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How mucus tames microbes

More than 200 square meters of our bodies   including the digestive tract  lungs  and urinary tract   are lined with mucus. In recent years  scientists have found some evidence that mucus is not just a physical barrier that traps bacteria and viruses  but it can also disarm pathogens and prevent them from causing infections.

A new study from MIT reveals that glycans   branched sugar molecules found in mucus   are responsible for most of this microbe-taming. There are hundreds of different glycans in mucus  and the MIT team discovered that these molecules can prevent bacteria from communicating with each other and forming infectious biofilms  effectively rendering them harmless.

 What we have in mucus is a therapeutic gold mine   says Katharina Ribbeck  the Mark Hyman  Jr. Career Development Professor of Biological Engineering at MIT.  These glycans have biological functions that are very broad and sophisticated. They have the ability to regulate how microbes behave and really tune their identity.

In this study  which appears today in Nature Microbiology  the researchers focused on glycans  interactions with Pseudomonas aeruginosa  an opportunistic pathogen that can cause infections in cystic fibrosis patients and people with compromised immune systems. Work now underway in Ribbeck s lab has shown that glycans can regulate the behavior of other microbes as well.

The lead author of the Nature Microbiology paper is MIT graduate student Kelsey Wheeler.

Powerful defenders

The average person produces several liters of mucus every day  and until recently this mucus was thought to function primarily as a lubricant and a physical barrier. However  Ribbeck and others have shown that mucus can actually interfere with bacterial behavior  preventing microbes from attaching to surfaces and communicating with one another.

In the new study  Ribbeck wanted to test whether glycans were involved in mucus  ability to control the behavior of microbes. These sugar molecules  a type of oligosaccharide  attach to proteins called mucins  the gel-forming building blocks of mucus  to form a bottlebrush-like structure. Mucus-associated glycans have been little studied  but Ribbeck thought they might play a major role in the microbe-disarming activity she had previously seen from mucus.

To explore that possibility  she isolated glycans and exposed them to Pseudomonas aeruginosa. Upon exposure to mucin glycans  the bacteria underwent broad shifts in behavior that rendered them less harmful to the host. For example  they no longer produced toxins  attached to or killed host cells  or expressed genes essential for bacterial communication.

This microbe-disarming activity had powerful consequences on the ability of this bacterium to establish infections. Ribbeck has shown that treatment of Pseudomonas-infected burn wounds with mucins and mucin glycans reduces bacterial proliferation  indicating the therapeutic potential of these virulence-neutralizing agents.

 We ve seen that intact mucins have regulatory effects and can cause behavioral switches in a whole range of pathogens  but now we can pinpoint the molecular mechanism and the entities that are responsible for this  which are the glycans   Ribbeck says.

In these experiments  the researchers used collections of hundreds of glycans  but they now plan to study the effects of individual glycans  which may interact specifically with different pathways or different microbes.

Bacterial interactions

Pseudomonas aeruginosa is just one of many opportunistic pathogens that healthy mucus keeps in check. Ribbeck is now studying the role of glycans in regulating other pathogens  including Streptococcus and the fungus Candida albicans  and she is also working on identifying receptors on microbe cell surfaces that interact with glycans.

Her work on Streptococcus has shown that glycans can block horizontal gene transfer  a process that microbes often use to spread genes for drug resistance.

Ribbeck and other researchers are now interested in using what they have learned about mucins and glycans to develop artificial mucus  which could offer a new way to treat diseases stemming from lost or defective mucus.

Harnessing the powers of mucus could also lead to new ways to treat antibiotic-resistant infections  because it offers a complementary strategy to traditional antibiotics  Ribbeck says.

 What we find here is that nature has evolved the ability to disarm difficult microbes  instead of killing them. This would not only help limit selective pressure for developing resistance  because they are not under pressure to find ways to survive  but it should also help create and maintain a diverse microbiome   she says.

Ribbeck suspects that glycans in mucus also play a key role in determining the composition of the microbiome   the trillions of bacterial cells that live inside the human body. Many of these microbes are beneficial to their human hosts  and glycans may be providing them with nutrients they need  or otherwise helping them to flourish  she says. In this way  mucus-associated glycans are similar to the many oligosaccharides found in human milk  which also contains a wide array of sugars that can regulate microbe behavior.

 This is a theme that is likely at play in many systems where the goal is to shape and manipulate communities inside the body  not just in humans but throughout the animal kingdom   Ribbeck says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering  the National Institutes of Health  the National Science Foundation  the National Institute of Environmental Health Sciences  and the MIT Deshpande Center for Technological Innovation.

Hallucinations are spooky and  fortunately  fairly rare  But  a new study suggests  the real question isn t so much why some people occasionally experience them  It s why all of us aren t hallucinating all the time

In the study  Stanford University School of Medicine neuroscientists stimulated nerve cells in the visual cortex of mice to induce an illusory image in the animals  minds  The scientists needed to stimulate a surprisingly small number of nerve cells  or neurons  in order to generate the perception  which caused the mice to behave in a particular way

 Back in 2012  we had described the ability to control the activity of individually selected neurons in an awake  alert animal   said Karl Deisseroth  MD  PhD  professor of bioengineering and of psychiatry and behavioral sciences   Now  for the first time  we ve been able to advance this capability to control multiple individually specified cells at once  and make an animal perceive something specific that in fact is not really there    and behave accordingly 

The study  to be published online July 18 in Science  holds implications for obtaining a better understanding of natural information processing in the brain  as well as psychiatric disorders such as schizophrenia  and points to the possibility of designing neural prosthetic devices with single cell resolution

Deisseroth is the study s senior author  Lead authorship is shared by staff scientists James Marshel  PhD  and Sean Quirin  PhD  graduate student Yoon Seok Kim  and postdoctoral scholar Timothy Machado  PhD

Using optogenetics

Deisseroth  who is a Howard Hughes Medical Institute investigator and holds the D  H  Chen Professorship  pioneered optogenetics  a technology enabling researchers to stimulate particular neurons in freely moving animals with pulses of light  and to observe the resulting effects on the animals  brain function and behavior

In the new study  Deisseroth and his colleagues inserted a combination of two genes into large numbers of neurons in the visual cortex of lab mice  One gene encoded a light sensitive protein that caused the neuron to fire in response to a pulse of laser light of a narrowly defined color    in this case  in the infrared spectrum  The other gene encoded a fluorescent protein that glowed green whenever the neuron was active

The scientists created cranial windows in the mice by removing a portion of the animals  skulls to expose part of the visual cortex  which in both mice and humans is responsible for processing information relayed from the retina  The investigators protected this exposed area with a clear glass covering  They could then use a device they developed for the purpose of the study to project holograms    three dimensional configurations of targeted photons    onto  and into  the visual cortex  These photons would land at precise spots along specific neurons  The researchers could monitor the resulting activity of nearly all individual neurons in two distinct layers of the cerebral cortex spanning about 1 square millimeter and containing on the order of several thousand neurons

With their heads fixed in a comfortable position  the mice were shown random series of horizontal and vertical bars displayed on a screen  The researchers observed and recorded which neurons in the exposed visual cortex were preferentially activated by one or the other orientation  From these results  the scientists were able to identify dispersed populations of individual neurons that were  tuned  to either horizontal or vertical visual displays

They were then able to  play back  these recordings in the form of holograms that produced spots of infrared light on just neurons that were responsive to horizontal  or to vertical  bars  The resulting downstream neuronal activity  even at locations relatively far from the stimulated neurons  was quite similar to that observed when the natural stimulus    a black horizontal or vertical bar on a white background    was displayed on the screen

The scientists trained the mice to lick the end of a nearby tube for water when they saw a vertical bar but not when they saw a horizontal one or saw neither  Over the course of several days  as the animals  ability to discriminate between horizontal and vertical bars improved  the scientists gradually reduced the black white contrast to make the task progressively harder  They found that the mice s performance perked up if the scientists supplemented the visual displays with simultaneous optogenetic stimulation  For example  if an animal s performance deteriorated as a result of a lowered contrast  the investigators could boost its discrimination powers by stimulating neurons previously identified as preferentially disposed to fire in response to a horizontal or vertical bar

This boost occurred only when the optogenetic stimulation was consistent with the visual stimulation    for example  a vertical bar display plus stimulation of neurons previously identified as likely to fire in response to vertically oriented bars

Hallucinating mice

Once the mice had become adept at discriminating between horizontal and vertical bars  the scientists were able to induce tube licking behavior in the mice simply by projecting the  vertical  holographic program onto the mice s visual cortex  But the mice wouldn t lick the tube if the  horizontal  program was projected instead

 Not only is the animal doing the same thing  but the brain is  too   Deisseroth said   So we know we re either recreating the natural perception or creating something a whole lot like it 

In their early experiments  the scientists had identified numerous neurons as being tuned to either a horizontal or a vertical orientation  but they hadn t yet directly stimulated each of those particular neurons optogenetically  Once the mice were trained  optogenetic stimulation of small numbers of these neurons was enough to get mice to respond with appropriate licking or nonlicking behavior

The researchers were surprised to find that optogenetically stimulating about 20 neurons    or fewer in some cases    selected only for being responsive to the right orientation  could produce the same neuronal activity and animal behavior that displaying the vertical or horizontal bar did

 It s quite remarkable how few neurons you need to specifically stimulate in an animal to generate a perception   Deisseroth said

 A mouse brain has millions of neurons  a human brain has many billions   he said   If just 20 or so can create a perception  then why are we not hallucinating all the time  due to spurious random activity? Our study shows that the mammalian cortex is somehow poised to be responsive to an amazingly low number of cells without causing spurious perceptions in response to noise 

Deisseroth is a member of Stanford Bio X and of the Wu Tsai Neurosciences Institute at Stanford

Stanford s Office of Technology Licensing has filed a patent application for intellectual property associated with the work

The work was funded by the Defense Advanced Research Projects Agency  HHMI  the National Institutes of Health (grants R01MH075957 and P50DA042012)  the Simons Foundation  the Wiegers Family Fund  the Nancy and James Grosfeld Foundation  the Sam and Betsy Reeves Fund  the H L  Snyder Foundation  the Burroughs Wellcome Foundation  the McKnight Foundation  the James S  McDonnell Foundation and the Swartz Foundation

Scientists restore some functions in a pig s brain hours after death

Circulation and cellular activity were restored in a pig s brain four hours after its death  a finding that challenges long held assumptions about the timing and irreversible nature of the cessation of some brain functions after death  Yale scientists report April 18 in the journal Nature.
The brain of a postmortem pig obtained from a meatpacking plant was isolated and circulated with a specially designed chemical solution. Many basic cellular functions  once thought to cease seconds or minutes after oxygen and blood flow cease  were observed  the scientists report.
 The intact brain of a large mammal retains a previously underappreciated capacity for restoration of circulation and certain molecular and cellular activities multiple hours after circulatory arrest   said senior author Nenad Sestan  professor of neuroscience  comparative medicine  genetics  and psychiatry.
However  researchers also stressed that the treated brain lacked any recognizable global electrical signals associated with normal brain function.
 At no point did we observe the kind of organized electrical activity associated with perception  awareness  or consciousness   said co first author Zvonimir Vrselja  associate research scientist in neuroscience.  Clinically defined  this is not a living brain  but it is a cellularly active brain.
Cellular death within the brain is usually considered to be a swift and irreversible process. Cut off from oxygen and a blood supply  the brain s electrical activity and signs of awareness disappear within seconds  while energy stores are depleted within minutes. Current understanding maintains that a cascade of injury and death molecules are then activated leading to widespread  irreversible degeneration.
However  researchers in Sestan s lab  whose research focuses on brain development and evolution  observed that the small tissue samples they worked with routinely showed signs of cellular viability  even when the tissue was harvested multiple hours postmortem. Intrigued  they obtained the brains of pigs processed for food production to study how widespread this postmortem viability might be in the intact brain. Four hours after the pig s death  they connected the vasculature of the brain to circulate a uniquely formulated solution they developed to preserve brain tissue  utilizing a system they call BrainEx. They found neural cell integrity was preserved  and certain neuronal  glial  and vascular cell functionality was restored.
The new system can help solve a vexing problem    the inability to apply certain techniques to study the structure and function of the intact large mammalian brain    which hinders rigorous investigations into topics like the roots of brain disorders  as well as neuronal connectivity in both healthy and abnormal conditions.
 Previously  we have only been able to study cells in the large mammalian brain under static or largely two dimensional conditions utilizing small tissue samples outside of their native environment   said co first author Stefano G. Daniele  an M.D./Ph.D. candidate.  For the first time  we are able to investigate the large brain in three dimensions  which increases our ability to study complex cellular interactions and connectivity.
While the advance has no immediate clinical application  the new research platform may one day be able to help doctors find ways to help salvage brain function in stroke patients  or test the efficacy of novel therapies targeting cellular recovery after injury  the authors say.
The research was primarily funded by the National Institutes of Health s (NIH) BRAIN Initiative.
 This line of research holds hope for advancing understanding and treatment of brain disorders and could lead to a whole new way of studying the postmortem human brain   said Andrea Beckel Mitchener  chief of functional neurogenomics at the NIH s National Institute of Mental Health  which co funded the research.
The researchers said that it is unclear whether this approach can be applied to a recently deceased human brain. The chemical solution used lacks many of the components natively found in human blood  such as the immune system and other blood cells  which makes the experimental system significantly different from normal living conditions. However  the researcher stressed any future study involving human tissue or possible revival of global electrical activity in postmortem animal tissue should be done under strict ethical oversight.
 Restoration of consciousness was never a goal of this research   said co author Stephen Latham  director of Yale s Interdisciplinary Center for Bioethics.  The researchers were prepared to intervene with the use of anesthetics and temperature reduction to stop organized global electrical activity if it were to emerge. Everyone agreed in advance that experiments involving revived global activity couldn t go forward without clear ethical standards and institutional oversight mechanisms.
There is an ethical imperative to use tools developed by the Brain Initiative to unravel mysteries of brain injuries and disease  said Christine Grady  chief of the Department of Bioethics at the NIH Clinical Center.
 It s also our duty to work with researchers to thoughtfully and proactively navigate any potential ethical issues they may encounter as they open new frontiers in brain science   she said.

Engineers create delicate sensor to monitor heart cells with minimal disruption

For the first time, engineers have demonstrated an electronic device to closely monitor beating heart cells without affecting their behavior. A collaboration between the University of Tokyo, Tokyo Women s Medical University and RIKEN in Japan produced a functional sample of heart cells with a soft nanomesh sensor in direct contact with the tissue. This device could aid study of other cells, organs and medicines. It also paves the way for future embedded medical devices.
Inside each of us beats a life-sustaining heart. Unfortunately, the organ is not always perfect and sometimes goes wrong. One way or another research on the heart is fundamentally important to us all. So when Sunghoon Lee, a researcher in Professor Takao Someya s group at the University of Tokyo, came up with the idea for an ultrasoft electronic sensor that could monitor functioning cells, his team jumped at the chance to use this sensor to study heart cells, or cardiomyocytes, as they beat.
 When researchers study cardiomyocytes in action they culture them on hard petri dishes and attach rigid sensor probes. These impede the cells  natural tendency to move as the sample beats, so observations do not reflect reality well,  said Lee.  Our nanomesh sensor frees researchers to study cardiomyocytes and other cell cultures in a way more faithful to how they are in nature. The key is to use the sensor in conjunction with a flexible substrate, or base, for the cells to grow on.
For this research, collaborators from Tokyo Women s Medical University supplied a healthy culture of cardiomyocytes derived from human stem cells. The base for the culture was a very soft material called fibrin gel. Lee placed the nanomesh sensor on top of the cell culture in a complex process, which involved removing and adding liquid medium at the proper times. This was important to correctly orient the nanomesh sensor.
 The fine mesh sensor is difficult to place perfectly. This reflects the delicate touch necessary to fabricate it in the first place,  continued Lee.  The polyurethane strands which underlie the entire mesh sensor are 10 times thinner than a human hair. It took a lot of practice and pushed my patience to its limit, but eventually I made some working prototypes.
To make the sensors, first a process called electro-spinning extrudes ultrafine polyurethane strands into a flat sheet, similar to how some common 3D printers work. This spiderweb like sheet is then coated in parylene, a type of plastic, to strengthen it. The parylene on certain sections of the mesh is removed by a dry etching process with a stencil. Gold is then applied to these areas to make the sensor probes and communication wires. Additional parylene isolates the probes so their signals do not interfere with one another.
With three probes, the sensor reads voltage present at three locations. The readout appears familiar to anyone who s watched a hospital drama as it s essentially a cardiogram. Thanks to the multiple probes, researchers can see propagation of signals, which result from and trigger the cells to beat. These signals are known as an action or field potential and are extremely important when assessing the effect of drugs on the heart.
 Drug samples need to get to the cell sample and a solid sensor would either poorly distribute the drug or prevent it reaching the sample altogether. So the porous nature of the nanomesh sensor was intentional and a driving force behind the whole idea,  said Lee.  Whether it s for drug research, heart monitors or to reduce animal testing, I can t wait to see this device produced and used in the field. I still get a powerful feeling when I see the close-up images of those golden threads.

E-bandage generates electricity, speeds wound healing in rats

Skin has a remarkable ability to heal itself. But in some cases, wounds heal very slowly or not at all, putting a person at risk for chronic pain, infection and scarring. Now, researchers have developed a self-powered bandage that generates an electric field over an injury, dramatically reducing the healing time for skin wounds in rats. They report their results in ACS Nano.
Chronic skin wounds include diabetic foot ulcers, venous ulcers and non-healing surgical wounds. Doctors have tried various approaches to help chronic wounds heal, including bandaging, dressing, exposure to oxygen and growth-factor therapy, but they often show limited effectiveness. As early as the 1960s, researchers observed that electrical stimulation could help skin wounds heal. However, the equipment for generating the electric field is often large and may require patient hospitalization. Weibo Cai, Xudong Wang and colleagues wanted to develop a flexible, self-powered bandage that could convert skin movements into a therapeutic electric field.
To power their electric bandage, or e-bandage, the researchers made a wearable nanogenerator by overlapping sheets of polytetrafluoroethylene (PTFE), copper foil and polyethylene terephthalate (PET). The nanogenerator converted skin movements, which occur during normal activity or even breathing, into small electrical pulses. This current flowed to two working electrodes that were placed on either side of the skin wound to produce a weak electric field. The team tested the device by placing it over wounds on rats   backs. Wounds covered by e-bandages closed within 3 days, compared with 12 days for a control bandage with no electric field. The researchers attribute the faster wound healing to enhanced fibroblast migration, proliferation and differentiation induced by the electric field.

Neuroscience-protein that divides the brain

A depiction of the different regions in the developing fly brain (left) and the roles of Slit-Robo and Netrin, in inhibiting cell mixing (right).
Credit: Kanazawa University
Boundaries between different regions of the brain are essential for the brain to function. Research to-date has shown that molecular machineries located at the cell membrane such as cell adhesion molecules are responsible for regulating the boundary formation. Specifically, Slit and Netrin are diffusible guidance molecules that regulate the attraction and/or repulsion of the cells. Cells that receive Slit or Netrin are repelled from its source. However, it is also known that some cells are attracted to the source of Netrin. Makoto Sato at Kanazawa University and colleagues report in iScience that these diffusible molecules are essential for the boundary formation in fly brains.
The visual center of the adult fly brain can stem from two parts of the larval fly brain, the inner proliferation center (IPC) and the outer proliferation center (OPC). Glial cells separate the IPC neurons and OPC neurons. Keeping the IPC and OPC separated ensures that they give rise to distinct brain regions.
Netrin becomes effective when received by the two receptor molecules Fra and Unc5. To examine the effects of Netrin, the researchers used gene editing and inactivated it in the larva visual centers. These flies were found to have the IPC neurons penetrating the OPC, with disrupted distribution of the OPC neurons and glial cells. The same effects were seen in Fra and Unc5 inactivated flies. Similarly, Slit becomes active when bound to its receptor, Robo. Inactivation of either Slit or Robo resulted in similar boundary defects.
The researchers also found that Netrin expressed in the IPC and OPC neurons is received by Fra and Unc5 expressed in the glial cells situated between the IPC and OPC. In contrast, Slit expressed in the glial cells is received by Robo expressed in the IPC and OPC.
These unique findings are important because the guidance molecules are different from molecules that act at cells membranes. However, it is very difficult to imagine how these guidance molecules govern the boundary formation. So, Sato and his team formulated a mathematical model of the functions of Slit and Netrin, and demonstrated that these guidance molecules can indeed regulate the formation of boundaries.
The exchange of Slit and Netrin with their respective partners, between the neurons and glial cells were simulated. Slit produced by glial cell always repels neurons. However, given that Netrin possesses attractive and repulsive properties, then how does Netrin function? The key idea of their model is that Netrin produced by neurons attracts glial cells when its concentration is low. But it is switched to become repellent when its concentration is high. This model shows that the balance between attraction and repulsion between neurons and glial cells regulates the boundary formation in the different brain regions. Thus, the report establishes a link between the diffusible guidance molecules and the boundary formation mechanism in multicellular organisms.
Since these signaling pathways are evolutionarily conserved from insects to mammals, their roles in establishing the tissue border may also be conserved across species, the team concludes. An elucidation of these novel pathways paves the way for preventing structural and thereby functional deformities in the brains of higher species, such as humans. Inhibition of cell mixing also aids in keeping toxic cells, such as cancer cells, from invading healthy ones