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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

First baby born via uterus transplant from a deceased donor

Currently, uterus donation is only available for women with family members who are willing to donate. With live donors in short supply, the new technique might help to increase availability and give more women the option of pregnancy. The first baby has been born following a uterus transplantation from a deceased donor, according to a case study from Brazil published in The Lancet. The study is also the first uterine transplantation in Latin America.
The new findings demonstrate that uterus transplants from deceased donors are feasible and may open access for all women with uterine infertility, without the need for live donors. However, the outcomes and effects of donations from live and deceased donors are yet to be compared, and the surgical and immunosuppression techniques will be optimised in the future.
The recipient of the transplant was a patient with uterine infertility. Previously, there have been 10 other uterus transplants from deceased donors attempted in the USA, Czech Republic and Turkey, but this is the first to result in a livebirth. The first childbirth following uterine transplantation from living donors occurred in Sweden in September 2013 and were also published in The Lancet. In total, there have been 39 procedures of this kind, resulting in 11 livebirths so far (see Comment Appendix).
Infertility affects 10-15% of couples of reproductive age. Of this group, one in 500 women have uterine anomalies due to congenital anomalies, or through unexpected malformation, hysterectomy, or infection. Before the advent of uterus transplants, the only available options to have a child were adoption or surrogacy.
The use of deceased donors could greatly broaden access to this treatment, and our results provide proof-of-concept for a new option for women with uterine infertility. says Dr Dani Ejzenberg, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, who led the research. The first uterus transplants from live donors were a medical milestone, creating the possibility of childbirth for many infertile women with access to suitable donors and the needed medical facilities. However, the need for a live donor is a major limitation as donors are rare, typically being willing and eligible family members or close friends. The numbers of people willing and committed to donate organs upon their own deaths are far larger than those of live donors, offering a much wider potential donor population.
The surgery took place in September 2016. The recipient of the uterus was a 32 year-old woman born without a uterus as a result of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. She had one in-vitro fertilisation (IVF) cycle four months before transplant, resulting in eight fertilised eggs which were cryopreserved.
The donor was 45 years old and died of subarachnoid haemorrhage (a type of stroke involving bleeding on the surface of the brain).
The uterus was removed from the donor and then transplanted into the recipient in surgery lasting 10.5 hours. The surgery involved connecting the donor uterus and recipients veins and arteries, ligaments, and vaginal canals.
After surgery, the recipient stayed in intensive care for two days, then spent six days on a specialised transplant ward. She received five immunosuppression drugs, as well as antimicrobials, anti-blood clotting treatment and aspirin while in hospital. Immunosuppression was continued outside of hospital until the birth.
Five months after transplantation, the uterus showed no signs of rejection, ultrasound scans showed no anomalies, and the recipient was having regular menstruation.
The fertilised eggs were implanted after seven months. The authors note that they were able to implant the fertilised eggs into the transplant uterus much earlier than previous uterus transplants (where this typically occurred after one year). Implantation was planned to be at six months, but the endometrium was not thick enough at this stage, so it was postponed for one month.
Ten days after implantation, the recipient was confirmed to be pregnant. Non-invasive prenatal testing was done at 10 weeks, showing a normal fetus, and ultrasound scans at 12 and 20 weeks revealed no fetal anomalies.
There were no issues during the recipients pregnancy, other than a kidney infection at 32 weeks which was treated with antibiotics in hospital.
The baby girl was born via caesarean section at 35 weeks and three days, and weighed 2550g (around 6lbs). The transplanted uterus was removed during the caesarean section and showed no anomalies.
Both the recipient and baby were discharged three days after birth, with an uneventful early follow-up. The immunosuppressive therapy was suspended at the end of the hysterectomy. At the age of seven months and 20 days (when the manuscript was written), the baby continued to breastfeed and weighed 7.2kg (15lbs and 14oz).
The authors note that transplants from deceased donors might have some benefits over donations from live donors, including removing surgical risks for a live donor, and that many countries already have well-established national systems to regulate and distribute organ donations from deceased donors. In addition, through implanting the fertilised eggs sooner they reduced the amount of time taking immunosuppression drugs, which could help to reduce side effects and costs.
The authors note that the transplant involved major surgery and recipients for uterus transplants would need to be healthy to avoid complications during or after this. They also note that the surgery used high doses of immunosuppression, which could be reduced in future. It also involved moderate levels of blood loss, although these were manageable.
The recipient and her partner received monthly psychological counselling from professionals specialised in transplants and fertility throughout before, during and after the transplant.
Writing in a linked Comment, Dr Antonio Pellicer, IVI-Roma, Italy, notes that while the procedure is a breakthrough, it is still in the early stages of refining and many questions are still unsolved. He says: All in all, the research to be done in this field (whether from alive or deceased donors) should maximise the livebirth rate, minimise the risks for the patients involved in the procedures (donor, recipient, and unborn child), and increase the availability of organs. With the expansion of the field, the number of procedures will increase, and this will allow the community to set different types of study designs, such as comparison studies (ideally randomised) or long prospective series. In an expanding field such as uterus transplantation, the role of collaborative networks and societies such as the International Society of Uterus Transplantation or new interest groups in already existing scientific societies will be crucial. They should promote education and guidance so that the groups performing uterus transplantation for the first time can benefit from the experience of the pioneers. They should also encourage forthcoming procedures to be done and reported in a transparent way by endorsing prospective registration of the procedures and by developing accurate registries.
This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and Hospital das Clínicas, University of São Paulo, Brazil. It was conducted by researchers from Hospital das Clínicas, University of São Paulo School of Medicine.

Playing high school football changes the teenage brain

Magnetic resonance imaging (MRI) brain scans have revealed that playing a single season of high school football can cause microscopic changes in the grey matter in young players brains. These changes are located in the front and rear of the brain, where impacts are most likely to occur, as well as deep inside the brain.
Credit: Nan-Jie Gong and Chunlei Liu, UC Berkeley
A single season of high school football may be enough to cause microscopic changes in the structure of the brain, according to a new study by researchers at the University of California, Berkeley, Duke University and the University of North Carolina at Chapel Hill.
The researchers used a new type of magnetic resonance imaging (MRI) to take brain scans of 16 high school players, ages 15 to 17, before and after a season of football. They found significant changes in the structure of the grey matter in the front and rear of the brain, where impacts are most likely to occur, as well as changes to structures deep inside the brain. All participants wore helmets, and none received head impacts severe enough to constitute a concussion.
The study, which is the cover story of the November issue of Neurobiology of Disease, is one of the first to look at how impact sports affect the brains of children at this critical age. This study was made available online in July 2018 ahead of final publication in print this month.
It is becoming pretty clear that repetitive impacts to the head, even over a short period of time, can cause changes in the brain, said study senior author Chunlei Liu, a professor of electrical engineering and computer sciences and a member of the Helen Wills Neuroscience Institute at UC Berkeley. This is the period when the brain is still developing, when it is not mature yet, so there are many critical biological processes going on, and it is unknown how these changes that we observe can affect how the brain matures and develops.
Concerning trends
One bonk to the head may be nothing to sweat over. But mounting evidence shows that repeated blows to the cranium -- such as those racked up while playing sports like hockey or football, or through blast injuries in military combat -- may lead to long-term cognitive decline and increased risk of neurological disorders, even when the blows do not cause concussion.
Over the past decade, researchers have found that an alarming number of retired soldiers and college and professional football players show signs of a newly identified neurodegenerative disease called chronic traumatic encephalopathy (CTE), which is characterized by a buildup of pathogenic tau protein in the brain. Though still not well understood, CTE is believed to cause mood disorders, cognitive decline and eventually motor impairment as a patient ages. Definitive diagnosis of CTE can only be made by examining the brain for tau protein during an autopsy.
These findings have raised concern over whether repeated hits to the head can cause brain damage in youth or high school players, and whether it is possible to detect these changes at an early age.
There is a lot of emerging evidence that just playing impact sports actually changes the brain, and you can see these changes at the molecular level in the accumulations of different pathogenic proteins associated with neurodegenerative diseases like Parkinsons and dementia, Liu said. We wanted to know when this actually happens -- how early does this occur?
A matter of grey and white
The brain is built of white matter, long neural wires that pass messages back and forth between different brain regions, and grey matter, tight nets of neurons that give the brain its characteristic wrinkles. Recent MRI studies have shown that playing a season or two of high school football can weaken white matter, which is mostly found nestled in the interior of the brain. Liu and his team wanted to know if repetitive blows to the head could also affect the brain s gray matter.
Grey matter in the cortex area is located on the outside of the brain, so we would expect this area to be more directly connected to the impact itself, Liu said.
The researchers used a new type of MRI called diffusion kurtosis imaging to examine the intricate neural tangles that make up gray matter. They found that the organization of the gray matter in players brains changed after a season of football, and these changes correlated with the number and position of head impacts measured by accelerometers mounted inside players helmets.
The changes were concentrated in the front and rear of the cerebral cortex, which is responsible for higher-order functions like memory, attention and cognition, and in the centrally located thalamus and putamen, which relay sensory information and coordinate movement.
Although our study did not look into the consequences of the observed changes, there is emerging evidence suggesting that such changes would be harmful over the long term, Liu said.
Tests revealed that students cognitive function did not change over the course of the season, and it is yet unclear whether these changes in the brain are permanent, the researchers say.
The brain microstructure of younger players is still rapidly developing, and that may counteract the alterations caused by repetitive head impacts,said first author Nan-Ji Gong, a postdoctoral researcher in the Department of Electrical Engineering and Computer Sciences at UC Berkeley.
However, the researchers still urge caution -- and frequent cognitive and brain monitoring -- for youth and high schoolers engaged in impact sports.
I think it would be reasonable to debate at what age it would be most critical for the brain to endure these sorts of consequences, especially given the popularity of youth football and other sports that cause impact to the brain, Liu said.

A new approach to detecting cancer earlier from blood tests

Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined liquid biopsy, epigenetic alterations and machine learning to develop a blood test to detect and classify cancer at its earliest stages.
The findings, published online today in Nature, describe not only a way to detect cancer, but hold promise of being able to find it earlier when it is more easily treated and long before symptoms ever appear, says Dr. De Carvalho, Senior Scientist at the cancer centre, University Health Network.
We are very excited at this stage, says Dr. De Carvalho. A major problem in cancer is how to detect it early. It has been a needle in the haystack problem of how to find that one-in-a-billion cancer-specific mutation in the blood, especially at earlier stages, where the amount of tumour DNA in the blood is minimal.
By profiling epigenetic alterations instead of mutations, the team was able to identify thousands of modifications unique to each cancer type. Then, using a big data approach, they applied machine learning to create classifiers able to identify the presence of cancer-derived DNA within blood samples and to determine what cancer type. This basically turns the one needle in the haystack problem into a more solvable thousands of needles in the haystack, where the computer just needs to find a few needles to define which haystack has needles.
The scientists tracked the cancer origin and type by comparing 300 patient tumour samples from seven disease sites (lung, pancreatic, colorectal, breast, leukemia, bladder and kidney) and samples from healthy donors with the analysis of cell-free DNA circulating in the blood plasma. In every sample, the floating plasma DNA matched the tumour DNA. The team has since expanded the research and has now profiled and successfully matched more than 700 tumour and blood samples from more cancer types.
Beyond the lab, next steps to further validate this approach include analysing data from large population health research studies already under way in several countries, where blood samples were collected months to years before cancer diagnosis. Then the approach will need to be ultimately validated in prospective studies for cancer screening.
Dr. De Carvalho is a trained immunologist (University of Sao Paulo, Brazil) with postdoctoral training in cancer epigenomics (University of Southern California, USA) whose research focuses on cancer epigenetics. He holds the Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy and is an Associate Professor in Cancer Epigenetics, Department of Medical Biophysics, University of Toronto.
The research was supported by University of Toronto s McLaughlin Centre, Canadian Institutes of Health Research, Canadian Cancer Society, Ontario Institute for Cancer Research through the Province of Ontario, and The Princess Margaret Cancer Foundation.
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Materials provided by University Health Network. Note: Content may be edited for style and length.
Journal Reference:
Shu Yi Shen, Rajat Singhania, Gordon Fehringer, Ankur Chakravarthy, Michael H. A. Roehrl, Dianne Chadwick, Philip C. Zuzarte, Ayelet Borgida, Ting Ting Wang, Tiantian Li, Olena Kis, Zhen Zhao, Anna Spreafico, Tiago da Silva Medina, Yadon Wang, David Roulois, Ilias Ettayebi, Zhuo Chen, Signy Chow, Tracy Murphy, Andrea Arruda, Grainne M. O’Kane, Jessica Liu, Mark Mansour, John D. McPherson, Catherine O’Brien, Natasha Leighl, Philippe L. Bedard, Neil Fleshner, Geoffrey Liu, Mark D. Minden, Steven Gallinger, Anna Goldenberg, Trevor J. Pugh, Michael M. Hoffman, Scott V. Bratman, Rayjean J. Hung, Daniel D. De Carvalho. Sensitive tumour detection and classification using plasma

Degenerating hair cells in the inner ear can be made to function again, suggests a new report.

There are more than 300 genetic defects that have been found to prevent the hair cells in the human inner ear  the sensory cells of the ear as it were, from working properly. This can result in severe hearing impairment and even to complete hearing loss. Together with researchers at the Medical School in Harvard, Boston, Lukas Landegger of MedUni Vienna s Department of Ear, Nose and Throat Diseases has now succeeded, for the very first time, to repair this defect in an animal model -- by using a modified, non-pathogenic adeno-associated virus (Anc80L65), which is introduced into the ear by way of a Trojan Horse to deliver genes to restore the functionality of the damaged hair cells.
The study has been published in the leading journal Nature Biotechnology. Lukas Landegger is doing his PhD at MedUni Vienna and is currently working at Harvard as part of his course.
At the moment, ENT experts are able to use cochlea implants as a technical solution for restoring the hearing of people with congenital hearing loss. The Medical University of Vienna has been a global leader in the development and use of cochlear implants since 1977, when the world s first multichannel cochlear implant was implanted in Vienna. However, these electronic implants with their twelve electrodes cannot 100% replace the more than 3,000 hair cells in the inner ear, which give as much finer hearing, says Wolfgang Gstöttner, Head of the ENT Department at MedUni Vienna.
Adeno-associated virus as a gene vector
The commonest form of congenital deafness in children is due to the genetic mutation of GJB2 and GJB6. This mutation prevents the protein connexin 26, which is responsible for the cells in the cell complex of the inner ear, from working properly. As a result, the small hairs in the cochlea do not form properly or do not function properly. However, so far no-one has successfully managed to introduce the repair genes into the hair cells to start them working again. The basis for correcting this and many other mutations has now been created in an animal model with the non-pathogenic adeno-associated virus (AAV) replicated in the laboratory. This virus is infiltrated into the hair cells as a gene vector (carrier). What was surprising was that, in addition to the inner hair cells that are responsible for signal transduction, it was also possible to treat the 90% of outer hair cells, which perform an important amplification function in the inner ear and have hitherto been virtually inaccessible for gene therapy. This adeno-associated virus has already been used for restoring liver cells and in the retina.
Once the functionality of the virus had been initially proven in the treatment of a mouse model for Usher syndrome, which is the commonest cause of deafblindness worldwide (Pan et al. Nat Biotechnol 2017), further studies are required to determine the tolerability of the vector, so that this approach will soon be available for treating newborn babies with congenital hearing loss.

Scientists are developing a new approach to restore the hearing loss.

Researchers have taken an important step toward what may become a new approach to restore the hearing loss. In a new study, out today in the European Journal of Neuroscience, scientists have been able to regrow the sensory hair cells found in the cochlea -- a part of the inner ear -- that converts sound vibrations into electrical signals and can be permanently lost due to age or noise damage.
Hearing impairment has long been accepted as a fact of life for the aging population -- an estimated 30 million Americans suffer from some degree of hearing loss. However, scientists have long observed that other animals -- namely birds, frogs, and fish -- have been shown to have the ability to regenerate lost sensory hair cells.
It s funny, but mammals are the oddballs in the animal kingdom when it comes to cochlear regeneration, said Jingyuan Zhang, Ph.D., with the University of Rochester Department of Biology and a co-author of the study. We re the only vertebrates that can t do it.
Research conducted in the lab of Patricia White, Ph.D., in 2012 identified a family of receptors -- called epidermal growth factor (EGF) -- responsible for activating support cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. She speculated that this signaling pathway could potentially be manipulated to produce a similar result in mammals. White is a research associate professor in the University of Rochester Medical Center (URMC) Del Monte Institute for Neuroscience and lead author of the current study.
In mice, the cochlea expresses EGF receptors throughout the animal s life, but they apparently never drive regeneration of hair cells, said White. Perhaps during mammalian evolution, there have been changes in the expression of intracellular regulators of EGF receptor family signaling. Those regulators could have altered the outcome of signaling, blocking regeneration. Our research is focused on finding a way switch the pathway temporarily, in order to promote both regeneration of hair cells and their integration with nerve cells, both of which are critical for hearing.
In the new study, which involved researchers from URMC and the Massachusetts Ear and Eye Infirmary, which is part of Harvard Medical School, the team tested the theory that signaling from the EGF family of receptors could play a role in cochlear regeneration in mammals. The researchers focused on a specific receptor called ERBB2 which is found in cochlear support cells.
The researchers investigated a number of different methods to activate the EGF signaling pathway. One set of experiments involved using a virus to target ERBB2 receptors. Another, involved mice genetically modified to overexpress an activated ERBB2. A third experiment involved testing two drugs, originally developed to stimulate stem cell activity in the eyes and pancreas, that are known activate ERBB2 signaling.
The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to proliferate and start the process of activating other neighboring stem cells to become new sensory hair cells. Furthermore, it appears that this process not only could impact the regeneration of sensory hair cells, but also support their integration with nerve cells.
The process of repairing hearing is a complex problem and requires a series of cellular events, said White. You have to regenerate sensory hair cells and these cells have to function properly and connect with the necessary network of neurons. This research demonstrates a signaling pathway that can be activated by different methods and could represent a new approach to cochlear regeneration and, ultimately, restoration of hearing

Drinking water lowers the risk of bladder infections

Bladder infections are extremely common among women. New research, however, shows that boosting water intake might reduce these infections by almost half.
a woman drinking water
Drinking plenty of water can help keep UTIs at bay.
A urinary tract infection (UTI) can affect any part of the urinary tract, including the urethra, bladder, ureters, or kidneys.
A bladder infection is the most common type of UTI.
Approximately half of all women will experience a UTI in their lifetime.
For those who experience this type of infection once, a solid 25 percent can expect to have another later on in life.
Women are likelier to develop a bladder infection than men due to differing anatomy — the female urethra is shorter than that of men, which means that bacteria can reach the bladder more easily.
Also, the urethra opening is closer to the rectum in women, and the rectum houses lots of bacteria. These bacteria are most commonly associated with UTIs.
Bladder infections, when caught early, don t usually cause serious complications, and they are easily treated with antibiotics.
If not treated, however, they can lead to kidney infections. Symptoms of bladder infections include a burning feeling while passing urine and frequent or intense urges to go to the bathroom, even if there is not a lot of urine to pass.
The new research, which was led by senior study author Dr. Yair Lotan, from the Simmons Cancer Center at the University of Texas Southwestern in Dallas, is now published in the journal JAMA Internal Medicine.

Existing drug shows promise for treating aggressive breast cancer

An existing antipsychotic drug could become the first targeted treatment for an aggressive type of breast cancer that is hard to treat.
Antipsychotic needle
An existing drug may help in the fight against breast cancer.
A study led by the University of Bradford in the United Kingdom reveals that the drug pimozide can reduce cancer cell numbers, growth, and spread in triple-negative breast cancer.
In a paper that is to feature in the journal Oncotarget, the researchers describe how they used laboratory cells and mice implanted with tumors to demonstrate the drug s effect.
Some of the tests they carried out also suggest that pimozide could be effective against non-small cell lung cancer, which is the most common form of lung cancer.
Following this success, the team has applied for a patent and intends to start clinical trials in humans as soon as funds permit.

Antibiotic may prevent breast cancer recurrence

One of cancer researchers top priorities is discovering ways to reduce the risk that cancer will recur or metastasize. A recent, small-scale study may have found a common, cost-effective drug that does just that.
Breast cancer cell
An antibiotic might help prevent breast cancer from coming back.
Cancer stem cells (CSCs), also known as tumor-initiating cells, are a hot topic among researchers.
These cells are resistant to current treatments and play a significant role in both metastasis and recurrence, which are two of the biggest challenges in cancer treatment.
Because of this, finding successful ways of clearing up CSCs is of great interest.
Researchers from the University of Salford in the United Kingdom may have uncovered a treatment that could play an important role.
These scientists spend their time testing drugs that the Food and Drug Administration (FDA) have already approved. They investigate whether any existing medicines might also be able to help in the fight against cancer.
Concentrating on drugs in this way means that if they do find an existing drug that works against cancer, it could potentially reach the clinic faster.
In a recent paper now published in the journal Frontiers in Oncology, the scientists outline the potential use of an antibiotic called doxycycline to clear up CSCs.

How can gold help repair muscle injuries?

Researchers have revealed that nanoparticles of gold, attached to natural anti-inflammatory agents, work well on inflammation and can also promote muscle regeneration.
a man with knee pain
Scientists now believe that we can use gold to help treat muscle injuries.
Muscle injuries can take a while to recover from. This is because inflammation that occurs soon after an injury can hang on for some time.
That inflammation might also be very easy to re-aggravate.
However, there may be some good news on the horizon for those with muscle strains or tears.
Scientists have now designed a way to combine a natural anti-inflammatory agent with tiny bits of gold.
They recently published the new findings in the Proceedings of the National Academy of Sciences.
Reducing inflammation
It has been known for some time that injections of an anti-inflammatory cytokine called interleukin 4 (IL-4) into an injured muscle can help that muscle recover faster.
There is a caveat, however; the substance breaks down quickly and requires multiple applications that can result in unwelcome side effects. The solution to this problem might (literally) be golden.