Tagged: Medicine Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 7:37 am on May 22, 2019 Permalink | Reply
    Tags: , , , Cancer Cell Line Encyclopedia, Database of Genotypes and Phenotypes, Gene Expression Omnibus, Medicine, , MSU’s Global Impact Initiative, Organoids, Scientists are using a lot of genomic data to identify medical issues sooner in patients but also using it to assist their scientific counterparts in researching diseases better., The Cancer Genome Atlas   

    From Michigan State University: “Big data helps identify better way to research breast cancer’s spread” 

    Michigan State Bloc

    From Michigan State University

    May 15, 2019
    Sarina Gleason
    Media Communications office
    (517) 355-9742
    sarina.gleason@cabs.msu.edu

    Bin Chen
    College of Human Medicine office
    616-234-2819
    chenbi12@msu.edu

    Scientists are using a lot of genomic data to identify medical issues sooner in patients, but they’re also using it to assist their scientific counterparts in researching diseases better.

    In a new study, Michigan State University researchers are analyzing large volumes of data, often referred to as big data, to determine better research models to fight the spread of breast cancer and test potential drugs. Current models used in the lab frequently involve culturing cells on flat dishes, or cell lines, to model tumor growth in patients.

    1

    The study is published in Nature Communications.

    This spreading, or metastasis, is the most common cause of cancer-related death, with around 90% of patients not surviving. To date, few drugs can treat cancer metastasis and knowing which step could go wrong in the drug discovery process can be a shot in the dark.

    “The differences between cell lines and tumor samples have raised the critical question to what extent cell lines can capture the makeup of tumors,” said Bin Chen, senior author and assistant professor in the College of Human Medicine.

    To answer this question, Chen and Ke Liu, first author of the study and a postdoctoral scholar, performed an integrative analysis of data taken from genomic databases including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Gene Expression Omnibus and the database of Genotypes and Phenotypes.

    “Leveraging open genomic data to discover new cancer therapies is our ultimate goal,” said Chen, who is part of MSU’s Global Impact Initiative. “But before we begin to pour a significant amount of money into expensive experiments, we need to evaluate early research models and choose the appropriate one for drug testing based on genomic features.”

    By using this data, the researchers found substantial differences between lab-created breast cancer cell lines and actual advanced, or metastatic, breast cancer tumor samples. Surprisingly, MDA-MB-231, a cancer cell line used in nearly all metastatic breast cancer research, showed little genomic similarities to patient tumor samples.

    “I couldn’t believe the result,” Chen said. “All evidence pointed to large differences between the two. But, on the flip side, we were able to identify other cell lines that closely resembled the tumors and could be considered, along with other criteria, as better options for this research.”

    The organoid model was found to most likely mirror patient samples. This newly developed technology uses 3D tissue cultures and can capture more of the complexities of how tumors form and grow.

    “Studies have shown that organoids can preserve the structural and genetic makeup of the original tumor,” Chen said. “We found at the gene expression level, it was able to do this, more so than cancer cell lines.”

    However, Chen and Liu added that both the organoids and cell lines couldn’t adequately model the immediate molecular landscape surrounding a tumor found at different sites in the body.

    They said knowing all these factors will help scientists interpret results, especially unexpected ones, and urge the scientific community to develop more sophisticated research models.

    “Our study demonstrates the power of leveraging open data to gain insights on cancer,” Chen said. “Any advances we can make in early research will help us facilitate the discovery of better therapies for people with breast cancer down the road.”

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    Stem Education Coalition

    Michigan State Campus

    Michigan State University (MSU) is a public research university located in East Lansing, Michigan, United States. MSU was founded in 1855 and became the nation’s first land-grant institution under the Morrill Act of 1862, serving as a model for future land-grant universities.

    MSU pioneered the studies of packaging, hospitality business, plant biology, supply chain management, and telecommunication. U.S. News & World Report ranks several MSU graduate programs in the nation’s top 10, including industrial and organizational psychology, osteopathic medicine, and veterinary medicine, and identifies its graduate programs in elementary education, secondary education, and nuclear physics as the best in the country. MSU has been labeled one of the “Public Ivies,” a publicly funded university considered as providing a quality of education comparable to those of the Ivy League.

    Following the introduction of the Morrill Act, the college became coeducational and expanded its curriculum beyond agriculture. Today, MSU is the seventh-largest university in the United States (in terms of enrollment), with over 49,000 students and 2,950 faculty members. There are approximately 532,000 living MSU alumni worldwide.

     
  • richardmitnick 8:31 am on May 21, 2019 Permalink | Reply
    Tags: "Scientists use molecular tethers and chemical ‘light sabers’ to construct platforms for tissue engineering", , , , Controlling cell growth and differentiation in tissue engineering, Hydrogels, Medicine, , The approach uses an enzyme called sortase., Tissue engineering could transform medicine.,   

    From University of Washington: “Scientists use molecular tethers and chemical ‘light sabers’ to construct platforms for tissue engineering” 

    U Washington

    From University of Washington

    May 20, 2019
    James Urton

    1
    Left-to-right, Cole DeForest, Gabrielle Benuska, Jared Shadish.Dennis Wise/University of Washington

    Tissue engineering could transform medicine. Instead of waiting for our bodies to regrow or repair damage after an injury or disease, scientists could grow complex, fully functional tissues in a laboratory for transplantation into patients.

    Proteins are key to this future. In our bodies, protein signals tell cells where to go, when to divide and what to do. In the lab, scientists use proteins for the same purpose — placing proteins at specific points on or within engineered scaffolds, and then using these protein signals to control cell migration, division and differentiation.

    But proteins in these settings are also fragile. To get them to stick to the scaffolds, researchers have traditionally modified proteins using chemistries that kill off more than 90% of their function. In a paper published May 20 in the journal Nature Materials, a team of researchers from the University of Washington unveiled a new strategy to keep proteins intact and functional by modifying them at a specific point so that they can be chemically tethered to the scaffold using light. Since the tether can also be cut by laser light, this method can create evolving patterns of signal proteins throughout a biomaterial scaffold to grow tissues made up of different types of cells.

    “Proteins are the ultimate communicators of biological information,” said corresponding author Cole DeForest, a UW assistant professor of chemical engineering and bioengineering, as well as an affiliate investigator with the UW Institute for Stem Cell & Regenerative Medicine. “They drive virtually all changes in cell function — differentiation, movement, growth, death.”

    For that reason, scientists have long employed proteins to control cell growth and differentiation in tissue engineering.

    “But the chemistries most commonly used by the community to bind proteins to materials, including scaffolds for tissue engineering, destroy the overwhelming majority of their function,” said DeForest, who is also a faculty member in the UW Molecular & Engineering Sciences Institute. “Historically, researchers have tried to compensate for this by simply overloading the scaffold with proteins, knowing that most of them will be inactive. Here, we’ve come up with a generalizable way to functionalize biomaterials reversibly with proteins while preserving their full activity.”

    Their approach uses an enzyme called sortase, which is found in many bacteria, to add a short synthetic peptide to each signal protein at a specific location: the C-terminus, a site present on every protein. The team designs that peptide such that it will tether the signal protein to specific locations within a fluid-filled biomaterial scaffold common in tissue engineering, known as a hydrogel.

    Targeting a single site on the signal protein is what sets the UW team’s approach apart. Other methods modify signal proteins by attaching chemical groups to random locations, which often disrupts the protein’s function. Modifying just the C-terminus of the protein is much less likely to disrupt its function, according to DeForest. The team tested the approach on more than half a dozen different types of proteins. Results show that modifying the C-terminus has no significant effect on protein function, and successfully tethers the proteins throughout the hydrogel.

    Their approach is analogous to hanging a piece of framed art on a wall. Instead of hammering nails randomly through the glass, canvas and frame, they string a single wire across the back of each frame to hang it on the wall.

    2
    Photorelease of proteins from a hydrogel. Top: The mCherry red fluorescent proteins are tethered to the hydrogel. Researchers can cleave the tether with directed light (blue arrows), releasing the mCherry from the hydrogel (blue arrows). Bottom: An image of the hydrogel after mCherry release patterned in the shape of the University of Washington mascot (black). Scale bar is 100 micrometers.Shadish, Benuska and DeForest, 2019, Nature Materials.

    In addition, the tethers can be cut by exposure to focused laser light, causing “photorelease” of the proteins. Using this scientific light saber allows the researchers to load a hydrogel with many different types of protein signals, and then expose the hydrogel to laser light to untether proteins from certain sections of the hydrogel. By selectively exposing only portions of the materials to the laser light, the team controlled where protein signals would stay tethered to the hydrogel.

    Untethering proteins is useful in hydrogels because cells could then take up those signals, bringing them into the cell’s interior where they can affect processes like gene expression.

    DeForest’s team tested the photorelease process using a hydrogel loaded with epidermal growth factor, a type of protein signal. They introduced a human cell line into the hydrogel and observed the growth factors binding to the cell membranes. The team used a beam of laser light to untether the protein signals on one side of an individual cell, but not the other side. On the tethered side of the cell, the proteins stayed on the outside of the cell since they were still stuck to the hydrogel. On the untethered side, the protein signals were internalized by the cell.

    “Based on how we target the laser light, we can ensure that different cells — or even different parts of single cells — are receiving different environmental signals,” said DeForest.

    3
    Photorelease of epidermal growth factor (EGF) proteins on one side of a human cell. Left: EGF (green) is tethered to a hydrogel a single human cell (center). The cell membrane binds EGF, making its membrane green. Middle: The hydrogel after using a laser to untether and release EGF proteins on the top portion of the cell. Right: An image showing the difference in green fluorescent color between post- and pre-release images. Note the increase in color in the top portion of the cell, which indicates that the cell has started to internalize the untethered EGF proteins but only on one side. Scale bar is 10 micrometers.Shadish, Benuska and DeForest, 2019, Nature Materials.

    This unique level of precision within a single cell not only helps with tissue engineering, but with basic research in cell biology, added DeForest. Researchers could use this platform to study how living cells respond to multiple combinations of protein signals, for example. This line of research would help scientists understand how protein signals work together to control cell differentiation, heal diseased tissue and promote human development.

    “This platform allows us to precisely control when and where bioactive protein signals are presented to cells within materials,” said DeForest. “That opens the door to many exciting applications in tissue engineering and therapeutics research.”

    Lead author on the paper is Jared Shadish, a UW doctoral student in chemical engineering. Co-author is Gabrielle Benuska, a UW undergraduate alumna who is currently an analyst for Point B Consulting. The research was funded by the National Science Foundation and the University of Washington.

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    Stem Education Coalition

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 1:29 pm on May 19, 2019 Permalink | Reply
    Tags: , , Medicine, RNA messages in the cell drive function, , Today there is no medical treatment for autism.   

    From The Conversation: “New autism research on single neurons suggests signaling problems in brain circuits” 

    Conversation
    From The Conversation

    1
    Artist impression of neurons communicating in the brain. whitehoune/Shutterstock.com

    May 17, 2019
    Dmitry Velmeshev

    Autism affects at least 2% of children in the United States – an estimated 1 in 59. This is challenging for both the patients and their parents or caregivers. What’s worse is that today there is no medical treatment for autism. That is in large part because we still don’t fully understand how autism develops and alters normal brain function.

    One of the main reasons it is hard to decipher the processes that cause the disease is that it is highly variable. So how do we understand how autism changes the brain?

    Using a new technology called single-nucleus RNA sequencing, we analyzed the chemistry inside specific brain cells from both healthy people and those with autism and identified dramatic differences that may cause this disease. These autism-specific differences could provide valuable new targets for drug development.

    I am a neuroscientist in the lab of Arnold Kreigstein, a researcher of human brain development at the University of California, San Francisco. Since I was a teenager, I have been fascinated by the human brain and computers and the similarities between the two. The computer works by directing a flow of information through interconnected electronic elements called transistors. Wiring together many of these small elements creates a complex machine capable of functions from processing a credit card payment to autopiloting a rocket ship. Though it is an oversimplification, the human brain is, in many respects, like a computer. It has connected cells called neurons that process and direct information flow – a process called synaptic transmission in which one neuron sends a signal to another.

    When I started doing science professionally, I realized that many diseases of the human brain are due to specific types of neurons malfunctioning, just like a transistor on a circuit board can malfunction either because it was not manufactured properly or due to wear and tear.

    RNA messages in the cell drive function

    Every cell in any living organism is made of the same types of biological molecules. Molecules called proteins create cellular structures, catalyze chemical reactions and perform other functions within the cell.

    Two related types of molecules – DNA and RNA – are made of sequences of just four basic elements and used by the cell to store information. DNA is used for hereditary long-term information storage; RNA is a short-lived message that signals how active a gene is and how much of a particular protein the cell needs to make. By counting the number of RNA molecules carrying the same message, researchers can get insights into the processes happening inside the cell.

    When it comes to the brain, scientists can measure RNA inside individual cells, identify the type of brain cell and and analyze the processes taking place inside it – for instance, synaptic transmission. By comparing RNA analyses of brain cells from healthy people not diagnosed with any brain disease with those done in patients with autism, researchers like myself can figure out which processes are different and in which cells.

    Until recently, however, simultaneously measuring all RNA molecules in a single cell was not possible. Researchers could perform these analyses only from a piece of brain tissue containing millions of different cells. This was complicated further because it was possible to collect these tissue samples only from patients who have already died.

    New tech pinpoints neurons affected in autism

    However, recent advances in technology allowed our team to measure RNA that is contained within the nucleus of a single brain cell. The nucleus of a cell contains the genome, as well as newly synthesized RNA molecules. This structure remains intact ever after the death of a cell and thus can be isolated from dead (also called postmortem) brain tissue.

    3
    Neurons in the upper (left) and deep layers of the human developing cortex. Chen & Kriegstein, 2015 Science/American Association for the Advancement of Science, CC BY-SA

    By analyzing single cellular nuclei from this postmortem brain of people with and without autism, we profiled the RNA within 100,000 single brain cells of many such individuals.

    Comparing RNA in specific types of brain cells between the individuals with and without autism, we found that some specific cell types are more altered than others in the disease.

    In particular, we found [Science]that certain neurons called upper-layer cortical neurons that exchange information between different regions of the cerebral cortex have an abnormal number of RNA-encoding proteins located at the synapse – the points of contacts between neurons where signals are transmitted from one nerve cell to another. These changes were detected in regions of the cortex vital for higher-order cognitive functions, such as social interactions.

    This suggests that synapses in these upper-layer neurons are malfunctioning, leading to changes in brain functions. In our study, we showed that upper-layer neurons had very different quantities of certain RNA compared to the same cells in healthy people. That was especially true in autism patients who suffered from the most severe symptoms, like not being able to speak.

    4
    New results suggest that the synapse formed by neurons in the upper layers of the cerebral cortex are not functioning correctly. CI Photos/Shutterstock.com

    Glial cells are also affected in autism

    In addition to neurons that are directly responsible for synaptic communication, we also saw changes in the RNA of other non-neuronal cells – called glia. Glia play important roles in regulating the behavior of neurons, including how they send and receive messages via the synapse. These may also play an important role in causing autism.

    So what do these findings mean for future medical treatment of autism?

    From these results, I and my colleagues understand that the same parts of the synaptic machinery which are critical for sending signals and transmitting information in the upper-layer neurons might be broken in many autism patients, leading to abnormal brain function.

    If we can repair these parts, or fine-tune neuronal function to a near-normal state, it might offer dramatic relief of symptoms for the patients. Studies are underway to deliver drugs and gene therapy to specific cell types in the brain, and many scientists including myself believe such approaches will be indispensable for future treatments of autism.

    See the full article here .

    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    Stem Education Coalition

    The Conversation launched as a pilot project in October 2014. It is an independent source of news and views from the academic and research community, delivered direct to the public.
    Our team of professional editors work with university and research institute experts to unlock their knowledge for use by the wider public.
    Access to independent, high quality, authenticated, explanatory journalism underpins a functioning democracy. Our aim is to promote better understanding of current affairs and complex issues. And hopefully allow for a better quality of public discourse and conversation.

     
  • richardmitnick 2:15 pm on May 17, 2019 Permalink | Reply
    Tags: , Bacteria-killing viruses – bacteriophages, , Cholera outbreaks occur worldwide, In regions of the world lacking clean water and proper sanitation 2.5 billion people are at risk., Medicine, , Phages are very specific and infect only their particular host species of bacteria., Phages infect and kill multi-drug resistant strains of bacteria just as well as drug-sensitive ones., Phages provide immediate protection., Potential weapons to fight bacteria that are resistant to multiple antibiotics   

    From The Conversation: “Viruses to stop cholera infections – the viral enemy of deadly bacteria could be humanity’s friend” 

    Conversation
    From The Conversation

    May 17, 2019

    Andrew Camilli
    Professor of Molecular Biology & Microbiology, Tufts University

    Minmin Yen
    Research Associate of Molecular Microbiology, Tufts University

    1

    In the latest of a string of high-profile cases in the U.S., a cocktail of bacteria-killing viruses successfully treated a cystic fibrosis [Nature Biotechnology] patient suffering from a deadly infection caused by a pathogen that was resistant to multiple forms of antibiotics.

    Curing infections is great, of course. But what about using these bacteria-killing viruses – bacteriophages – to prevent infections in the first place? Could this work for some diseases? Although using viruses to prevent infections caused by bacterial infections might seem counterintuitive, in the case of bacteriophages: “The enemy of my enemy is my friend.”

    Discovered a little more than 100 years ago [BMC], bacteriophages, or phages, are generating renewed interest as potential weapons to fight bacteria that are resistant to multiple antibiotics – the so-called superbugs. Although the recent phage therapy has been focused on the treatment of sick patients, preventing infection stops a disease before it begins, keeping people healthy and preventing the spread of the germ to others.

    We are microbiologists [Nature Communications] who study cholera because this ancient disease continues to thrive and can have a devastating impact on communities and entire countries. The Camilli lab has been focused on the disease for over two decades. We are interested in developing vaccines and phage products to prevent cholera from sickening people and triggering outbreaks.

    3
    This cholera patient is drinking oral rehydration solution in order to counteract his cholera-induced dehydration. Centers for Disease Control and Prevention’s Public Health Image Library

    Cholera outbreaks occur worldwide

    In the case of cholera, which is caused by the bacterium Vibrio cholerae, prevention is preferred because it spreads like wildfire once it strikes a community. When this bacterial pathogen is ingested, it inhabits the small intestine, where it releases a potent toxin that triggers vomiting and watery diarrhea, which cause severe dehydration. The vomiting and diarrhea encourage the spread of the pathogen within households and contaminate local water sources. Left untreated, cholera kills 40% of its victims, sometimes within hours of the onset of symptoms. Fortunately, death can be largely prevented by prompt rehydration of cholera victims.

    In regions of the world lacking clean water and proper sanitation, 2.5 billion people are at risk, and the CDC estimates that there are up to 4 million cholera cases per year. New epidemics such as the recent massive epidemic in Yemen which has so far sickened over 1.2 million people and the outbreak in Mozambique are often the consequence of humanitarian crises. War and natural disasters often cause shortages of clean water and impact the poorest and most vulnerable communities.

    Cholera is highly transmissible in the community and within households. During outbreaks, an estimated 80% of cases are believed to result from rapid transmission within households, presumably occurring through contamination of household food, water or surfaces with diarrhea or vomit from the initial cholera victim.

    Family members typically experience cholera symptoms themselves two to three days after the initial household member became sick. Thus, the people in the most danger are usually siblings and loved ones taking care of the sick person. There is currently no approved medical intervention to immediately protect household members from contracting cholera when it strikes a household. Vaccines for cholera require at least 10 days to take effect, and thus miss the mark in this emergency situation.

    Prevention of cholera using phages

    To address this need, we developed a cocktail of phages to be taken orally each day by household members prior to, or soon after, exposure to Vibrio cholerae to protect them from contracting the disease. We believe the phages should remain in the intestinal tract long enough to serve as a shield against the incoming cholera bacteria. Although this has only been proven in animal models of cholera, we hope that the phage cocktail will work similarly in humans. There are three advantages to using phages in this manner.

    First, phages provide immediate protection. By acting fast, phages can eliminate the cholera bacteria from the gut in a targeted manner. That is important because cholera kills quickly.

    Second, phages infect and kill multi-drug resistant strains of bacteria just as well as drug-sensitive ones. This is crucial since the cholera bacteria have become multi-drug resistant [ALJM] in many parts of the world due to widespread antibiotic use [The Lancet].

    Third, in contrast to antibiotics, which kill bacteria indiscriminately, phages are very specific and infect only their particular host species of bacteria. Thus, when using phages against a pathogen, they will not disrupt the good bacteria residing in and on our patients’ bodies which are part of the microbiome. In research in our lab phages, called ICP1, ICP2 and ICP3, which we are using, kill only Vibrio cholerae and should not disrupt the good bacteria in the intestinal tract. This is important because our good bacteria are essential for defending the body against other pathogens and vital for our general nutrition and health.

    4
    People fill buckets with water from a well that is alleged to be contaminated water with the bacterium Vibrio cholera, on the outskirts of Yemen. Yemen’s raging two-year conflict has served as an incubator for lethal cholera. AP Photo/Hani Mohammed

    From test tube to product

    In collaboration with international researchers, we have been studying the cholera bacteria and its phages for over two decades at Tufts University, trying to uncover the details of how cholera spreads and how phages might affect its spread. The use of phages for prevention of cholera transmission was a natural outcome of this research, but by no means was it straightforward.

    Development of our phage product required finding phages that kill Vibrio cholerae in the intestinal tract, having intimate knowledge of how the phages infect the bacteria and discovering how the bacteria become resistant to the phages and how this affects their virulence.

    Our goal now is to test the phage cocktail in people during a cholera epidemic. Specifically, we need to determine if it is effective at preventing cholera transmission to family members in households where cholera strikes.

    In this day and age, we need to change the paradigm of relying entirely on antibiotics to treat infections and develop other types of antimicrobial solutions. It’s time to bring phages in from the cold, and utilize them both for treating multi-drug resistant bacterial infections and in the prevention of infections.

    See the full article here .

    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    Stem Education Coalition

    The Conversation launched as a pilot project in October 2014. It is an independent source of news and views from the academic and research community, delivered direct to the public.
    Our team of professional editors work with university and research institute experts to unlock their knowledge for use by the wider public.
    Access to independent, high quality, authenticated, explanatory journalism underpins a functioning democracy. Our aim is to promote better understanding of current affairs and complex issues. And hopefully allow for a better quality of public discourse and conversation.

     
  • richardmitnick 8:59 am on May 15, 2019 Permalink | Reply
    Tags: "‘Impossible’ nano-sized protein cages made with the help of gold", , Artificial protein cages, Geometry problem: the wrong shape, , Medicine, , The building block of a protein cage is an 11-sided shape,   

    From University of Oxford: “‘Impossible’ nano-sized protein cages made with the help of gold” 

    U Oxford bloc

    From University of Oxford

    15 May 2019

    1

    A collaborative effort between the University of Oxford and the Malopolska Centre of Biotechnology, Jagiellonian University in Poland, has produced a super-stable artificial protein ball that apparently defies the rules of geometry and which may have applications in materials science and medicine.

    Researchers are interested in making artificial protein cages in the hope that they can design them to have useful properties not found in nature. There are two challenges to achieving this goal. The first is the geometry problem: some proteins may have great potential utility but have the wrong shape to assemble into cages. The second problem is complexity: in nature the many proteins that form a protein cage are held together by a complex network of chemical bonds and these are very difficult to predict and simulate.

    In new work, published in Nature, researchers found a way to solve both of these problems.

    Professor Heddle, senior author of the research, said: ‘We were able to replace the complex interactions between proteins with a simple ‘staple’ consisting of a single gold atom. This simplifies the design problem and allows us to imbue the cages with new properties such as assembly and disassembly on demand.’

    The research has also found a way to get around the geometrical problem: the building block of a protein cage is an 11-sided shape. Theoretically this should not be able to form the faces of a regular convex polyhedron. However the research has found that while this is mathematically true, some so-called ‘impossible shapes’ can assemble into cages which are so close to being regular that the errors are not noticeable.

    Central to the study was the ability to characterise different cages, as well the ability to monitor and thereby understand the (dis)assembly dynamically. This work was done in the groups of Professors Justin Benesch and Philipp Kukura at Oxford, using innovative mass measurement approaches with a particular focus on biomolecular structure and assembly.

    Justin Benesch, in the Department of Chemistry, said: ‘The ability to interrogate the cages using the advanced mass measurement approaches we have developed here in Oxford, both on the level of their assembly and the constituent building block, was key to not just validating their structure, but also the mechanism by which they are formed.’

    The potential implications of the work are far-reaching. The researchers hope that the work can be expanded further to produce cages with new structures and new capabilities with potential applications particularly in drug delivery.

    See the full article here.


    five-ways-keep-your-child-safe-school-shootings
    Please help promote STEM in your local schools.

    Stem Education Coalition

    U Oxford campus

    Oxford is a collegiate university, consisting of the central University and colleges. The central University is composed of academic departments and research centres, administrative departments, libraries and museums. The 38 colleges are self-governing and financially independent institutions, which are related to the central University in a federal system. There are also six permanent private halls, which were founded by different Christian denominations and which still retain their Christian character.

    The different roles of the colleges and the University have evolved over time.

     
  • richardmitnick 10:40 am on May 11, 2019 Permalink | Reply
    Tags: An array of artificial synapses designed by researchers at Stanford and Sandia National Laboratories can mimic how the brain processes and stores information., , , , Medicine,   

    From Stanford University: “Stanford researchers’ artificial synapse is fast, efficient and durable” 

    Stanford University Name
    From Stanford University

    April 25, 2019
    Taylor Kubota

    1
    An array of artificial synapses designed by researchers at Stanford and Sandia National Laboratories can mimic how the brain processes and stores information. (Image credit: Armantas Melianas and Scott Keene)

    The brain’s capacity for simultaneously learning and memorizing large amounts of information while requiring little energy has inspired an entire field to pursue brain-like – or neuromorphic – computers. Researchers at Stanford University and Sandia National Laboratories previously developed [Nature Materials] one portion of such a computer: a device that acts as an artificial synapse, mimicking the way neurons communicate in the brain.

    In a paper published online by the journal Science on April 25, the team reports that a prototype array of nine of these devices performed even better than expected in processing speed, energy efficiency, reproducibility and durability.

    Looking forward, the team members want to combine their artificial synapse with traditional electronics, which they hope could be a step toward supporting artificially intelligent learning on small devices.

    “If you have a memory system that can learn with the energy efficiency and speed that we’ve presented, then you can put that in a smartphone or laptop,” said Scott Keene, co-author of the paper and a graduate student in the lab of Alberto Salleo, professor of materials science and engineering at Stanford who is co-senior author. “That would open up access to the ability to train our own networks and solve problems locally on our own devices without relying on data transfer to do so.”

    A bad battery, a good synapse

    The team’s artificial synapse is similar to a battery, modified so that the researchers can dial up or down the flow of electricity between the two terminals. That flow of electricity emulates how learning is wired in the brain. This is an especially efficient design because data processing and memory storage happen in one action, rather than a more traditional computer system where the data is processed first and then later moved to storage.

    Seeing how these devices perform in an array is a crucial step because it allows the researchers to program several artificial synapses simultaneously. This is far less time consuming than having to program each synapse one-by-one and is comparable to how the brain actually works.

    In previous tests of an earlier version of this device, the researchers found their processing and memory action requires about one-tenth as much energy as a state-of-the-art computing system needs in order to carry out specific tasks. Still, the researchers worried that the sum of all these devices working together in larger arrays could risk drawing too much power. So, they retooled each device to conduct less electrical current – making them much worse batteries but making the array even more energy efficient.

    The 3-by-3 array relied on a second type of device – developed by Joshua Yang at the University of Massachusetts, Amherst, who is co-author of the paper – that acts as a switch for programming synapses within the array.

    “Wiring everything up took a lot of troubleshooting and a lot of wires. We had to ensure all of the array components were working in concert,” said Armantas Melianas, a postdoctoral scholar in the Salleo lab. “But when we saw everything light up, it was like a Christmas tree. That was the most exciting moment.”

    During testing, the array outperformed the researchers’ expectations. It performed with such speed that the team predicts the next version of these devices will need to be tested with special high-speed electronics. After measuring high energy efficiency in the 3-by-3 array, the researchers ran computer simulations of a larger 1024-by-1024 synapse array and estimated that it could be powered by the same batteries currently used in smartphones or small drones. The researchers were also able to switch the devices over a billion times – another testament to its speed – without seeing any degradation in its behavior.

    “It turns out that polymer devices, if you treat them well, can be as resilient as traditional counterparts made of silicon. That was maybe the most surprising aspect from my point of view,” Salleo said. “For me, it changes how I think about these polymer devices in terms of reliability and how we might be able to use them.”

    Room for creativity

    The researchers haven’t yet submitted their array to tests that determine how well it learns but that is something they plan to study. The team also wants to see how their device weathers different conditions – such as high temperatures – and to work on integrating it with electronics. There are also many fundamental questions left to answer that could help the researchers understand exactly why their device performs so well.

    “We hope that more people will start working on this type of device because there are not many groups focusing on this particular architecture, but we think it’s very promising,” Melianas said. “There’s still a lot of room for improvement and creativity. We only barely touched the surface.”

    To read all stories about Stanford science, subscribe to the biweekly Stanford Science Digest.

    This work was funded by Sandia National Laboratories, the U.S. Department of Energy, the National Science Foundation, the Semiconductor Research Corporation, the Stanford Graduate Fellowship fund, and the Knut and Alice Wallenberg Foundation for Postdoctoral Research at Stanford University.

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings
    Please help promote STEM in your local schools.

    Stem Education Coalition

    Stanford University campus. No image credit

    Stanford University

    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

    Stanford University Seal

     
  • richardmitnick 11:55 am on May 6, 2019 Permalink | Reply
    Tags: "Organ bioprinting gets a breath of fresh air", 3D printing replacement organs, , , Medicine, ,   

    From Rice University and UW Medicine: “Organ bioprinting gets a breath of fresh air” 

    U Washington
    University of Washington

    UW Medicine Newsroom

    Rice U bloc

    From Rice University

    May 2, 2019
    David Ruth
    713-348-6327
    david@rice.edu

    Jade Boyd
    713-348-6778
    jadeboyd@rice.edu

    Bioengineers clear major hurdle on path to 3D printing replacement organs.

    Bioengineers have cleared a major hurdle on the path to 3D printing replacement organs with a breakthrough technique for bioprinting tissues.

    1
    The May 3 issue of Science features a breakthrough bioprinting technique developed by Rice University bioengineer Jordan Miller and colleagues. (Reprinted with permission from AAAS. Photo by Dan Sazer, Jeff Fitlow and Jordan Miller/Rice University)

    The new innovation allows scientists to create exquisitely entangled vascular networks that mimic the body’s natural passageways for blood, air, lymph and other vital fluids.

    The research is featured on the cover of this week’s issue of Science. It includes a visually stunning proof-of-principle — a hydrogel model of a lung-mimicking air sac in which airways deliver oxygen to surrounding blood vessels. Also reported are experiments to implant bioprinted constructs containing liver cells into mice.

    The work was led by bioengineers Jordan Miller of Rice University and Kelly Stevens of the University of Washington (UW) and included 15 collaborators from Rice, UW, Duke University, Rowan University and Nervous System, a design firm in Somerville, Massachusetts.

    “One of the biggest road blocks to generating functional tissue replacements has been our inability to print the complex vasculature that can supply nutrients to densely populated tissues,” said Miller, assistant professor of bioengineering at Rice’s Brown School of Engineering. “Further, our organs actually contain independent vascular networks — like the airways and blood vessels of the lung or the bile ducts and blood vessels in the liver. These interpenetrating networks are physically and biochemically entangled, and the architecture itself is intimately related to tissue function. Ours is the first bioprinting technology that addresses the challenge of multivascularization in a direct and comprehensive way.”

    Stevens, assistant professor of bioengineering in the UW College of Engineering, assistant professor of pathology in the UW School of Medicine, and an investigator at the UW Medicine Institute for Stem Cell and Regenerative Medicine, said multivascularization is important because form and function often go hand in hand.

    3
    Rice University bioengineering graduate student Bagrat Grigoryan led the development of a new technique for 3D printing tissue with entangled vascular networks similar to the body’s natural passageways for blood, air and other vital fluids. (Photo by Jeff Fitlow/Rice University)

    “Tissue engineering has struggled with this for a generation,” Stevens said. “With this work we can now better ask, ‘If we can print tissues that look and now even breathe more like the healthy tissues in our bodies, will they also then functionally behave more like those tissues?’ This is an important question, because how well a bioprinted tissue functions will affect how successful it will be as a therapy.”

    The goal of bioprinting healthy, functional organs is driven by the need for organ transplants. More than 100,000 people are on transplant waiting lists in the United States alone, and those who do eventually receive donor organs still face a lifetime of immune-suppressing drugs to prevent organ rejection. Bioprinting has attracted intense interest over the past decade because it could theoretically address both problems by allowing doctors to print replacement organs from a patient’s own cells. A ready supply of functional organs could one day be deployed to treat millions of patients worldwide.

    “We envision bioprinting becoming a major component of medicine within the next two decades,” Miller said.

    4
    Rice University bioengineers (from left) Bagrat Grigoryan, Jordan Miller and Daniel Sazer and collaborators created a breakthrough bioprinting technique that could speed development of technology for 3D printing replacement organs and tissues. (Photo by Jeff Fitlow/Rice University)

    “The liver is especially interesting because it performs a mind-boggling 500 functions, likely second only to the brain,” Stevens said. “The liver’s complexity means there is currently no machine or therapy that can replace all its functions when it fails. Bioprinted human organs might someday supply that therapy.”

    To address this challenge, the team created a new open-source bioprinting technology dubbed the “stereolithography apparatus for tissue engineering,” or SLATE. The system uses additive manufacturing to make soft hydrogels one layer at a time.

    Layers are printed from a liquid pre-hydrogel solution that becomes a solid when exposed to blue light. A digital light processing projector shines light from below, displaying sequential 2D slices of the structure at high resolution, with pixel sizes ranging from 10-50 microns. With each layer solidified in turn, an overhead arm raises the growing 3D gel just enough to expose liquid to the next image from the projector. The key insight by Miller and Bagrat Grigoryan, a Rice graduate student and lead co-author of the study, was the addition of food dyes that absorb blue light. These photoabsorbers confine the solidification to a very fine layer. In this way, the system can produce soft, water-based, biocompatible gels with intricate internal architecture in a matter of minutes.

    5
    Rice University bioengineer Daniel Sazer prepares a scale-model of a lung-mimicking air sac for testing. In experiments, air is pumped into the sac in a pattern that mimics breathing while blood is flowed through a surrounding network of blood vessels to oxygenate human red blood cells. (Photo by Jeff Fitlow/Rice University)

    Tests of the lung-mimicking structure showed that the tissues were sturdy enough to avoid bursting during blood flow and pulsatile “breathing,” a rhythmic intake and outflow of air that simulated the pressures and frequencies of human breathing. Tests found that red blood cells could take up oxygen as they flowed through a network of blood vessels surrounding the “breathing” air sac. This movement of oxygen is similar to the gas exchange that occurs in the lung’s alveolar air sacs.

    To design the study’s most complicated lung-mimicking structure, which is featured on the cover of Science, Miller collaborated with study co-authors Jessica Rosenkrantz and Jesse Louis-Rosenberg, co-founders of Nervous System.

    “When we founded Nervous System it was with the goal of adapting algorithms from nature into new ways to design products,” Rosenkrantz said. “We never imagined we’d have the opportunity to bring that back and design living tissues.”

    6
    Experiments performed by Rice University and University of Washington researchers explored whether liver cells called hepatocytes would function normally if they were incorporated into a bioprinted implant and surgically implanted in mice for 14 days. (Image courtesy of Jordan Miller/Rice University)

    In the tests of therapeutic implants for liver disease, the team 3D printed tissues, loaded them with primary liver cells and implanted them into mice. The tissues had separate compartments for blood vessels and liver cells and were implanted in mice with chronic liver injury. Tests showed that the liver cells survived the implantation.

    Miller said the new bioprinting system can also produce intravascular features, like bicuspid valves that allow fluid to flow in only one direction. In humans, intravascular valves are found in the heart, leg veins and complementary networks like the lymphatic system that have no pump to drive flow.

    “With the addition of multivascular and intravascular structure, we’re introducing an extensive set of design freedoms for engineering living tissue,” Miller said. “We now have the freedom to build many of the intricate structures found in the body.”

    Miller and Grigoryan are commercializing key aspects of the research through a Houston-based startup company called Volumetric. The company, which Grigoryan has joined full time, is designing and manufacturing bioprinters and bioinks.

    7
    Assistant professor Kelly Stevens (left) and graduate student Daniel Corbett (right) from the University of Washington Departments of Bioengineering and Pathology helped develop a new method to bioprint liver tissue. (Photo by Dennis R. Wise/University of Washington)

    Miller, a longstanding champion of open-source 3D printing, said all source data from the experiments in the published Science study are freely available [see the Science paper above]. In addition, all 3D printable files needed to build the stereolithography printing apparatus are available, as are the design files for printing each of the hydrogels used in the study.

    See the full Rice university article here .
    See the full U Washington Medicine article here .


    five-ways-keep-your-child-safe-school-shootings

    Stem Education Coalition

    Rice U campus

    In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

    This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

    About UW Medicine

    UW Medicine is one of the top-rated academic medical systems in the world. With a mission to improve the health of the public, UW Medicine educates the next generation of physicians and scientists, leads one of the world’s largest and most comprehensive biomedical research programs, and provides outstanding care to patients from across the globe.

    The UW School of Medicine, part of the UW Medicine system, leads the internationally recognized, community-based WWAMI Program, serving the states of Washington, Wyoming, Alaska, Montana and Idaho. The school has been ranked No. 1 in the nation in primary-care training for more than 20 years by U.S. News & World Report. It is also second in the nation in federal research grants and contracts with $749.9 million in total revenue (fiscal year 2016) according to the Association of American Medical Colleges.

    UW Medicine has more than 27,000 employees and an annual budget of nearly $5 billion. Also part of the UW Medicine system are Airlift Northwest and the UW Physicians practice group, the largest physician practice plan in the region. UW Medicine shares in the ownership and governance of the Seattle Cancer Care Alliance with Fred Hutchinson Cancer Research Center and Seattle Children’s, and also shares in ownership of Children’s University Medical Group with Seattle Children’s.

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 9:31 am on May 4, 2019 Permalink | Reply
    Tags: "Putting vision models to the test", , , Medicine, , , Study shows that artificial neural networks can be used to drive brain activity.   

    From MIT News: “Putting vision models to the test” 

    MIT News
    MIT Widget

    From MIT News

    May 2, 2019
    Anne Trafton

    1
    A computer model of vision created by MIT neuroscientists designed these images that can stimulate very high activity in individual neurons. Image: Pouya Bashivan

    Study shows that artificial neural networks can be used to drive brain activity.

    MIT neuroscientists have performed the most rigorous testing yet of computational models that mimic the brain’s visual cortex.

    Using their current best model of the brain’s visual neural network, the researchers designed a new way to precisely control individual neurons and populations of neurons in the middle of that network. In an animal study, the team then showed that the information gained from the computational model enabled them to create images that strongly activated specific brain neurons of their choosing.

    The findings suggest that the current versions of these models are similar enough to the brain that they could be used to control brain states in animals. The study also helps to establish the usefulness of these vision models, which have generated vigorous debate over whether they accurately mimic how the visual cortex works, says James DiCarlo, the head of MIT’s Department of Brain and Cognitive Sciences, an investigator in the McGovern Institute for Brain Research and the Center for Brains, Minds, and Machines, and the senior author of the study.

    “People have questioned whether these models provide understanding of the visual system,” he says. “Rather than debate that in an academic sense, we showed that these models are already powerful enough to enable an important new application. Whether you understand how the model works or not, it’s already useful in that sense.”

    MIT postdocs Pouya Bashivan and Kohitij Kar are the lead authors of the paper, which appears in the May 2 online edition of Science.

    Neural control

    Over the past several years, DiCarlo and others have developed models of the visual system based on artificial neural networks. Each network starts out with an arbitrary architecture consisting of model neurons, or nodes, that can be connected to each other with different strengths, also called weights.

    The researchers then train the models on a library of more than 1 million images. As the researchers show the model each image, along with a label for the most prominent object in the image, such as an airplane or a chair, the model learns to recognize objects by changing the strengths of its connections.

    It’s difficult to determine exactly how the model achieves this kind of recognition, but DiCarlo and his colleagues have previously shown that the “neurons” within these models produce activity patterns very similar to those seen in the animal visual cortex in response to the same images.

    In the new study, the researchers wanted to test whether their models could perform some tasks that previously have not been demonstrated. In particular, they wanted to see if the models could be used to control neural activity in the visual cortex of animals.

    “So far, what has been done with these models is predicting what the neural responses would be to other stimuli that they have not seen before,” Bashivan says. “The main difference here is that we are going one step further and using the models to drive the neurons into desired states.”

    To achieve this, the researchers first created a one-to-one map of neurons in the brain’s visual area V4 to nodes in the computational model. They did this by showing images to animals and to the models, and comparing their responses to the same images. There are millions of neurons in area V4, but for this study, the researchers created maps for subpopulations of five to 40 neurons at a time.

    “Once each neuron has an assignment, the model allows you to make predictions about that neuron,” DiCarlo says.

    The researchers then set out to see if they could use those predictions to control the activity of individual neurons in the visual cortex. The first type of control, which they called “stretching,” involves showing an image that will drive the activity of a specific neuron far beyond the activity usually elicited by “natural” images similar to those used to train the neural networks.

    The researchers found that when they showed animals these “synthetic” images, which are created by the models and do not resemble natural objects, the target neurons did respond as expected. On average, the neurons showed about 40 percent more activity in response to these images than when they were shown natural images like those used to train the model. This kind of control has never been reported before.

    “That they succeeded in doing this is really amazing. It’s as if, for that neuron at least, its ideal image suddenly leaped into focus. The neuron was suddenly presented with the stimulus it had always been searching for,” says Aaron Batista, an associate professor of bioengineering at the University of Pittsburgh, who was not involved in the study. “This is a remarkable idea, and to pull it off is quite a feat. It is perhaps the strongest validation so far of the use of artificial neural networks to understand real neural networks.”

    In a similar set of experiments, the researchers attempted to generate images that would drive one neuron maximally while also keeping the activity in nearby neurons very low, a more difficult task. For most of the neurons they tested, the researchers were able to enhance the activity of the target neuron with little increase in the surrounding neurons.

    “A common trend in neuroscience is that experimental data collection and computational modeling are executed somewhat independently, resulting in very little model validation, and thus no measurable progress. Our efforts bring back to life this ‘closed loop’ approach, engaging model predictions and neural measurements that are critical to the success of building and testing models that will most resemble the brain,” Kar says.

    Measuring accuracy

    The researchers also showed that they could use the model to predict how neurons of area V4 would respond to synthetic images. Most previous tests of these models have used the same type of naturalistic images that were used to train the model. The MIT team found that the models were about 54 percent accurate at predicting how the brain would respond to the synthetic images, compared to nearly 90 percent accuracy when the natural images are used.

    “In a sense, we’re quantifying how accurate these models are at making predictions outside the domain where they were trained,” Bashivan says. “Ideally the model should be able to predict accurately no matter what the input is.”

    The researchers now hope to improve the models’ accuracy by allowing them to incorporate the new information they learn from seeing the synthetic images, which was not done in this study.

    This kind of control could be useful for neuroscientists who want to study how different neurons interact with each other, and how they might be connected, the researchers say. Farther in the future, this approach could potentially be useful for treating mood disorders such as depression. The researchers are now working on extending their model to the inferotemporal cortex, which feeds into the amygdala, which is involved in processing emotions.

    “If we had a good model of the neurons that are engaged in experiencing emotions or causing various kinds of disorders, then we could use that model to drive the neurons in a way that would help to ameliorate those disorders,” Bashivan says.

    The research was funded by the Intelligence Advanced Research Projects Agency, the MIT-IBM Watson AI Lab, the National Eye Institute, and the Office of Naval Research.

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings
    Please help promote STEM in your local schools.


    Stem Education Coalition

    MIT Seal

    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

    MIT Campus

     
  • richardmitnick 2:35 pm on May 2, 2019 Permalink | Reply
    Tags: "A comprehensive map of how Alzheimer’s affects the brain", , Medicine, , MIT researchers have performed the first comprehensive analysis of the genes that are expressed in individual brain cells of patients with Alzheimer’s disease., The brain cells of men and women vary significantly in how their genes respond to the disease, The results allowed the team to identify distinctive cellular pathways that are affected in neurons and other types of brain cells., The study revealed that a process called axon myelination is significantly disrupted in patients with Alzheimer’s.   

    From MIT News: “A comprehensive map of how Alzheimer’s affects the brain” 

    MIT News
    MIT Widget

    From MIT News

    May 1, 2019
    Anne Trafton

    1
    In the Alzheimer’s affected brain, abnormal levels of the beta-amyloid protein clump together to form plaques (seen in brown) that collect between neurons and disrupt cell function. Abnormal collections of the tau protein accumulate and form tangles (seen in blue) within neurons, harming synaptic communication between nerve cells. Image: National Institute on Aging, NIH

    2
    Oligodendrocytes from a patient with Alzheimer’s (bottom row) and a non-Alzheimer’s subject (top row) are labeled in red. The green stain reveals a protein encoded by a gene called QDRP, which MIT researchers found is expressed at much higher levels in oligodendrocytes from Alzheimer’s patients. Image: Zhuyu Peng

    MIT researchers have performed the first comprehensive analysis of the genes that are expressed in individual brain cells of patients with Alzheimer’s disease. The results allowed the team to identify distinctive cellular pathways that are affected in neurons and other types of brain cells.

    This analysis could offer many potential new drug targets for Alzheimer’s, which afflicts more than 5 million people in the United States.

    “This study provides, in my view, the very first map for going after all of the molecular processes that are altered in Alzheimer’s disease in every single cell type that we can now reliably characterize,” says Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute of MIT and Harvard. “It opens up a completely new era for understanding Alzheimer’s.”

    The study revealed that a process called axon myelination is significantly disrupted in patients with Alzheimer’s. The researchers also found that the brain cells of men and women vary significantly in how their genes respond to the disease.

    Kellis and Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, are the senior authors of the study, which appears in the May 1 online edition of Nature. MIT postdocs Hansruedi Mathys and Jose Davila-Velderrain are the lead authors of the paper.

    Single-cell analysis

    The researchers analyzed postmortem brain samples from 24 people who exhibited high levels of Alzheimer’s disease pathology and 24 people of similar age who did not have these signs of disease. All of the subjects were part of the Religious Orders Study, a longitudinal study of aging and Alzheimer’s disease. The researchers also had data on the subjects’ performance on cognitive tests.

    The MIT team performed single-cell RNA sequencing on about 80,000 cells from these subjects. Previous studies of gene expression in Alzheimer’s patients have measured overall RNA levels from a section of brain tissue, but these studies don’t distinguish between cell types, which can mask changes that occur in less abundant cell types, Tsai says.

    “We wanted to know if we could distinguish whether each cell type has differential gene expression patterns between healthy and diseased brain tissue,” she says. “This is the power of single-cell-level analysis: You have the resolution to really see the differences among all the different cell types in the brain.”

    Using the single-cell sequencing approach, the researchers were able to analyze not only the most abundant cell types, which include excitatory and inhibitory neurons, but also rarer, non-neuronal brain cells such as oligodendrocytes, astrocytes, and microglia. The researchers found that each of these cell types showed distinct gene expression differences in Alzheimer’s patients.

    Some of the most significant changes occurred in genes related to axon regeneration and myelination. Myelin is a fatty sheath that insulates axons, helping them to transmit electrical signals. The researchers found that in the individuals with Alzheimer’s, genes related to myelination were affected in both neurons and oligodendrocytes, the cells that produce myelin.

    Most of these cell-type-specific changes in gene expression occurred early in the development of the disease. In later stages, the researchers found that most cell types had very similar patterns of gene expression change. Specifically, most brain cells turned up genes related to stress response, programmed cell death, and the cellular machinery required to maintain protein integrity.

    Bruce Yankner, a professor of genetics and neurology at Harvard Medical School, described the study as “a tour de force of molecular pathology.”

    “This is the first comprehensive application of single-cell RNA sequencing technology to Alzheimer’s disease,” says Yankner, who was not involved in the research. “I anticipate this will be a very valuable resource for the field and will advance our understanding of the molecular basis of the disease.”

    Sex differences

    The researchers also discovered correlations between gene expression patterns and other measures of Alzheimer’s severity such as the level of amyloid plaques and neurofibrillary tangles, as well as cognitive impairments. This allowed them to identify “modules” of genes that appear to be linked to different aspects of the disease.

    “To identify these modules, we devised a novel strategy that involves the use of an artificial neural network and which allowed us to learn the sets of genes that are linked to the different aspects of Alzheimer’s disease in a completely unbiased, data-driven fashion,” Mathys says. “We anticipate that this strategy will be valuable to also identify gene modules associated with other brain disorders.”

    The most surprising finding, the researchers say, was the discovery of a dramatic difference between brain cells from male and female Alzheimer’s patients. They found that excitatory neurons and other brain cells from male patients showed less pronounced gene expression changes in Alzheimer’s than cells from female individuals, even though those patients did show similar symptoms, including amyloid plaques and cognitive impairments. By contrast, brain cells from female patients showed dramatically more severe gene-expression changes in Alzheimer’s disease, and an expanded set of altered pathways.

    “That’s when we realized there’s something very interesting going on. We were just shocked,” Tsai says.

    So far, it is unclear why this discrepancy exists. The sex difference was particularly stark in oligodendrocytes, which produce myelin, so the researchers performed an analysis of patients’ white matter, which is mainly made up of myelinated axons. Using a set of MRI scans from 500 additional subjects from the Religious Orders Study group, the researchers found that female subjects with severe memory deficits had much more white matter damage than matched male subjects.

    More study is needed to determine why men and women respond so differently to Alzheimer’s disease, the researchers say, and the findings could have implications for developing and choosing treatments.

    “There is mounting clinical and preclinical evidence of a sexual dimorphism in Alzheimer’s predisposition, but no underlying mechanisms are known. Our work points to differential cellular processes involving non-neuronal myelinating cells as potentially having a role. It will be key to figure out whether these discrepancies protect or damage the brain cells only in one of the sexes — and how to balance the response in the desired direction on the other,” Davila-Velderrain says.

    The researchers are now using mouse and human induced pluripotent stem cell models to further study some of the key cellular pathways that they identified as associated with Alzheimer’s in this study, including those involved in myelination. They also plan to perform similar gene expression analyses for other forms of dementia that are related to Alzheimer’s, as well as other brain disorders such as schizophrenia, bipolar disorder, psychosis, and diverse dementias.

    The research was funded by the National Institutes of Health, the JBP Foundation, and the Swiss National Science Foundation.

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings
    Please help promote STEM in your local schools.


    Stem Education Coalition

    MIT Seal

    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

    MIT Campus

     
  • richardmitnick 2:11 pm on May 2, 2019 Permalink | Reply
    Tags: , , Medicine, , Vasopressin may reduce social impairments in the developmental disorder   

    From Stanford University – Medicine: “Hormone reduces social impairment in kids with autism” 

    Stanford University Name
    From Stanford University – Medicine

    May 1, 2019

    Erin Digitale
    digitale@stanford.edu

    In a Stanford study of 30 children with autism, intranasal vasopressin improved social skills more than a placebo, suggesting that the hormone may treat core features of the disorder.

    2
    Opposite approaches to altering the activity of vasopressin in the brain improved some social deficits in people with autism.
    Drotyk Roman/shutterstock.com

    1
    A pilot study led by Antonio Hardan and Karen Parker found that social behavior in children with autism improved after they inhaled a hormone called vasopressin.
    Steve Fisch

    Social behavior improved in children with autism after they inhaled a hormone called vasopressin, a pilot study by researchers at the Stanford University School of Medicine has found. It is the first study to test intranasal vasopressin for any indication in children.

    Although small, the placebo-controlled study of 30 children provides early evidence that vasopressin may reduce social impairments in the developmental disorder, which affects 1 in 59 U.S. children. The findings were published online May 1 in Science.

    “Social deficits are one of the core features of autism and a challenging area for many kids with the disorder,” said the study’s lead author, Karen Parker, PhD, associate professor of psychiatry and behavioral sciences at Stanford. “Some of these kids want to socially connect but aren’t capable of doing so.”

    The other core features of autism are poor verbal communication skills and restricted, repetitive behaviors. No existing medications address any core features of the disorder.

    In the trial, parents’ and experts’ ratings of social behavior improved more in children treated with vasopressin than in those given a placebo. Vasopressin-treated children also experienced some reductions in anxiety and repetitive behaviors.

    “We saw this across multiple measures independently,” Parker said. “It is really exciting.”

    “We might finally have an agent that will target these core features that are very hard to treat,” said the study’s senior author, Antonio Hardan, MD, professor of psychiatry and behavioral sciences at Stanford. The researchers are now testing vasopressin in 100 additional children with autism to see if the pilot findings can be repeated.

    “Before getting too excited, I want us to replicate this, and more importantly I want others to replicate our findings,” added Hardan, who is also director of the Autism and Developmental Disabilities Clinic at Lucile Packard Children’s Hospital Stanford. Large trials are also needed to assure the drug’s safety.
    Sex-specific social hormones

    Vasopressin is a tiny protein hormone, nine amino acids long, manufactured in the hypothalamus. It differs by two amino acids from oxytocin, another hormone made in the same part of the brain.

    Although both hormones play roles in social behavior, there are sex differences in their activity. Parker’s early research in animal models showed that, in males, vasopressin influences pair-bonding and fathering behavior. Oxytocin regulates aspects of childbirth and certain maternal behaviors, such as milk letdown during nursing.

    Oxytocin has been tested as an autism treatment with mixed results; Parker and Hardan previously showed that among autistic children whose oxytocin levels were low to begin with, giving that hormone improved aspects of social behavior. However, many children with autism do not have low oxytocin levels.

    Vasopressin’s social effects in males made the researchers wonder if this hormone influences autism. The disorder is male-biased, with 4 or 5 males affected for every female.

    Parker and Hardan have previously shown that, compared with typically developing children, those with autism have lower vasopressin levels in their cerebrospinal fluid, which bathes the brain and spinal cord. Among children with autism, those with the lowest CSF vasopressin levels also have the lowest social functioning, the researchers have shown.

    Dosing with vasopressin

    The Stanford team recruited 30 children with autism, all of whom were 6 to 12 years old and had an IQ of at least 50. The participants were randomly assigned, in a double-blind fashion, to receive intranasal vasopressin or a placebo. Participants took daily doses of their assigned medication for four weeks.

    At the beginning and end of the trial, several measurements were used to assess autism symptoms. Participants’ parents completed questionnaires rating their children’s social abilities. In the lab, the researchers tested participants’ ability to recognize emotional states in images of people’s eyes or facial expressions. Children’s repetitive behaviors and anxiety levels were also measured. The researchers also completed physical and clinical chemistry measurements to evaluate the safety of the treatment.

    Children’s social abilities improved more after vasopressin than placebo, according to the parents’ and researchers’ observations, as did children’s performance on objective lab tests of social abilities. Vasopressin also reduced anxiety symptoms.

    The changes in social ability and anxiety were greatest among children whose vasopressin levels were highest at the beginning of the study, a finding that surprised the researchers, given that their prior work had showed the lowest social abilities in children with the lowest vasopressin levels.

    In addition, among children with the highest vasopressin at baseline, vasopressin treatment reduced restricted and repetitive behaviors. This finding did not extend to participants with lower baseline vasopressin.

    The findings will guide larger trials of vasopressin. “Identifying who responds and why is really important,” Parker said. Because autism exists on a spectrum, with some people more severely affected than others, treatments must be individualized, she said.

    If the findings of the pilot trial are replicated, it will also be important to validate the safety of the hormone in large populations and to understand which aspects of social behavior are most improved by vasopressin, Hardan added. “Is it motivation, affiliation, attachment? Ability to understand others’ mental states or read facial expressions or body language?” he said. “This has opened up a lot of possibilities for individuals with autism.”

    Other Stanford co-authors of the study are research scientist Ozge Oztan, PhD; clinical research coordinator Robin Libove; former life sciences researcher Noreen Mohsin; research scientist Debra Karhson, PhD; former assistant clinical research coordinator Raena Sumiyoshi; incoming medical resident Jacqueline Summers; Kyle Hinman, MD, clinical assistant professor of psychiatry and behavioral sciences; Kara Motonaga, MD, clinical associate professor of pediatrics; Jennifer Phillips, PhD, clinical associate professor of psychiatry and behavioral sciences; former postdoctoral scholar Dean Carson, PhD; Lawrence Fung, MD, PhD, clinical assistant professor of psychiatry and behavioral sciences; and Joseph Garner, DPhil, associate professor of comparative medicine.

    Parker, Hardan, Fung and Garner are members of the Stanford Maternal & Child Health Research Institute. Parker, Hardan and Garner are also members of Stanford Bio-X and the Wu Tsai Neurosciences Institute at Stanford. Garner is a faculty fellow of Stanford ChEM-H.

    The research was supported by the National Institutes of Health (grants R21MH100387, R21HD083629, R01HD091972, K08MH111750 and T32MH019908), Autism Speaks, a Bass Society Pediatric Fellowship, the Mosbacher Family Fund for Autism Research, the Teresa and Charles Michael Endowed Fund for Autism Research and Education, the Stanford Maternal & Child Health Research Institute and the Yani Calmidis Memorial Fund for Autism Research.

    See the full article here .


    five-ways-keep-your-child-safe-school-shootings
    Please help promote STEM in your local schools.

    Stem Education Coalition

    Stanford Medicine integrates research, medical education and health care at its three institutions – Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children’s Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu.

    Stanford University campus. No image credit

    Stanford University

    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

    Stanford University Seal

     
c
Compose new post
j
Next post/Next comment
k
Previous post/Previous comment
r
Reply
e
Edit
o
Show/Hide comments
t
Go to top
l
Go to login
h
Show/Hide help
shift + esc
Cancel
%d bloggers like this: