Exercise alters brain chemistry to protect aging synapses

 

Couple jogging in the park

When elderly people stay active, their brains have more of a class of proteins that enhances the connections between neurons to maintain healthy cognition, a UC San Francisco study has found.

This protective impact was found even in people whose brains at autopsy were riddled with toxic proteins associated with Alzheimer's and other neurodegenerative diseases.

"Our work is the first that uses human data to show that synaptic protein regulation is related to physical activity and may drive the beneficial cognitive outcomes we see," said Kaitlin Casaletto, PhD, an assistant professor of neurology and lead author on the study, which appears in the January 7 issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

The beneficial effects of physical activity on cognition have been shown in mice but have been much harder to demonstrate in people.

Casaletto, a neuropsychologist and member of the Weill Institute for Neurosciences, worked with William Honer, MD, a professor of psychiatry at the University of British Columbia and senior author of the study, to leverage data from the Memory and Aging Project at Rush University in Chicago. That project tracked the late-life physical activity of elderly participants, who also agreed to donate their brains when they died.

"Maintaining the integrity of these connections between neurons may be vital to fending off dementia, since the synapse is really the site where cognition happens," Casaletto said. "Physical activity -- a readily available tool -- may help boost this synaptic functioning."

More Proteins Mean Better Nerve Signals

Honer and Casaletto found that elderly people who remained active had higher levels of proteins that facilitate the exchange of information between neurons. This result dovetailed with Honer's earlier finding that people who had more of these proteins in their brains when they died were better able to maintain their cognition late in life.

To their surprise, Honer said, the researchers found that the effects ranged beyond the hippocampus, the brain's seat of memory, to encompass other brain regions associated with cognitive function.

"It may be that physical activity exerts a global sustaining effect, supporting and stimulating healthy function of proteins that facilitate synaptic transmission throughout the brain," Honer said.

Synapses Safeguard Brains Showing Signs of Dementia

The brains of most older adults accumulate amyloid and tau, toxic proteins that are the hallmarks of Alzheimer's disease pathology. Many scientists believe amyloid accumulates first, then tau, causing synapses and neurons to fall apart.

Casaletto previously found that synaptic integrity, whether measured in the spinal fluid of living adults or the brain tissue of autopsied adults, appeared to dampen the relationship between amyloid and tau, and between tau and neurodegeneration.

"In older adults with higher levels of the proteins associated with synaptic integrity, this cascade of neurotoxicity that leads to Alzheimer's disease appears to be attenuated," she said. "Taken together, these two studies show the potential importance of maintaining synaptic health to support the brain against Alzheimer's disease."

The ‘surprisingly simple’ arithmetic of smell

 

Locust

Smell a cup of coffee.

Smell it inside or outside; summer or winter; in a coffee shop with a scone; in a pizza parlor with pepperoni -- even at a pizza parlor with a scone! -- coffee smells like coffee.

Why don't other smells or different environmental factors "get in the way," so to speak, of the experience of smelling individual odors? Researchers at the McKelvey School of Engineering at Washington University in St. Louis turned to their trusted research subject, the locust, to find out.

What they found was "surprisingly simple," according to Barani Raman, professor of biomedical engineering. Their results were published in the journal Proceedings of the National Academy of Sciences.

Raman and colleagues have been working with locusts for years, watching their brains and their behaviors related to smell in an attempt to engineer bomb-sniffing locusts. Along the way, they've made substantial gains when it comes to understanding the mechanisms at play when it comes to locusts' sense of smell.

To understand how it is that a locust can consistently recognize smells regardless of context, they took a cue from Ivan Pavlov. Like Pavlov's dogs, locusts were trained to associate an odor with food, their preference being a blade of grass. After going a day without food, a locust was exposed to a puff of odor (a puff of hexanol or isoamyl acetate), then given a blade of grass. In as few as six such presentations, the locust learned to open its palps (sensory appendages close to the mouth) in expectation of a snack after simply smelling the "training odorant." Just like us recognizing coffee, the trained locust could recognize the odor and did not let other factors get in the way.

At this point, researchers began looking at which neurons were firing when the locust was exposed to the odor under different conditions, including in conjunction with other smells, in humid or dry conditions, when they were starved or fully fed, trained or untrained, and for different amounts of time.

Under different circumstances, it turned out, researchers saw highly inconsistent patterns of neurons were activated even though the locust palps opened every time. "The neural responses were highly variable," Raman said. "That seemed to be at odds with what the locusts were doing, behaviorally."

How could variable neural responses produce consistent or stable behavior? To probe this, researchers turned to a machine-learning algorithm. "We wanted to see if given these variable neural response patterns, can we predict the locust behavior?" Raman said. "The answer was yes, we can."

The algorithm turned out to be very simple to interpret. It exploited two functional types of neurons: there are ON neurons, which are activated when an odorant is present, and there are OFF neurons, which are silenced when an odorant is present but become activated after the odor presentation ends.

"You can think of the ON neurons as conveying 'evidence for' an odor being present, and OFF neurons as 'evidence against' that odor being present," Raman said. To recognize an odorant's presence, researchers simply needed to add evidence for the odorant being present (i.e. add the spikes across all ON neurons) and subtract evidence against that odor being present (i.e. add the spikes across all OFF neurons). If the result was above a certain threshold, machine learning would predict the locust smelled the odor.

"We were surprised to find that this simple approach is all that was needed to robustly recognize an odorant," Raman said.

Raman likened the process to shopping for a shirt. Say you have a list of qualities you're looking for -- cotton, long sleeves, button-down, solid color, maybe a front pocket to hold your glasses -- and a few dealbreakers, such as dry-clean only or polka dots.

You may get lucky and find a shirt that is precisely what you are looking for. But, more pragmatically, you would make a purchase as long as many of the features you are looking for are present and the majority of features that are deal breakers are not presen

Chemists use DNA to build the world’s tiniest antenna

Researchers at Université de Montréal have created a nanoantenna to monitor the motions of proteins. Reported this week in Nature Methods, the device is a new method to monitor the structural change of proteins over time -- and may go a long way to helping scientists better understand natural and human-designed nanotechnologies.

"The results are so exciting that we are currently working on setting up a start-up company to commercialize and make this nanoantenna available to most researchers and the pharmaceutical industry," said UdeM chemistry professor Alexis Vallée-Bélisle, the study's senior author.

An antenna that works like a two-way radio

Over 40 years ago, researchers invented the first DNA synthesizer to create molecules that encode genetic information. "In recent years, chemists have realized that DNA can also be employed to build a variety of nanostructures and nanomachines," added the researcher, who also holds the Canada Research Chair in Bioengineering and Bionanotechnology.

"Inspired by the 'Lego-like' properties of DNA, with building blocks that are typically 20,000 times smaller than a human hair, we have created a DNA-based fluorescent nanoantenna, that can help characterize the function of proteins." he said

"Like a two-way radio that can both receive and transmit radio waves, the fluorescent nanoantenna receives light in one colour, or wavelength, and depending on the protein movement it senses, then transmits light back in another colour, which we can detect."

One of the main innovations of these nanoantennae is that the receiver part of the antenna is also employed to sense the molecular surface of the protein studied via molecular interaction.

One of the main advantages of using DNA to engineer these nanoantennas is that DNA chemistry is relatively simple and programmable," said Scott Harroun, an UdeM doctoral student in chemistry and the study's first author.

"The DNA-based nanoantennas can be synthesized with different lengths and flexibilities to optimize their function," he said. "One can easily attach a fluorescent molecule to the DNA, and then attach this fluorescent nanoantenna to a biological nanomachine, such as an enzyme.

"By carefully tuning the nanoantenna design, we have created five nanometer-long antenna that produces a distinct signal when the protein is performing its biological function."

Fluorescent nanoantennas open many exciting avenues in biochemistry and nanotechnology, the scientists believe.

"For example, we were able to detect, in real time and for the first time, the function of the enzyme alkaline phosphatase with a variety of biological molecules and drugs," said Harroun. "This enzyme has been implicated in many diseases, including various cancers and intestinal inflammation.

"In addition to helping us understand how natural nanomachines function or malfunction, consequently leading to disease, this new method can also help chemists identify promising new drugs as well as guide nanoengineers to develop improved nanomachines," added Dominic Lauzon, a co-author of the study doing his PhD in chemistry at UdeM.

One main advance enabled by these nanoantennas is also their ease-of-use, the scientists said.

Securing data transfers with relativity

Data encryption concept photo illustration

The volume of data transferred is constantly increasing, but the absolute security of these exchanges cannot be guaranteed, as shown by cases of hacking frequently reported in the news. To counter hacking, a team from the University of Geneva (UNIGE), Switzerland, has developed a new system based on the concept of "zero-knowledge proofs," the security of which is based on the physical principle of relativity: information cannot travel faster than the speed of light. Thus, one of the fundamental principles of modern physics allows for secure data transfer. This system allows users to identify themselves in complete confidentiality without disclosing any personal information, promising applications in the field of cryptocurrencies and blockchain. These results can be read in the journal Nature.

When a person -- the so called 'prover' -- wants to confirm their identity, for example when they want to withdraw money from an ATM, they must provide their personal data to the verifier, in our example the bank, which processes this information (e.g. the identification number and the pin code). As long as only the prover and the verifier know this data, confidentiality is guaranteed. If others get hold of this information, for example by hacking into the bank's server, security is compromised.

Zero-knowledge proof as a solution

To counter this problem, the prover should ideally be able to confirm their identity, without revealing any information at all about their personal data. But is this even possible? Surprisingly the answer is yes, via the concept of a zero-knowledge proof. "Imagine I want to prove a mathematical theorem to a colleague. If I show them the steps of the proof, they will be convinced, but then have access to all the information and could easily reproduce the proof," explains Nicolas Brunner, a professor in the Department of Applied Physics at the UNIGE Faculty of Science. "On the contrary, with a zero-knowledge proof, I will be able to convince them that I know the proof, without giving away any information about it, thus preventing any possible data recovery."

The principle of zero-knowledge proof, invented in the mid-1980s, has been put into practice in recent years, notably for cryptocurrencies. However, these implementations suffer from a weakness, as they are based on a mathematical assumption (that a specific encoding function is difficult to decode). If this assumption is disproved -- which cannot be ruled out today -- security is compromised because the data would become accessible. Today, the Geneva team is demonstrating a radically different system in practice: a relativistic zero-knowledge proof. Security is based here on a physics concept, the principle of relativity, rather than on a mathematical hypothesis. The principle of relativity -- that information does not travel faster than light -- is a pillar of modern physics, unlikely to be ever challenged. The Geneva researchers' protocol therefore offers perfect security and is guaranteed over the long term.

Dual verification based on a three-colorability problem

Implementing a relativistic zero-knowledge proof involves two distant verifier/prover pairs and a challenging mathematical problem. "We use a three-colorability problem. This type of problem consists of a graph made up of a set of nodes connected or not by links," explains Hugo Zbinden, professor in the Department of Applied Physics at the UNIGE. Each node is given one out of three possible colours -- green, blue or red -- and two nodes that are linked together must be of different colours. These three-colouring problems, here featuring 5,000 nodes and 10,000 links, are in practice impossible to solve, as all possibilities must be tried. So why do we need two pairs of checker/prover?

"To confirm their identity, the provers will no longer have to provide a code, but demonstrate to the verifier that they know a way to three-colour a certain graph," continues Nicolas Brunner. To be sure, the verifiers will randomly choose a large number of pairs of nodes on the graph connected by a link, then ask their respective prover what colour the node is. Since this verification is done almost simultaneously, the provers cannot communicate with each other during the test, and therefore cannot cheat. Thus, if the two colours announced are always different, the verifiers are convinced of the identity of the provers, because they actually know a three-colouring of this graph. "It's like when the police interrogates two criminals at the same time in separate offices: it's a matter of checking that their answers match, without allowing them to communicate with each other," says Hugo Zbinden. In this case, the questions are almost simultaneous, so the provers cannot communicate with each other, as this information would have to travel faster than light, which is of course impossible. Finally, to prevent the verifiers from reproducing the graph, the two provers constantly change the colour code in a correlated manner: what was green becomes blue, blue becomes red, etc. "In this way, the proof is made and verified, without revealing any information about it," says the Geneva-based physicist.

 

Keep Walking

The calf muscle in your legs is your second heart.

 

Everyone knows that the heart pumps blood, right? But did you know that your body has a second blood pump? It’s your calf muscles! That’s right, the calf muscles in your legs are your second heart! 

The human body is engineered such that when you walk, the calf muscles pump venous blood back toward your heart.

The veins in your calf act like a reservoir for blood your body does not need in circulation at any given time. These reservoir veins are called muscle venous sinuses. When the calf muscle contracts, blood is squeezed out of the veins and pushed up along the venous system. These veins have one-way valves which keep the blood flowing in the correct direction toward the heart, and also prevent gravity from pulling blood back down your legs.

Walking or running enables your foot to  play a major role in the pumping mechanism of the calves. The foot itself also has its own (smaller) venous reservoir. During the first motion of taking a step, as you put weight on your foot, the foot venous reservoir blood is squeezed out and ‘primes’ the calf reservoir. Then, in the later stages of a step, the calf muscle contracts and pumps the blood up the leg, against gravity. The valves keep the blood flowing in the right direction and prevents gravity from pulling the blood right back down.

Thus, when you are immobile for long periods of time (sitting in an airplane, car seat, or chair for hours) your calf muscle is not contracting much and the blood stagnates.

That’s why walking or running is so good for overall blood circulation. It prevents blood pooling and helps prevent potentially dangerous blood clots called deep vein thrombosis(DVT).

Another condition called venous insufficiency, or venous reflux can cause blood to pool in your legs due to the failure of the valves to work properly. In this condition, the valves fail to prevent the backflow of blood down your legs. Symptoms of venous insufficiency can include heavy, tired, throbbing, painful legs, ankle swelling, bulging varicose veins, cramps, itching, restless leg, skin discolouration and even skin ulceration. Venous insufficiency is a very common disorder, affecting over 40 million people in the U.S.

In cases when a person is even more immobile, such as laying in a hospital bed, the pooled blood can become stagnant and develop into a blood clot. This is called a deep vein thrombosis (DVT). DVT can cause leg pain and swelling and is dangerous because a blood clot can break off and travel in your blood stream and get lodged in your lungs.

- By Louis Prevosti, MD