Scientists from Singapore have streamlined the process of using human stem cells to mass produce GABAergic neurons (GNs) in the laboratory. This new protocol provides scientists with a robust source of GNs to study many psychiatric and neurological disorders such as autism, schizophrenia, and epilepsy, which are thought to develop at least in part due to GN dysfunction.
GNs are inhibitory neurons that reduce neuronal activation, and make up roughly 20 per cent of the human brain. They work alongside excitatory neurons (ENs) to ensure balanced neural activity for normal brain function. The coordinated interplay between GNs and ENs orchestrate specific activation patterns in the brain, which are responsible for our behaviour, emotions, and higher reasoning. Functional impairment of GNs results in imbalanced neural activity, thereby contributing to the symptoms observed in many psychiatric disorders.
The availability of high quality, functional human GN populations would facilitate the development of good models for studying psychiatric disorders, as well as for screening drug effects on specific populations of neurons. Scientists worldwide have been hard at work trying to generate a consistent supply of GNs in the laboratory, but have been faced with many challenges. Protocols involving multiple complex stages, poor yield, and requiring a long time to generate mature and functional GNs are just some of the limitations encountered.
Many of these limitations have now been overcome by the development of a rapid and robust protocol to generate GNs from human pluripotent stem cells (hPSCs) in a single step. With the addition of a specific combination of factors, hPSCs turn into mature and functional GNs in a mere six – eight weeks. This is about two – three times faster than the 10 - 30 weeks required for previous protocols. In addition, this new protocol is highly efficient, with GNs making up more than 80 per cent of the final neuron population.
To develop this protocol, the team from Duke-NUS Medical School (Duke-NUS), A*STAR’s Genome Institute of Singapore (GIS) and the National Neuroscience Institute (NNI) first identified genetic factors involved in GN development in the brain. The team then tried many different combinations of these factors, and succeeded in confirming that mature and functional human GNs were indeed generated.
“Just like how a balance of Yin and Yang is needed in order to stay healthy, a balance of ENs and GNs is required for normal brain function. We now know a fair bit about ENs because we have good protocols to make them. However, we still know very little of the other player, the GNs, because current protocols do not work well. Yet, when these GNs malfunction our brain goes haywire,” commented Dr Alfred Sun, a Research Fellow at NNI and co-first author of the publication alongside Mr Qiang Yuan, an NUS Graduate School PhD student.
“Our quick, efficient and easy way to mass produce GNs for lab use is a game changer for neuroscience and drug discovery. With increased recognition of the essential role of GNs in almost all neurological and psychiatric diseases, we envisage our new method to be widely used to advance research and drug screening,” said Dr Shawn Je, Assistant Professor in the Neuroscience and Behavioural Disorders Programme at Duke-NUS, and senior author of the study.
The speed and efficiency of generating GNs with this new protocol provides researchers unprecedented access to the quantities of neurons necessary for studying the role of GNs in disease mechanisms. Drugs and small molecules may now be screened at an unparalleled rate to discover the next blockbuster treatment for autism, schizophrenia, and epilepsy.
According to legend, Pythagoras invented a cup to prevent his students from drinking too greedily. If they overfilled the cup, it would immediately drain out all the fluid. The trick works thanks to a U-shaped tube in the center of the cup. As long as the liquid level is below the highest point in the U-tube, only the entrance side of the tube will be filled. As soon as the liquid level in the cup is higher, the weight of all that fluid forces liquid up and around the bend. This kicks off a siphoning effect that pulls all the fluid out. Coincidentally, this is the same way that toilet flushing works! Pulling the handle releases extra water into the bowl that raises the fluid level higher than the highest point in a U-bend. That establishes a siphon, which (provided nothing has clogged the pipe), empties the toilet bowl. (Video credit: Periodic Videos)
Warrior of the grassland - Anup Deodhar - The Comedy Wildlife.
Neuroscientists call for deep collaboration to ‘crack’ the human brain
The time is ripe, the communication technology is available, for teams from different labs and different countries to join efforts and apply new forms of grassroots collaborative research in brain science. This is the right way to gradually upscale the study of the brain so as to usher it into the era of Big Science, claim neuroscientists in Portugal, Switzerland and the United Kingdom. And they are already putting ideas into action.
In a Comment in the journal Nature, an international trio of neuroscientists outlines a concrete proposal for jump-starting a new, bottom-up, collaborative “big science” approach to neuroscience research, which they consider crucial to tackle the still unsolved great mysteries of the brain.
How does the brain function, from molecules to cells to circuits to brain systems to behavior? How are all these levels of complexity integrated to ultimately allow consciousness to emerge in the human brain?
The plan now proposed by Zach Mainen, director of research at the Champalimaud Centre for the Unknown, in Lisbon, Portugal; Michael Häusser, professor of Neuroscience at University College London, United Kingdom; and Alexandre Pouget, professor of neuroscience at the University of Geneva, Switzerland, is inspired by the way particle physics teams nowadays mount their huge accelerator experiments to discover new subatomic particles and ultimately to understand the evolution of the Universe.
“Some very large physics collaborations have precise goals and are self-organized”, says Zach Mainen. More specifically, his model is the ATLAS experiment at the European Laboratory of Particle Physics (CERN, near Geneva), which includes nearly 3,000 scientists from tens of countries and was able (together with its “sister” experiment, CMS) to announce the discovery of the long-sought Higgs boson in July 2012.
Although the size of the teams involved in neuroscience may not be nearly comparable to the CERN teams, the collaborative principles should be very similar, according to Zach Mainen. “What we propose is very much in the physics style, a kind of 'Grand Unified Theory’ of brain research, he says. "Can we do it? Clearly, it’s not going to happen within five years, but we do have theories that need to be tested, and the underlying principles of how to do it will be much the same as in physics.”
To help push neuroscience research to take the leap into the future, the three neuroscientists propose some simple principles, at least in theory: “focus on a single brain function”; “combine experimentalists and theorists”; “standardize tools and methods”; “share data”; “assign credit in new ways”. And one of the fundamental premises to make this possible is to “engender a sphere of trust within which it is safe [to share] data, resources and plans”, they write.
Needless to say, the harsh competitiveness of the field is not a fertile ground for this type of “deep” collaborative effort. But the authors themselves are already putting into practice the principles they advocate in their article.
“We have a group of 20 researchers (10 theorists and 10 experimentalists), about half in the US and half in the UK, Switzerland and Portugal” says Zach Mainen. The group will focus on only one well-defined goal: the foraging behavior for food and water resources in the mouse, recording activity from as much of the brain as possible - at least several dozen brain areas.
“By collaboration, we don’t mean business as usual; we really mean it”, concludes Zach Mainen. “We’ll have 10 labs doing the same experiments, with the same gear, the same computer programs. The data we will obtain will go into the cloud and be shared by the 20 labs. It’ll be almost as a global lab, except it will be distributed geographically.”
An ultralight high-performance mechanical watch made with graphene is unveiled today in Geneva at the Salon International De La Haute Horlogerie thanks to a unique collaboration.
The University of Manchester has collaborated with watchmaking brand Richard Mille and McLaren F1 to create world’s lightest mechanical chronograph by pairing leading graphene research with precision engineering.
The RM 50-03 watch was made using a unique composite incorporating graphene to manufacture a strong but lightweight new case to house the delicate watch mechanism. The graphene composite known as Graph TPT weighs less than previous similar materials used in watchmaking.
Graphene is the world’s first two-dimensional material at just one-atom thick. It was first isolated at The University of Manchester in 2004 and has the potential to revolutionise a large number of applications including, high-performance composites for the automotive and aerospace industries, as well as flexible, bendable mobile phones and tablets and next-generation energy storage.
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“She has autonomy. She has a strong will. But she can’t move. So in many ways her life is my life. It’s bigger than me, it controls me, and it makes me fight like never before. We spend so much time together that she’s a part of me. She knows how important she is to me. She had childhood cancer. Her heart failed three times. And I was by her side the entire time. I never realized that I could love someone as much as this. She could never hurt me. She could never hurt anyone. We always ask her: ‘Are you angry?’, ‘Are you mad?’ And she always says ‘no.’ She laughs when I laugh. And right now I’m trying not to cry. Because she’ll cry if I cry.” (São Paulo, Brazil)
David Silverman @tubatron
1st appearance of Milhouse in 1st Butterfinger storyboard 11/18/1988 (missed the anni thing by a few weeks – )
(Image caption: Young neurons (pink), responsible for encoding new memories, must compete with mature neurons (green) to survive and integrate into the hippocampal circuit. Credit: Kathleen McAvoy, Sahay Lab)
Making memories stronger and more precise during aging
When it comes to the billions of neurons in your brain, what you see at birth is what get — except in the hippocampus. Buried deep underneath the folds of the cerebral cortex, neural stem cells in the hippocampus continue to generate new neurons, inciting a struggle between new and old as the new attempts to gain a foothold in the memory-forming center of the brain.
In a study published online in Neuron, Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General Hospital and the Broad Institute of MIT and Harvard in collaboration with an international team of scientists found they could bias the competition in favor of the newly generated neurons.
“The hippocampus allows us to form new memories of ‘what, when and where’ that help us navigate our lives,” said HSCI Principal Faculty member and the study’s corresponding author, Amar Sahay, PhD, “and neurogenesis—the generation of new neurons from stem cells—is critical for keeping similar memories separate.”
As the human brain matures, the connections between older neurons become stronger, more numerous, and more intertwined, making integration for the newly formed neurons more difficult. Neural stem cells become less productive, leading to a decline in neurogenesis. With fewer new neurons to help sort memories, the aging brain can become less efficient at keeping separate and faithfully retrieving memories.
The research team selectively overexpressed a transcription factor, Klf9, only in older neurons in mice, which eliminated more than one-fifth of their dendritic spines, increased the number of new neurons that integrated into the hippocampus circuitry by two-fold, and activated neural stem cells.
When the researchers returned the expression of Klf9 back to normal, the old dendritic spines reformed, restoring competition. However, the previously integrated neurons remained.
“Because we can do this reversibly, at any point in the animals life we can rejuvenate the hippocampus with extra, new, encoding units,” said Sahay, who is also an investigator with the MGH Center for Regenerative Medicine.
The authors employed a complementary strategy in which they deleted a protein important for dendritic spines, Rac1, only in the old neurons and achieved a similar outcome, increasing the survival of the new neurons.
In order to keep two similar memories separate, the hippocampus activates two different populations of neurons to encode each memory in a process called pattern separation. When there is overlap between these two populations, researchers believe it is more difficult for an individual to distinguish between two similar memories formed in two different contexts, to discriminate between a Sunday afternoon stroll through the woods from a patrol through enemy territory in a forest, for example. If the memories are encoded in overlapping populations of neurons, the hippocampus may inappropriately retrieve either. If the memories are encoded in non-overlapping populations of neurons, the hippocampus stores them separately and retrieves them only when appropriate.
Mice with increased neurogenesis had less overlap between the two populations of neurons and had more precise and stronger memories, which, according to Sahay, demonstrates improved pattern separation.
Mice with increased neurogenesis in middle age and aging cohorts exhibited better memory precision.
“We believe that by increasing the hippocampus’s ability to do what it supposed to do and not retrieve past experiences when it shouldn’t can help,” Sahay said. This may be particularly useful for individuals suffering from post-traumatic stress disorder, mild cognitive impairment, or age-related memory loss.
Friday, Oct. 20, NASA astronauts Randy Bresnik and Joe Acaba ventured outside the International Space Station for a 6 hour and 49 minute spacewalk. Just like you make improvements to your home on Earth, astronauts living in space periodically go outside the space station to make updates on their orbiting home.
All spacewalks begin inside the space station. Astronauts Paolo Nespoli and Mark Vande Hei helped each spacewalker put on their suit, known as an Extravehicular Mobility Unit (EMU).
They then enter an airlock and regulate the pressure so that they can enter the vacuum of space safely. If they did not regulate the pressure safely, the astronauts could experience something referred to as “the bends” – similar to scuba divers.
Once the two astronauts exited the airlock and were outside the space station, they went to their respective work stations.
Bresnik replaced a failed fuse on the end of the Dextre robotic arm extension, which helps capture visiting vehicles.
During that time, Acaba set up a portable foot restraint to help him get in the right position to install a new camera.
While he was getting set up, he realized that there was unexpected wearing on one of his safety tethers. Astronauts have multiple safety mechanisms for spacewalking, including a “jet pack” on their spacesuit. That way, in the unlikely instance they become untethered from the station, the are able to propel back to safety.
Bresnik was a great teammate and brought Acaba a spare safety tether to use.
Once Acaba secured himself in the foot restraint that was attached to the end of the station’s robotic arm, he was maneuvered into place to install a new HD camera. Who was moving the arm? Astronauts inside the station were carefully moving it into place!
And, ta da! Below you can see one of the first views from the new enhanced HD camera…(sorry, not a GIF).
After Acaba installed the new HD camera, he repaired the camera system on the end of the robotic arm’s hand. This ensures that the hand can see the vehicles that it’s capturing.
Bresnik, completed all of his planned tasks and moved on to a few “get ahead” tasks. He first started removing extra thermal insulation straps around some spare pumps. This will allow easier access to these spare parts if and when they’re needed in the future.
He then worked to install a new handle on the outside of space station. That’s a space drill in the above GIF.
After Acaba finished working on the robotic arm’s camera, he began greasing bearings on the new latching end effector (the arm’s “hand”), which was just installed on Oct. 5.
The duo completed all planned spacewalk tasks, cleaned up their work stations and headed back to the station’s airlock.
Once safely inside the airlock and pressure was restored to the proper levels, the duo was greeted by the crew onboard.
They took images of their spacesuits to document any possible tears, rips or stains, and took them off.
Coverage ended at 2:36 p.m. EDT after 6 hours and 49 minutes. We hope the pair was able to grab some dinner and take a break!
You can watch the entire spacewalk HERE, or follow @Space_Station on Twitter and Instagram for regular updates on the orbiting laboratory.
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