the tumor. These high pressures can cause blood flow to stall or even reverse and vessels tocollapse,” Reinhart-King said. “So fluid, including the drugs, cannot reach the tumor tissue.”

    3
    Image of a mammary tumor stained for cell nuclei (in blue), blood vessels (in green) and the protein beta-catenin that causes cells to stick together (in red) (Reinhart-King Lab / Vanderbilt)

    Unlike in previous work in this area, Reinhart-King and Bordeleau see the vascular breakdown as a product of the stiffening of the tumor and its matrix, which triggers proteins in cells to alter vascular growth and integrity. Previous work has targeted chemical factors, in particular vascular endothelial growth factor.

    “The idea that you would want to restore barrier integrity and help blood vessels is not a new one,” Reinhart-King said. “The idea that we discovered is that it’s controlled through matrix stiffness.” This, in turn, suggests that promoting healthy vasculature through a softening of the extracellular matrix would use the tumor itself as a conduit for delivering cancer-killing drugs.

    “What we show,” Reinhart-King said, “is that we can drive a lot of the same behaviors that are typically thought to occur due to chemical changes, by changing the mechanical properties of the tumor.”

    This work was supported by National Institutes of Health grants R01-HL127499 and R01-CA163255 and National Science Foundation awards 1055502 and 435755.

    See the full article here .

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    Vanderbilt Campus

     
  • richardmitnick 4:02 pm on January 16, 2017 Permalink | Reply
    Tags: , , Connectome project, Medicine, Multiregional brain-on-a-chip,   

    From Wyss: “Multiregional brain on a chip” 

    Harvard bloc tiny
    Wyss Institute bloc
    Wyss Institute

    January 14, 2017
    Leah Burrows

    Model allows researchers to study how diseases like schizophrenia impact different regions of the brain simultaneously.

    Harvard University researchers have developed a multiregional brain-on-a-chip that models the connectivity between three distinct regions of the brain. The in vitro model was used to extensively characterize the differences between neurons from different regions of the brain and to mimic the system’s connectivity.

    The research was published in the Journal of Neurophysiology.

    2
    Three areas populated with neurons representing different regions of the brain are interconnected by thin neuronal process (in green) to allow the study of complex diseases. Credit: Disease Biophysics Group/Harvard University

    “The brain is so much more than individual neurons,” said Ben Maoz, co-first author of the paper and a Technology Development Fellow at the Wyss Institute for Biologically Inspired Engineering, and Postdoctoral Fellow in the Disease Biophysics Group in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). “It’s about the different types of cells and the connectivity between different regions of the brain. When modeling the brain, you need to be able to recapitulate that connectivity because there are many different diseases that attack those connections.”

    “Roughly twenty-six percent of the US healthcare budget is spent on neurological and psychiatric disorders,” said Wyss Institute Core Faculty member Kit Parker and the Tarr Family Professor of Bioengineering and Applied Physics Building at SEAS. “Tools to support the development of therapeutics to alleviate the suffering of these patients is not only the human thing to do, it is the best means of reducing this cost.”

    Researchers from the Wyss Institute and the Disease Biophysics Group at SEAS modeled three regions of the brain most affected by schizophrenia — the amygdala, hippocampus and prefrontal cortex.

    They began by characterizing the cell composition, protein expression, metabolism, and electrical activity of neurons from each region in vitro.

    “It’s no surprise that neurons in distinct regions of the brain are different but it is surprising just how different they are,” said Stephanie Dauth, co-first author of the paper and former postdoctoral fellow in the Disease Biophysics Group. “We found that the cell-type ratio, the metabolism, the protein expression and the electrical activity all differ between regions in vitro. This shows that it does make a difference which brain region’s neurons you’re working with.”

    Next, the team looked at how these neurons change when they’re communicating with one another. To do that, they cultured cells from each region independently and then let the cells establish connections via guided pathways embedded in the chip.

    The researchers then measured cell composition and electrical activity again and found that the cells dramatically changed when they were in contact with neurons from different regions.

    “When the cells are communicating with other regions, the cellular composition of the culture changes, the electrophysiology changes, all these inherent properties of the neurons change,” said Maoz. “This shows how important it is to implement different brain regions into in vitro models, especially when studying how neurological diseases impact connected regions of the brain.”

    To demonstrate the chip’s efficacy in modeling disease, the team doped different regions of the brain with the drug Phencyclidine hydrochloride — commonly known as PCP — which simulates schizophrenia. The brain-on-a-chip allowed the researchers for the first time to look at both the drug’s impact on the individual regions as well as its downstream effect on the interconnected regions in vitro.

    The brain-on-a-chip could be useful for studying any number of neurological and psychiatric diseases, including drug addiction, post traumatic stress disorder, and traumatic brain injury.

    “To date, the Connectome project has not recognized all of the networks in the brain,” said Parker. “In our studies, we are showing that the extracellular matrix network is an important part of distinguishing different brain regions and that, subsequently, physiological and pathophysiological processes in these brain regions are unique. This advance will not only enable the development of therapeutics, but fundamental insights as to how we think, feel, and survive.”

    This research was coauthored by Sean P. Sheehy, Matthew A. Hemphill, Tara Murty, Mary Kate Macedonia, Angie M. Greer and Bogdan Budnik. It was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Defense Advanced Research Projects Agency.

    See the full article here .

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 9:41 am on January 16, 2017 Permalink | Reply
    Tags: , , Autism Risk May Arise From Sex-Specific Traits, Medicine, , SNP - single nucleotide polymorphism   

    From SA: “Autism Risk May Arise From Sex-Specific Traits” 

    Scientific American

    Scientific American

    January 16, 2017
    Ann Griswold

    Genetic sequences that code for physical features that differ between boys and girls also seem to contribute to risk for the disorder.

    1
    Alena Baranova, EyeEm, Getty Images

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    Basic biology: Different genetic variants contribute to autism risk in boys versus girls. Alfred Pasieka / Science Photo Library

    Genetic variants that shape physical features that vary with sex, such as waist-to-hip ratio, may also affect autism risk, according to a new study.

    Many of the genes involved in these features are not linked to autism or even the brain. Instead, they help establish basic physical differences between the sexes, says lead investigator Lauren Weiss, associate professor of psychiatry at the University of California, San Francisco.

    “Whatever general biological sex differences cause a [variant] to have a different effect on things like height in males and females, those same mechanisms seem to be contributing to autism risk,” she says. The work appeared in November in PLOS Genetics.

    The results bolster the notion that mutations in some genes contribute to autism’s skewed sex ratio: The condition is diagnosed in about five boys for every girl. That may be because girls require a bigger genetic hit to show features of the condition, because sex hormones in the womb boost the risk in boys or because autism is easier to detect in boys than in girls.

    The new study is the first to look at sex differences in common genetic variants called single nucleotide polymorphisms (SNPs). It shows that the sexes differ in which autism-linked SNPs they have, but not in the overall number of such SNPs.

    Separate sets:

    Weiss and her team analyzed published genetic data from four databases and unpublished data from five others. Altogether, they reviewed information from 8,646 individuals with autism, including 1,468 girls and women. They also analyzed data from 15,028 controls, some of whom are related to people in the autism group.

    The researchers first identified SNPs that differ between males with autism and their unaffected family members and unrelated controls. They then repeated the procedure for girls and women with autism.

    These two analyses revealed distinct sets of SNPs associated with autism: a set of five SNPs in boys and men and a separate set of three SNPs in girls and women. None of the variants have previously been associated with autism.

    The researchers then compared males who have autism with females who have the condition. They found similar levels of genetic variation in the two groups, with equal numbers of autism risk genes affected. This result suggests that common variants do not contribute to a stronger genetic hit in girls with autism.

    Body of data:

    When the researchers compared people who have autism with controls, they did not find any differences in SNPs in genes that respond to sex hormones.

    The team then looked at 11 SNPs known to influence height, weight, body mass index, hip and waist measurements in women, and 15 variants that influence these physical traits in men. They found more of these sex-specific SNPs in people with autism than in controls. None of these SNPs have previously been associated with autism.

    The findings suggest that different SNPs contribute to autism risk in boys and girls.

    The fact that some of these SNPs also shape physical traits in a sex-specific way is particularly interesting, says Meng-Chuan Lai, assistant professor in psychiatry at the University of Toronto, who was not involved in the study. Scientists should examine whether sex differences in brain structure in people with autism track with the sex-specific SNPs, he says.

    Weiss says she hopes the findings will spur researchers to pay more attention to the influences of sex when sifting through genomic data. Outfitting genetic repositories with the option to sort data by sex would be the next step for that approach.

    See the full article here .

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    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

     
  • richardmitnick 10:23 am on January 13, 2017 Permalink | Reply
    Tags: , , , Medicine, , Sugar stands accused   

    From Harvard: “Sugar stands accused” This Is Important for All 

    Harvard University

    Harvard University

    Sugar was in the dock at Harvard Law School this week, accused of a prime role in the twin epidemics of obesity and diabetes sweeping the country.

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    Gary Taubes signs copies of his book “The Case Against Sugar” following his talk for the Food Law and Policy Clinic. The acclaimed science writer hypothesizes that sugar “has deleterious effects on the human body that lead to obesity and diabetes, and that it should be considered a prime suspect [in the national dietary epidemic].” Stephanie Mitchell/Harvard Staff Photographer

    Science journalist and author Gary Taubes ’77 made his case that sugar consumption — which has risen dramatically over the last century — drives metabolic dysfunction that makes people sick. The hour-long talk was sponsored by the Food Law and Policy Clinic and drawn from Taubes’ new book, The Case Against Sugar.

    A reputation for “empty calories” — devoid of vitamins and nutrients but otherwise no different from other foods containing an equal number of calories — has allowed sugar to maintain a prominent place in the U.S. diet. Taubes is dubious. First, all calories are not equal because the body metabolizes different foods in different ways. More specifically, there may be something about eating too much sugar — in particular fructose, which is metabolized in the liver — that implicates it in metabolic disease.

    “I’m making an argument that sugar is uniquely toxic,” said Taubes. “It has deleterious effects on the human body that lead to obesity and diabetes.”

    Taubes laid out a case that he admitted was “largely circumstantial,” though one he considers compelling enough that it would gain at least an indictment from an impartial jury. The problem with the evidence, he said, is that public health researchers haven’t focused enough attention on sugar.

    “The research doesn’t exist beyond reasonable doubt that sugar is to blame,” Taubes said.

    Diabetes, Taubes noted, was once a rare disease. He traced its rise through the 1800s and 1900s from just a fraction of 1 percent of the cases seen at Massachusetts General Hospital to a condition that afflicts nearly 10 percent of the U.S. population, according to the Centers for Disease Control and Prevention. That increase, he said, coincides with an increase in sugar in the American diet.

    He tied today’s problems to both the sugar industry and some of the scientists responsible for informing the public about diet. Two researchers prominent in Harvard’s history didn’t escape blame: Elliott Joslin, the founder of the Harvard-affiliated Joslin Diabetes Center, and Frederick Stare, the founder of the Harvard T.H. Chan School of Public Health’s Nutrition Department.

    See the full article here .

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    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:12 am on January 13, 2017 Permalink | Reply
    Tags: , Could affect future treatments for some types of infertility, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, , Medicine, Metabolic proteins relocate to jump-start an embryo’s genome, UCLA study finds   

    From UCLA: “Metabolic proteins relocate to jump-start an embryo’s genome, UCLA study finds” 

    UCLA bloc

    UCLA

    January 12, 2017
    Sarah C.P. Williams

    FINDINGS

    1
    No image caption. No image credit.

    To turn on its genome — the full set of genes inherited from each parent — a mammalian embryo needs to relocate a group of proteins, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have discovered. The metabolic proteins, normally found in the energy-generating mitochondria of cells, move to the DNA-containing nuclei about two days after a mouse embryo is fertilized, according to the new study, led by senior author Utpal Banerjee.

    BACKGROUND

    Early in development, a mammalian embryo — or zygote — has all the materials it needs to grow and divide from genes and proteins that were contained in the egg cell. But after a few cell divisions, the zygote needs to activate its own genome. Researchers have never fully understood how this shift is made. They knew that certain metabolic compounds, such a pyruvate, were required, but had also observed that the mitochondria — which normally process pyruvate into energy — were small and inactive during this stage of development.

    METHOD

    Banerjee, a professor of molecular, cell, and developmental biology and co-director of the UCLA Broad Stem Cell Research Center, and colleagues confirmed that pyruvate was required for zygotes to activate their genomes by growing mouse zygotes in a culture dish lacking pyruvate. Then, in both mouse and human embryos, researchers used a number of methods to determine the location of proteins that process pyruvate through a metabolic program called the TCA cycle. Just before the embryos activated their genomes, the two-cell stage in mice, the TCA cycle proteins moved from the mitochondria to the nuclei of cells, the researchers discovered. While mouse cells grown in dishes lacking pyruvate normally stopped growing at the two-cell stage, the researchers could rescue these cells by adding a metabolic compound that’s produced by the TCA cycle. Repeating some of the experiments in human embryos, they confirmed that the metabolic proteins move from the mitochondria to the nucleus just as the genome is activated — at the six- to eight-cell stage for humans.

    IMPACT

    The importance of metabolic proteins to early embryonic development could affect future treatments for some types of infertility. In addition, the researchers hypothesize that some stem cells that have similar metabolic properties to early zygotes — including cancer stem cells — may relocate the TCA cycle proteins. Better understanding of the relocation could shed light on stem cell biology and alter cancer treatments.

    AUTHORS

    In addition to Banerjee, the first authors of the study are Raghavendra Nagaraj and Mark Sharpley; the co-authors are Daniel Braas, Fangtao Chi, Amander Clark, Rachel Kim and Yonggang Zhou, all of UCLA.

    JOURNAL

    The study was published in the journal Cell.

    FUNDING

    The study was funded by an NIH Director’s Pioneer Award (DP1DK098059-04) and by the UCLA Broad Stem Cell Research Center.

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    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 10:34 am on January 11, 2017 Permalink | Reply
    Tags: , Medicine, , , A healthy lifestyle may help you sidestep Alzheimer’s   

    From HMS: “A healthy lifestyle may help you sidestep Alzheimer’s” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 09, 2017
    Heidi Godman

    1
    No image caption. No image credit

    January is an inspiring time to make resolutions about eating a healthy diet and exercising more, maybe because you want to look or feel better. Personally, those reasons aren’t always enough to keep me from skipping a workout if I have too much on my schedule. I guess I’m a typical mom, putting my family and my job first.

    But this year, I have plenty of renewed inspiration to put my health first, and it’s the kind that will keep me up at night if I don’t stick to it: evidence suggests that adopting healthier lifestyle habits may help you thwart or even prevent the development of Alzheimer’s disease. Dementia runs in my family.

    About Alzheimer’s

    Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of two types of protein in the brain: tangles (tau) and plaques (amyloid-beta). Eventually, Alzheimer’s kills brain cells and takes people’s lives.

    What causes Alzheimer’s? We still aren’t sure. “For 1% of all cases, there are three genes that determine definitively whether you will have Alzheimer’s, and all three relate to amyloid-beta production, which in these cases is likely the cause of Alzheimer’s,” says Dr. Gad Marshall, associate medical director of clinical trials at the Center for Alzheimer Research and Treatment at Harvard-affiliated Brigham and Women’s Hospital. “For the other 99%, amyloid and tau are closely associated with Alzheimer’s, but many things may contribute to the development of symptoms, such as inflammation in the brain, vascular risk factors, and lifestyle.”

    Promising evidence

    So far, evidence suggests that several healthy habits may help ward off Alzheimer’s. Consider the following steps.

    Exercise. “The most convincing evidence is that physical exercise helps prevent the development of Alzheimer’s or slow the progression in people who have symptoms,” says Dr. Marshall. “The recommendation is 30 minutes of moderately vigorous aerobic exercise, three to four days per week.”

    Eat a Mediterranean diet. “This has been shown to help thwart Alzheimer’s or slow its progression. A recent study showed that even partial adherence to such a diet is better than nothing, which is relevant to people who may find it difficult to fully adhere to a new diet,” says Dr. Marshall. The diet includes fresh vegetables and fruits; whole grains; olive oil; nuts; legumes; fish; moderate amounts of poultry, eggs, and dairy; moderate amounts of red wine; and red meat only sparingly.

    Get enough sleep. “Growing evidence suggests that improved sleep can help prevent Alzheimer’s and is linked to greater amyloid clearance from the brain,” says Dr. Marshall. Aim for seven to eight hours per night.

    Not as certain

    We have some — but not enough — evidence that the following lifestyle choices help prevent Alzheimer’s.

    Learn new things. “We think that cognitively stimulating activities may be helpful in preventing Alzheimer’s, but the evidence for their benefit is often limited to improvement in a learned task, such as a thinking skills test, that does not generalize to overall improvement in thinking skills and activities of daily living,” says Dr. Marshall.

    Connect socially. “We think that greater social contact helps prevent Alzheimer’s,” explains Dr. Marshall, but so far, “there is only information from observational studies.”

    Drink — but just a little. There is conflicting evidence about the benefit of moderate alcohol intake (one drink per day for women, one or two for men) and reduced risk of Alzheimer’s. “It is thought that wine in particular, and not other forms of alcohol, may be helpful, but this has not been proved,” says Dr. Marshall.

    What you should do

    Even though we don’t have enough evidence that all healthy lifestyle choices prevent Alzheimer’s, we do know they can prevent other chronic problems. For example, limiting alcohol intake can help reduce the risk for certain cancers, such as breast cancer. So it’s wise to make as many healthy lifestyle choices as you can. “They’re all beneficial, and if they wind up helping you avoid Alzheimer’s, all the better,” says Dr. Marshall.

    But don’t feel like you need to rush into a ramped-up routine of living a healthier lifestyle. All it takes if one small change at a time, such as:

    exercising an extra day per week.
    getting rid of one unhealthy food from your diet.
    going to bed half an hour earlier, or shutting off electronic gadgets half an hour earlier than normal, to help you wind down.
    listening to a new kind of music, or listening to a podcast about a topic you’re unfamiliar with.
    or having lunch with a friend you haven’t seen in a while.

    Once you make one small change, try making another. Over time, they will add up. My change is that I’m going to add 15 more minutes to my exercise routine; that way, I’ll rack up more exercise minutes per week, and I won’t feel bad if I have to skip a workout now and then. By putting my health first, I’ll be in better shape for my family and my job, and hopefully, I’ll be better off in older age.

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:13 am on January 11, 2017 Permalink | Reply
    Tags: , Here’s how to build a whirligig, Inspired by a whirligig toy Stanford bioengineers develop a 20-cent hand-powered blood centrifuge, Medicine, ,   

    From Stanford: “Inspired by a whirligig toy, Stanford bioengineers develop a 20-cent, hand-powered blood centrifuge” 

    Stanford University Name
    Stanford University

    January 10, 2017
    Kris Newby

    Stanford bioengineers have developed an ultra-low-cost, human-powered blood centrifuge. With rotational speeds of up to 125,000 revolutions per minute, the device separates blood plasma from red cells in 1.5 minutes, no electricity required.


    Access mp4 video here .
    Inspired by a toy, Stanford bioengineers have developed an inexpensive, human-powered blood centrifuge that will enable precise diagnosis and treatment of diseases like malaria, African sleeping sickness and tuberculosis in the poor, off-the-grid regions where these diseases are most prevalent. Video by Kurt Hickman

    Here’s how to build a whirligig: Thread a loop of twine through two holes in a button. Grab the loop ends, then rhythmically pull. As the twine coils and uncoils, the button spins at a dizzying speed.

    Now, using the same mechanical principles, Stanford bioengineers have created an ultra-low-cost, human-powered centrifuge that separates blood into its individual components in only 1.5 minutes. Built from 20 cents of paper, twine and plastic, a “paperfuge” can spin at speeds of 125,000 rpm and exert centrifugal forces of 30,000 Gs.

    “To the best of my knowledge, it’s the fastest spinning object driven by human power,” said Manu Prakash, an assistant professor of bioengineering at Stanford.

    A centrifuge is critical for detecting diseases such as malaria, African sleeping sickness, HIV and tuberculosis. This low-cost version will enable precise diagnosis and treatment in the poor, off-the-grid regions where these diseases are most prevalent.

    The physics and test results of this device are published in the Jan. 10 issue of Nature Biomedical Engineering.

    No electricity required

    When used for disease testing, a centrifuge separates blood components and makes pathogens easier to detect. A typical centrifuge spins fluid samples inside an electric-powered, rotating drum. As the drum spins, centrifugal forces separate fluids by density into layers within a sample tube. In the case of blood, heavy red cells collect at the bottom of the tube, watery plasma floats to the top, and parasites, like those that cause malaria, settle in the middle.

    Prakash, who specializes in low-cost diagnostic tools for underserved regions, recognized the need for a new type of centrifuge after he saw an expensive centrifuge being used as a doorstop in a rural clinic in Uganda because there was no electricity to run it.

    “There are more than a billion people around the world who have no infrastructure, no roads, no electricity. I realized that if we wanted to solve a critical problem like malaria diagnosis, we needed to design a human-powered centrifuge that costs less than a cup of coffee,” said Prakash, who was senior author on the study.

    Inspired by spinning toys, Prakash began brainstorming design ideas with Saad Bhamla, a postdoctoral research fellow in his lab and first author on the paper. After weeks of exploring ways to convert human energy into spinning forces, they began focusing on toys invented before the industrial age – yo-yos, tops and whirligigs.

    “One night I was playing with a button and string, and out of curiosity, I set up a high-speed camera to see how fast a button whirligig would spin. I couldn’t believe my eyes,” said Bhamla, when he discovered that the whirring button was rotating at 10,000 to 15,000 rpms.

    After two weeks of prototyping, he mounted a capillary of blood on a paper-disc whirligig and was able to centrifuge blood into layers. It was a definitive proof-of-concept, but before he went to the next step in the design process, he and Prakash decided to tackle a scientific question no one else had: How does a whirligig actually work?

    The other string theory

    Bhamla recruited three undergraduate engineering students from MIT and Stanford to build a mathematical model of how the devices work. The team created a computer simulation to capture design variables like disc size, string elasticity and pulling force. They also borrowed equations from the physics of supercoiling DNA strands to understand how hand-forces move from the coiling strings to power the spinning disc.

    “There are some beautiful mathematics hidden inside this object,” Prakash said.

    Once the engineers validated their models against real-world prototype performance, they were able to create a prototype with rotational speeds of up to 125,000 rpm, a magnitude significantly higher than their first prototypes.

    “From a technical spec point of view, we can match centrifuges that cost from $1,000 to $5,000,” said Prakash.

    In parallel, they improved the device’s safety and began testing configurations that could be used to test live parasites in the field. From lab-based trials, they found that malaria parasites could be separated from red blood cells in 15 minutes. And by spinning the sample in a capillary precoated with acridine orange dye, glowing malaria parasites could be identified by simply placing the capillary under a microscope.

    Bhamla and Prakash, who recently returned from fieldwork in Madagascar, are currently conducting a paperfuge field validation trial for malaria diagnostics with PIVOT and Institut Pasteur, community-health collaborators based in Madagascar.

    A frugal science toolbox

    Paperfuge is the third invention from the Prakash lab driven by a frugal design philosophy, where engineers rethink traditional medical tools to lower costs and bring scientific capabilities out of the lab and into hands of health care workers in resource-poor areas.

    The first was the foldscope, a fully functional, under-a-dollar paper microscope that can be used for diagnosing blood-borne diseases such as malaria, African sleeping sickness and Chagas. To date there are 50,000 foldscopes in the hands of people around the world, and a spinoff company recently launched a Kickstarter campaign to ship 1 million more.

    The second was a $5 programmable kid’s chemistry set, inspired by hand-crank music boxes, which enables the execution of precise chemical assays in the field.

    Prakash’s dream is that these tools will enable health workers, field ecologists and children in the most remote areas of the world to carry a complete laboratory in a backpack.

    “Frugal science is about democratizing scientific tools to get them out to people around the world,” said Prakash.

    Prakash is also a member of Stanford Bio-X and Stanford ChEM-H, a senior fellow at the Stanford Center for Innovation in Global Health and an affiliate of the Stanford Woods Institute for the Environment.

    Other co-authors on the paper are Brandon Benson, Chew Chai, Georgios Katsikis and Aanchal Johri.

    This work was supported by the Stanford-Spectrum Clinical and Translational Science Award from the National Center for Advancing Translational Sciences (NCATS), a Stanford School of Medicine Dean’s Postdoctoral Fellowship, the Pew Foundation, the Moore Foundation, a National Science Foundation Career Award and the National Institutes of Health (NIH) New Innovator Award.

    See the full article here .

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  • richardmitnick 8:35 am on January 10, 2017 Permalink | Reply
    Tags: , , , Medicine, , or TADs, , Syndactyly, topologically associating domains   

    From NYT: “A Family’s Shared Defect Sheds Light on the Human Genome” 

    New York Times

    The New York Times

    JAN. 9, 2017
    NATALIE ANGIER

    1
    Headcase Design

    They said it was their family curse: a rare congenital deformity called syndactyly, in which the thumb and index finger are fused together on one or both hands. Ten members of the extended clan were affected, and with each new birth, they told Stefan Mundlos of the Max Planck Institute for Molecular Genetics, the first question was always: “How are the baby’s hands? Are they normal?”

    Afflicted relatives described feeling like outcasts in their village, convinced that their “strange fingers” repulsed everybody they knew — including their unaffected kin. “One woman told me that she never received a hug from her father,” Dr. Mundlos said. “He avoided her.”

    The family, under promise of anonymity, is taking part in a study by Dr. Mundlos and his colleagues of the origin and development of limb malformations. And while the researchers cannot yet offer a way to prevent syndactyly, or to entirely correct it through surgery, Dr. Mundlos has sought to replace the notion of a family curse with “a rational answer for their condition,” he said — and maybe a touch of pioneers’ pride.

    The scientists have traced the family’s limb anomaly to a novel class of genetic defects unlike any seen before, a finding with profound implications for understanding a raft of heretofore mysterious diseases.

    The mutations affect a newly discovered design feature of the DNA molecule called topologically associating domains, or TADs. It turns out that the vast informational expanse of the genome is divvied up into a series of manageable, parochial and law-abiding neighborhoods with strict nucleic partitions between them — each one a TAD.

    2
    The hand of a woman with syndactyly, the congenital fusion of fingers. The deformity may range from a slight degree of webbing to almost complete fusion as shown here. Credit SPL/Science Source

    Breach a TAD barrier, and you end up with the molecular equivalent of that famous final scene in Mel Brooks’s comedy, “Blazing Saddles,” when the cowboy actors from one movie set burst through a wall and onto the rehearsal stage of a campy Fred Astaire-style musical. Soon fists, top hats and cream pies are flying.

    By studying TADs, researchers hope to better fathom the deep structure of the human genome, in real time and three dimensions, and to determine how a quivering, mucilaginous string of some three-billion chemical subunits that would measure more than six-feet long if stretched out nonetheless can be coiled and compressed down to four-10,000ths of an inch, the width of a cell nucleus — and still keep its operational wits about it.

    “DNA is a super-long molecule packed into a very small space, and it’s clear that it’s not packed randomly,” Dr. Mundlos said. “It follows a very intricate and controlled packing mechanism, and TADs are a major part of the folding protocol.”

    For much of the past 50 years, genetic research has focused on DNA as a kind of computer code, a sequence of genetic “letters” that inscribe instructions for piecing together amino acids into proteins, which in turn do the work of keeping us alive.

    Read Between the Folds

    Most of the genetic diseases deciphered to date have been linked to mishaps in one or another protein recipe. Scanning the DNA of patients with Duchenne muscular dystrophy, for example, scientists have identified telltale glitches in the gene that encodes dystrophin, a protein critical to muscle stability.

    At the root of Huntington’s disease, which killed the folk singer Woody Guthrie, are short, repeated bits of nucleic nonsense sullying the code for huntingtin, an important brain protein. The mutant product that results soon shatters into neurotoxic shards.

    Yet researchers soon realized there was much more to the genome than the protein codes it enfolded. “We were caught up in the idea of genetic information being linear and one-dimensional,” said Job Dekker, a biologist at the University of Massachusetts Medical School.

    For one thing, as the sequencing of the complete human genome revealed, the portions devoted to specifying the components of hemoglobin, collagen, pepsin and other proteins account for just a tiny fraction of the whole, maybe 3 percent of human DNA’s three billion chemical bases.

    And there was the restless physicality of the genome, the way it arranged itself during cell division into 23 spindly pairs of chromosomes that could be stained and studied under a microscope, and then somehow, when cell replication was through, merged back together into a baffling, ever-wriggling ball of chromatin — DNA wrapped in a protective packaging of histone proteins.

    3
    Stefan Mundlos of the Max Planck Institute for Molecular Genetics in Germany studies the origin and development of limb malformations, some of which are caused by a novel class of genetic defects. Credit Norbert Michalke/Max Planck Institute for Molecular Genetics, Berlin

    What was the link, scientists wondered, between the shape and animation of the DNA molecule at any given moment, in any given cell — and every cell has its own copy of the genome — and the relative mouthiness or muteness of the genetic information the DNA holds?

    “We realized that in order to understand how genetic information is controlled, we had to figure out how DNA was folded in space,” said Bing Ren of the University of California, San Diego.

    Using a breakthrough technology developed by Dr. Dekker and his colleagues called chromosome conformation capture, researchers lately have made progress in tracking the deep structure of DNA. In this approach, chromatin is chemically “frozen” in place, enzymatically chopped up and labeled, and then allowed to reassemble.

    The pieces that find each other again, scientists have determined, are those that were physically contiguous in the first place — only now all their positions and relationships are clearly marked.

    Through chromosome conformation studies and related research, scientists have discovered the genome is organized into about 2,000 jurisdictions, and they are beginning to understand how these TADs operate.

    As with city neighborhoods, TADs come in a range of sizes, from tiny walkable zones a few dozen DNA subunits long to TADs that sprawl over tens of thousands of bases and you’re better off taking the subway. TAD borders serve as folding instructions for DNA. “They’re like the dotted lines on a paper model kit,” Dr. Dekker said.

    TAD boundaries also dictate the rules of genetic engagement.

    Scientists have long known that protein codes are controlled by an assortment of genetic switches and enhancers — noncoding sequences designed to flick protein production on, pump it into high gear and muzzle it back down again. The new research indicates that switches and enhancers act only on those genes, those protein codes, stationed within their own precincts.

    Because TADs can be quite large, the way the Upper West Side of Manhattan comprises an area of about 250 square blocks, a genetic enhancer located at the equivalent of, say, Lincoln Center on West 65th Street, can amplify the activity of a gene positioned at the Cathedral of St. John the Divine, 45 blocks north.

    But under normal circumstances, one thing an Upper West Side enhancer will not do is reach across town to twiddle genes residing on the Upper East Side.

    4
    Scientists have learned that disruptions of the genome’s boundaries may cause syndactyly and other diseases, including some pediatric brain disorders that affect the brain’s white matter. Credit Living Art Enterprises, LLC/Science Source

    “Genes and regulatory elements are like people,” Dr. Dekker said. “They care about and communicate with those in their own domain, and they ignore everything else.”

    Breaking Boundaries

    What exactly do these boundaries consist of, that manage to both direct the proper folding of the DNA molecule and prevent cross talk between genes and gene switches in different domains? Scientists are not entirely sure, but preliminary results indicate that the boundaries are DNA sequences that attract the attention of sticky, roughly circular proteins called cohesin and CTCF, which adhere thickly to the boundary sequences like insulating tape.

    Between those boundary points, those clusters of insulating proteins, the chromatin strand can loop up and over like the ribbon in a birthday bow, allowing genetic elements distributed along the ribbon to touch and interact with one another. But the insulating proteins constrain the movement of each chromatin ribbon, said Richard A. Young of the Whitehead Institute for Biomedical Research, and keep it from getting entangled with neighboring loops — and the genes and regulatory elements located thereon.

    The best evidence for the importance of TADs is to see what happens when they break down. Researchers have lately linked a number of disorders to a loss of boundaries between genomic domains, including cancers of the colon, esophagus, brain and blood.

    In such cases, scientists have failed to find mutations in any of the protein-coding sequences commonly associated with the malignancies, but instead identified DNA damage that appeared to shuffle around or eliminate TAD boundaries. As a result, enhancers from neighboring estates suddenly had access to genes they were not meant to activate.

    Reporting in the journal Science, Dr. Young and his colleagues described a case of leukemia in which a binding site for insulator proteins had been altered not far from a gene called TAL1, which if improperly activated is known to cause leukemia. In this instance, disruption of the nearby binding site, Dr. Young said, “broke up the neighborhood and allowed an outside enhancer to push TAL1 to the point of tumorigenesis,” the production of tumors.

    Now that researchers know what to look for, he said, TAD disruptions may prove to be a common cause of cancer. The same may be true of developmental disorders — like syndactyly.

    In journals like Cell and Nature, Dr. Mundlos and his co-workers described their studies of congenital limb malformations in both humans and mice. The researchers have detected major TAD boundary disruptions that allowed the wrong control elements to stimulate muscle genes at the wrong time and in the wrong tissue.

    “If a muscle gene turns on in the cartilage of developing digits,” Dr. Mundlos said, “you get malformations.”

    Edith Heard, director of the genetics and developmental biology department at the Institut Curie in France, who with Dr. Dekker coined the term TAD, said that while researchers were just beginning to get a handle on the architecture of DNA, “suddenly a lot of things are falling into place. We’re coming into a renaissance time for understanding how the genome works.”

    See the full article here .

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  • richardmitnick 12:48 pm on January 8, 2017 Permalink | Reply
    Tags: A test that will detect all of the major cancer types, , , Medicine,   

    From MIT Tech Review: “Liquid Biopsies Are About to Get a Billion Dollar Boost’ 

    MIT Technology Review
    M.I.T Technology Review

    January 6, 2017
    Michael Reilly

    A billion dollars sounds like a lot of money. But when your ambitions are as big as the cancer-detection startup Grail Bio’s are, it might not be enough.

    As CEO and ex-Googler Jeff Huber puts it, Grail’s aim is to create “a test that will detect all of the major cancer types.” Already the recipient of $100 million in funding from DNA sequencing company Illumina and a series of tech luminaries, Grail believes that adding another zero to its cash balance will put its lofty goals within reach. The company announced Thursday that it plans to raise $1 billion, has “indications of interest” from investors, and would move quickly to secure the hefty cash infusion.

    Whether Grail succeeds turns on the company’s ability to dramatically expand an emerging technology known as the liquid biopsy. It works by sequencing DNA from someone’s blood and looking for tell-tale fragments that indicate the presence of cancer. Dennis Lo, a doctor in Hong Kong, was among the first to show the technique’s promise. He’d previously used it to detect fetal DNA in a mother’s bloodstream. That led to a much safer form of screening for Down’s syndrome that is now in wide use.

    Lo has experimented with liquid biopsy as a way to catch liver and nasopharyngeal cancers, with some encouraging results. But he urged caution in assuming the technique could be translated to all cancers.

    Grail, which was spun out of Illumina about a year ago, has launched its first trials to see whether liquid biopsies can spot cancers earlier and more reliably than other screening tests.

    For his part, Huber seems to understand that he’s got a mountain to climb. After losing his wife to colorectal cancer, Grail’s mission is deeply personal. He acknowledges that detecting cancer DNA may be difficult, because the disease mutates rapidly as it advances, and varies immensely from one type to another. He says his company will rely on sequencing the DNA of tens of thousands of subjects to build a library of cancer DNA that computers can then decipher.

    Beyond the high-minded talk of turning the tide in the war against cancer, though, is a more cynical reading of the situation. As a unit within Illumina, Grail was an expensive, long-shot bet to create a new market for its gene sequencing machines. As a separate, now cash-rich company, Grail figures to become one of Illumina’s biggest customers. And venture capital will foot the bill, whether or not the experiment works.

    See the full article here .

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  • richardmitnick 1:35 pm on January 6, 2017 Permalink | Reply
    Tags: , , Medicine, Researchers identify different 'types' of Alzheimer’s based on protein clumps in the brain,   

    From Science Alert: “Researchers identify different ‘types’ of Alzheimer’s based on protein clumps in the brain” 

    ScienceAlert

    Science Alert

    4 JAN 2017
    JOSH HRALA

    1
    Juan Gaertner/Shutterstock

    Alzheimer’s isn’t just one disease.

    An international team of researchers has found evidence that the specific type of protein clumps in a person’s brain might help identify different ‘types’ of Alzheimer’s disease.

    These findings might help future researchers and doctors accurately identify different subtypes of the disease, making treatments and diagnostic practices more specialised, pushing us one step closer to conquering Alzheimer’s.

    While you might not have heard of different ‘types’ of Alzheimer’s before, researchers have previously found that the disease – which was once thought of as one single ailment – operates differently based on what subtype of the disease a person has.

    In short, there are three known types of Alzheimer’s: typical Alzheimer’s, posterior cortical atrophy Alzheimer’s, and rapidly progressive Alzheimer’s.

    “Because the presentation varies from person to person, there has been suspicion for years that Alzheimer’s represents more than one illness,” said Dale Bredesen, from the University of California, Los Angeles, who was not involved in the new study but did earlier work to identify the three subtypes.

    “The important implications of this are that the optimal treatment may be different for each group, there may be different causes, and, for future clinical trials, it may be helpful to study specific groups separately.”

    Earlier studies like the one Bredesen was involved with suggested that these subtypes might reveal themselves in how amyloid-beta peptides self-assemble into protein fibres known as fibrils in the brains of those with Alzheimer’s.

    Now, a team of researchers working with the National Institutes of Health (NIH) in the US and other agencies have found that these fibrils – which you can think of as ‘protein clumps’ – do, in fact, correlate with the different subtypes of the disease.

    To come to that conclusion, the team – led by Robert Tycko, from the NIH – analysed the fibrils inside 37 different tissue samples from 18 individuals with each individual having one of the three subtypes of Alzheimer’s.

    When complete, the team found that the fibrils housed inside the tissue samples had a specific structure for those with typical Alzheimer’s and posterior cortical atrophy, meaning that the presence of these structures could be a go-to indicator of these two types.

    Those suffering from the rapidly progressive form of the disease, on the other hand, had a multitude of fibril structures, making it a lot harder to identify because there wasn’t one specific structure belonging to it.

    What these findings suggest is that doctors might be able to analyse tissue samples from patients who have been diagnosed with Alzheimer’s to accurately judge which subtype of the disease they have.

    That would mean they could then potentially administer a more suitable treatment for that specific type, offering new hope to those suffering from the disease.

    Also, understanding how the three subtypes differ could lead to better, more specific treatments that can help us push forward to finding a cure for the disease in general.

    “A better understanding of the neurotoxic amyloid-beta aggregates and of correlations between their structure and disease subtypes might help the development of new diagnostic tests and treatments for Alzheimer’s disease,” the team said.

    It’s important to note, though, that the sample size used for the recent study was quite small, with the team only analysing tissue from 18 individuals. It will take a more comprehensive pool of data before any conclusions can be drawn, though this is definitely a good first step.

    In the US alone, about 5.4 million people suffer from Alzheimer’s, costing individuals and families up to US$5,000 per year for care and costing the economy at large a whopping $236 billion per year. Finding a cure, or at least better treatments, is a major pursuit for scientists across the globe.

    The team’s work was published in Nature.

    See the full article here .

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