Computers Worldwide Are Vulnerable to Attack

A team of computer science researchers has uncovered a line of attack that breaks all Spectre defenses, meaning that billions of computers and other devices across the globe are just as vulnerable today as they were when Spectre was first announced.

From:  University of Virginia School of Engineering and Applied Science

April 30, 2021 -- In 2018, industry and academic researchers revealed a potentially devastating hardware flaw that made computers and other devices worldwide vulnerable to attack.

Researchers named the vulnerability Spectre because the flaw was built into modern computer processors that get their speed from a technique called "speculative execution," in which the processor predicts instructions it might end up executing and preps by following the predicted path to pull the instructions from memory. A Spectre attack tricks the processor into executing instructions along the wrong path. Even though the processor recovers and correctly completes its task, hackers can access confidential data while the processor is heading the wrong way.

Since Spectre was discovered, the world's most talented computer scientists from industry and academia have worked on software patches and hardware defenses, confident they've been able to protect the most vulnerable points in the speculative execution process without slowing down computing speeds too much.

They will have to go back to the drawing board.

A team of University of Virginia School of Engineering computer science researchers has uncovered a line of attack that breaks all Spectre defenses, meaning that billions of computers and other devices across the globe are just as vulnerable today as they were when Spectre was first announced. The team reported its discovery to international chip makers in April and will present the new challenge at a worldwide computing architecture conference in June.

The researchers, led by Ashish Venkat, William Wulf Career Enhancement Assistant Professor of Computer Science at UVA Engineering, found a whole new way for hackers to exploit something called a "micro-op cache," which speeds up computing by storing simple commands and allowing the processor to fetch them quickly and early in the speculative execution process. Micro-op caches have been built into Intel computers manufactured since 2011.

Venkat's team discovered that hackers can steal data when a processor fetches commands from the micro-op cache.

"Think about a hypothetical airport security scenario where TSA lets you in without checking your boarding pass because (1) it is fast and efficient, and (2) you will be checked for your boarding pass at the gate anyway," Venkat said. "A computer processor does something similar. It predicts that the check will pass and could let instructions into the pipeline. Ultimately, if the prediction is incorrect, it will throw those instructions out of the pipeline, but this might be too late because those instructions could leave side-effects while waiting in the pipeline that an attacker could later exploit to infer secrets such as a password."

Because all current Spectre defenses protect the processor in a later stage of speculative execution, they are useless in the face of Venkat's team's new attacks. Two variants of the attacks the team discovered can steal speculatively accessed information from Intel and AMD processors.

"Intel's suggested defense against Spectre, which is called LFENCE, places sensitive code in a waiting area until the security checks are executed, and only then is the sensitive code allowed to execute," Venkat said. "But it turns out the walls of this waiting area have ears, which our attack exploits. We show how an attacker can smuggle secrets through the micro-op cache by using it as a covert channel."

Venkat's team includes three of his computer science graduate students, Ph.D. student Xida Ren, Ph.D. student Logan Moody and master's degree recipient Matthew Jordan. The UVA team collaborated with Dean Tullsen, professor of the Department of Computer Science and Engineering at the University of California, San Diego, and his Ph.D. student Mohammadkazem Taram to reverse-engineer certain undocumented features in Intel and AMD processors.

They have detailed the findings in their paper: "I See Dead ?ops: Leaking Secrets via Intel/AMD Micro-Op Caches."

This newly discovered vulnerability will be much harder to fix.

"In the case of the previous Spectre attacks, developers have come up with a relatively easy way to prevent any sort of attack without a major performance penalty" for computing, Moody said. "The difference with this attack is you take a much greater performance penalty than those previous attacks."

"Patches that disable the micro-op cache or halt speculative execution on legacy hardware would effectively roll back critical performance innovations in most modern Intel and AMD processors, and this just isn't feasible," Ren, the lead student author, said.

"It is really unclear how to solve this problem in a way that offers high performance to legacy hardware, but we have to make it work," Venkat said. "Securing the micro-op cache is an interesting line of research and one that we are considering."

Venkat's team has disclosed the vulnerability to the product security teams at Intel and AMD. Ren and Moody gave a tech talk at Intel Labs worldwide April 27 to discuss the impact and potential fixes. Venkat expects computer scientists in academia and industry to work quickly together, as they did with Spectre, to find solutions.

The team's paper has been accepted by the highly competitive International Symposium on Computer Architecture, or ISCA. The annual ISCA conference is the leading forum for new ideas and research results in computer architecture and will be held virtually in June.

Venkat is also working in close collaboration with the Processor Architecture Team at Intel Labs on other micro-architectural innovations, through the National Science Foundation/Intel Partnership on Foundational Microarchitecture Research Program.

Venkat was well prepared to lead the UVA research team into this discovery. He has forged a long-running partnership with Intel that started in 2012 when he interned with the company while he was a computer science graduate student at the University of California, San Diego.

This research, like other projects Venkat leads, is funded by the National Science Foundation and Defense Advanced Research Projects Agency.

Venkat is also one of the university researchers who co-authored a paper with collaborators Mohammadkazem Taram and Tullsen from UC San Diego that introduce a more targeted microcode-based defense against Spectre. Context-sensitive fencing, as it is called, allows the processor to patch running code with speculation fences on the fly.

Introducing one of just a handful more targeted microcode-based defenses developed to stop Spectre in its tracks, "Context-Sensitive Fencing: Securing Speculative Execution via Microcode Customization" was published at the ACM International Conference on Architectural Support for Programming Languages and Operating Systems in April 2019. The paper was also selected as a top pick among all computer architecture, computer security, and VLSI design conference papers published in the six-year period between 2014 and 2019.

The new Spectre variants Venkat's team discovered even break the context-sensitive fencing mechanism outlined in Venkat's award-winning paper. But in this type of research, breaking your own defense is just another big win. Each security improvement allows researchers to dig even deeper into the hardware and uncover more flaws, which is exactly what Venkat's research group did.

Computer scientists discover new vulnerability affecting computers globally -- ScienceDaily 

Lithium Battery Parts Can Be Recycled

New recycling method, without crushing or melting, replenishes lithium in electrodes while keeping existing structure intact – and performance is nearly as good as new ones

From:  Aalto University (in Finland)

April 22, 2021 -- The proliferation of electric cars, smartphones, and portable devices is leading to an estimated 25 percent increase globally in the manufacturing of rechargeable batteries each year. Many raw materials used in the batteries, such as cobalt, may soon be in short supply. The European Commission is preparing a new battery decree, which would require the recycling of 95 percent of the cobalt in batteries. Yet existing battery recycling methods are far from perfect.

Researchers at Aalto University have now discovered that electrodes in lithium batteries containing cobalt can be reused as is after being newly saturated with lithium. In comparison to traditional recycling, which typically extracts metals from crushed batteries by melting or dissolving them, the new process saves valuable raw materials, and likely also energy.

‘In our earlier study of how lithium cobalt oxide batteries age, we noticed that one of the main causes of battery deterioration is the depletion of lithium in the electrode material. The structures can nevertheless remain relatively stable, so we wanted to see if they can be reused,’ explains Professor Tanja Kallio at Aalto University.

Almost like new

Rechargeable lithium-ion batteries have two electrodes between which electrically charged particles move. Lithium cobalt oxide is used in one electrode and, in most of the batteries, the other is made of carbon and copper.

In traditional battery recycling methods, some of batteries’ raw materials are lost and lithium cobalt oxide turns into other cobalt compounds, which require a lengthy chemical refinement process to turn them back into electrode material. The new method sidesteps this painstaking process: by replenishing the spent lithium in the electrode through an electrolysis process, commonly used in industry, the cobalt compound can be directly reused.

The results show that the performance of electrodes newly saturated with lithium is almost as good as that of those made of new material. Kallio believes that with further development the method would also work on an industrial scale.

‘By reusing the structures of batteries we can avoid a lot of the labour that is common in recycling and potentially save energy at the same time. We believe that the method could help companies that are developing industrial recycling,’ Kallio says.

The researchers next aim to see if the same method could also be used with the nickel-based batteries of electric cars.

The research was published in ChemSusChem journal.

https://www.aalto.fi/en/news/battery-parts-can-be-recycled-without-crushing-or-melting

Australia Populated from New Guinea?

First Australian populations followed footpath ‘superhighways’ across the continent of Australia/New Guinea

From: Santa Fe Institute

April 29, 2021 -- The best path across the desert is rarely the straightest. For the first human inhabitants of Sahul — the super-continent that underlies modern Australia and New Guinea — camping at the next spring, stream, or rock shelter allowed them to thrive for hundreds of generations. Those who successfully traversed the landmarks made their way across the continent, spreading from their landfall in the Northwest across the continent, making their way to all corners of Australia and New Guinea.

By simulating the physiology and decisions of early way-finders, an international team* of archaeologists, geographers, ecologists, and computer scientists has mapped the probable “superhighways” that led to the first peopling of the Australian continent some 50,000-70,000 years ago. Their study, published in Nature Human Behaviour, is the largest reconstruction of a network of human migration paths into a new landscape. It is also the first to apply rigorous computational analysis at the continental scale, testing 125 billion possible pathways.

"We decided it would be really interesting to look at this question of human migration because the ways that we conceptualize a landscape should be relatively steady for a hiker in the 21st century and a person who was way-finding into a new region 70,000 years ago,” says archaeologist and computational social scientist Stefani Crabtree, who led the study. Crabtree is a Complexity Fellow at the Santa Fe Institute and Assistant Professor at Utah State University. “If it's a new landscape and we don't have a map, we're going to want to know how to efficiently move throughout a space, where to find water, and where to camp — and we'll orient ourselves based on high points around the lands.”

“One of the really big unanswered questions of prehistory is how Australia was populated in the distant past. Scholars have debated it for at least a hundred and fifty years,” says co-author Devin White, an archaeologist and remote sensing scientist at Sandia National Laboratories. “It is the largest and most complex project of its kind that I’d ever been asked to take on.” 

To re-create the migrations across Sahul, the researchers first needed to simulate the topography of the supercontinent. They “drained” the oceans that now separate mainland Australia from New Guinea and Tasmania. Then, using hydrological and paleo-geographical data, they reconstructed inland lakes, major rivers, promontory rocks, and mountain ranges that would have attracted the gaze of a wandering human.

Next, the researchers programmed in-silico stand-ins for the human travelers. The team adapted an algorithm called “From Everywhere to Everywhere,” created by White*, to program the way-finders based on the caloric needs of a 25-year-old female carrying 10 kg of water and tools.

The researchers imbued these individuals with the realistic goal of staying alive, which could be achieved by finding water sources. Like backcountry hikers, the digital travelers were drawn to prominent landmarks like rocks and foothills, and the program exacted a caloric toll for activities such as hiking uphill within the artificial landscape. 

When the researchers “landed” the way-finders at two points on the coast of the re-created continent, they began to traverse it, using landmarks to navigate in search of freshwater. The algorithms simulated a staggering 125 billion possible pathways, run on a Sandia supercomputer, and a pattern emerged: the most-frequently traveled routes carved distinct “superhighways” across the continent, forming a notable ring-shaped road around the right portion of Australia; a western road; and roads that transect the continent. A subset of these superhighways map to archaeological sites where early rock art, charcoal, shell, and quartz tools have been found.

“Australia’s not only the driest, but it’s also the flattest populated continent on Earth,” says co-author Sean Ulm, an archaeologist and Distinguished Professor at James Cook University. Ulm is also Deputy Director of the Australian Research Council Centre of Excellence for Australian Biodiversity and Heritage (CABAH), whose researchers contributed to the project. “Our research shows that prominent landscape features and water sources were critical for people to navigate and survive on the continent. In many Aboriginal societies, landscape features are known to have been created by ancestral beings during the Dreaming. Every ridgeline, hill, river, beach and water source is named, storied and inscribed into the very fabric of societies, emphasising the intimate relationship between people and place. The landscape is literally woven into peoples’ lives and their histories. It seems that these relationships between people and Country probably date back to the earliest peopling of the continent.”

The results suggest that there are fundamental rules humans follow as they move into new landscapes and that the researchers’ approach could shed light on other major migrations in human history, such as the first waves of migration out of Africa at least 120,000 years ago.

Future work, Crabtree says, could inform the search for undiscovered archaeological sites, or even apply the techniques to forecast the movements of human migration in the near future, as populations flee drowning coastlines and climate disruptions.

Read the paper, “Landscape rules predict optimal superhighways for the first peopling of Sahul” in Nature Human Behaviour (April 29, 2021)

https://www.santafe.edu/news-center/news/first-australian-populations-followed-footpath-superhighways-across-continent

The Possibility of Life on Mars

The possibility of life on Mars is a subject of interest in astrobiology due to its proximity and similarities to Earth.  To date, no proof of past or present life has been found on Mars.  Cumulative evidence suggests that during the ancient Noachian time period, the surface environment of Mars had liquid water and may have been habitable for microorganisms. But, the existence of habitable conditions does not necessarily indicate the presence of life.

Scientific searches for evidence of life began in the 19th century and continue today via telescopic investigations and deployed probes. While early work focused on phenomenology and bordered on fantasy, the modern scientific inquiry has emphasized the search for water, chemical biosignatures in the soil and rocks at the planet's surface, and biomarker gases in the atmosphere.

Mars is of particular interest for the study of the origins of life because of its similarity to the early Earth. This is especially so since Mars has a cold climate and lacks plate tectonics or continental drift, so has remained almost unchanged since the end of the Hesperian period. At least two thirds of Mars' surface is more than 3.5 billion years old, and Mars may thus hold the best record of the prebiotic conditions leading to life, even if life does not or has never existed there, which might have started developing as early as 4.48 billion years ago.

Following the confirmation of the past existence of surface liquid water, the Curiosity, Perseverance and Opportunity rovers started searching for evidence of past life, including a past biosphere based on autotrophic, chemotrophic, or chemolithoautotrophic microorganisms, as well as ancient water, including fluvio-lacustrine environments (plains related to ancient rivers or lakes) that may have been habitable.  The search for evidence of habitability, taphonomy (related to fossils), and organic compounds on Mars is now a primary NASA and ESA objective.

The findings of organic compounds inside sedimentary rocks and of boron on Mars are of interest as they are precursors for prebiotic chemistry.  Such findings, along with previous discoveries that liquid water was clearly present on ancient Mars, further supports the possible early habitability of Gale Crater on Mars.  Currently, the surface of Mars is bathed with ionizing radiation, and Martian soil is rich in perchlorates toxic to microorganisms.  Therefore, the consensus is that if life exists—or existed—on Mars, it could be found or is best preserved in the subsurface, away from present-day harsh surface processes.

In June 2018, NASA announced the detection of seasonal variation of methane levels on Mars. Methane could be produced by microorganisms or by geological means.  The European ExoMars Trace Gas Orbiter started mapping the atmospheric methane in April 2018, and the 2022 ExoMars rover Rosalind Franklin will drill and analyze subsurface samples, while the NASA Mars 2020 rover Perseverance, having landed successfully, will cache dozens of drill samples for their potential transport to Earth laboratories in the late 2020s or 2030s. As of February 8, 2021, an updated status of studies considering the possible detection of lifeforms on Venus (via of phosphine) and Mars (via methane) was reported.

Early Speculation

Mars' polar ice caps were discovered in the mid-17th century.  In the late 18th century, William Herschel proved they grow and shrink alternately, in the summer and winter of each hemisphere. By the mid-19th century, astronomers knew that Mars had certain other similarities to Earth, for example that the length of a day on Mars was almost the same as a day on Earth. They also knew that its axial tilt was similar to Earth's, which meant it experienced seasons just as Earth does—but of nearly double the length owing to its much longer year.  These observations led to increase in speculation that the darker albedo features were water and the brighter ones were land, whence followed speculation on whether Mars may be inhabited by some form of life.

In 1854, William Whewell, a fellow of Trinity College, Cambridge, theorized that Mars had seas, land and possibly life forms.  Speculation about life on Mars exploded in the late 19th century, following telescopic observation by some observers of apparent Martian canals—which were later found to be optical illusions. Despite this, in 1895, American astronomer Percival Lowell published his book Mars, followed by Mars and its Canals in 1906, proposing that the canals were the work of a long-gone civilization.  This idea led British writer H. G. Wells to write The War of the Worlds in 1897, telling of an invasion by aliens from Mars who were fleeing the planet's desiccation.

Spectroscopic analysis of Mars' atmosphere began in earnest in 1894, when U.S. astronomer William Wallace Campbell showed that neither water nor oxygen were present in the Martian atmosphere.  The influential observer Eugène Antoniadi used the 83-cm (32.6 inch) aperture telescope at Meudon Observatory at the 1909 opposition of Mars and saw no canals, the outstanding photos of Mars taken at the new Baillaud dome at the Pic du Midi observatory also brought formal discredit to the Martian canals theory in 1909, and the notion of canals began to  fall out of favor.

Potential for Habitability

Chemical, physical, geological, and geographic attributes shape the environments on Mars. Isolated measurements of these factors may be insufficient to deem an environment habitable, but the sum of measurements can help predict locations with greater or lesser habitability potential.  The two current ecological approaches for predicting the potential habitability of the Martian surface use 19 or 20 environmental factors, with an emphasis on water availability, temperature, the presence of nutrients, an energy source, and protection from solar ultraviolet and galactic cosmic radiation.

Scientists do not know the minimum number of parameters for determination of habitability potential, but they are certain it is greater than one or two of the factors in the table below.  Similarly, for each group of parameters, the habitability threshold for each is to be determined.  Laboratory simulations show that whenever multiple lethal factors are combined, the survival rates plummet quickly.  There are no full-Mars simulations published yet that include all of the biocidal factors combined.  Furthermore, the possibility of Martian life having a far different biochemistry and habitability requirements than the terrestrial biosphere is an open question.

Liquid Water on Mars

Liquid water is a necessary but not sufficient condition for life as humans know it, as habitability is a function of a multitude of environmental parameters.  Liquid water cannot exist on the surface of Mars except at the lowest elevations for minutes or hours.  Liquid water does not appear at the surface itself, but it could form in minuscule amounts around dust particles in snow heated by the Sun.  Also, the ancient equatorial ice sheets beneath the ground may slowly sublimate or melt, accessible from the surface via caves.

Water on Mars exists almost exclusively as water ice, located in the Martian polar ice caps and under the shallow Martian surface even at more temperate latitudes.  A small amount of water vapor is present in the atmosphere.  There are no bodies of liquid water on the Martian surface because its atmospheric pressure at the surface averages 600 pascals (0.087 psi)—about 0.6% of Earth's mean sea level pressure—and because the temperature is far too low, (210 K (−63 °C)) leading to immediate freezing. Despite this, about 3.8 billion years ago, there was a denser atmosphere, higher temperature, and vast amounts of liquid water flowed on the surface, including large oceans.

It has been estimated that the primordial oceans on Mars would have covered between 36% and 75% of the planet.  On November 22, 2016, NASA reported finding a large amount of underground ice in the Utopia Planitia region of Mars. The volume of water detected has been estimated to be equivalent to the volume of water in Lake Superior.  Analysis of Martian sandstones, using data obtained from orbital spectrometry, suggests that the waters that previously existed on the surface of Mars would have had too high a salinity to support most Earth-like life. Tosca et al. found that the Martian water in the locations they studied all had water activity, a_w ≤ 0.78 to 0.86—a level fatal to most Terrestrial life.  Haloarchaea, however, are able to live in hypersaline solutions, up to the saturation point.

In June 2000, possible evidence for current liquid water flowing at the surface of Mars was discovered in the form of flood-like gullies.  Additional similar images were published in 2006, taken by the Mars Global Surveyor, that suggested that water occasionally flows on the surface of Mars. The images showed changes in steep crater walls and sediment deposits, providing the strongest evidence yet that water coursed through them as recently as several years ago.

There is disagreement in the scientific community as to whether or not the recent gully streaks were formed by liquid water. Some suggest the flows were merely dry sand flows.  Others suggest it may be liquid brine near the surface, but the exact source of the water and the mechanism behind its motion are not understood.

In July 2018, scientists reported the discovery of a subglacial lake on Mars, 1.5 km (0.93 mi) below the southern polar ice cap, and extending sideways about 20 km (12 mi), the first known stable body of water on the planet.  The lake was discovered using the MARSIS radar on board the Mars Express orbiter, and the profiles were collected between May 2012 and December 2015.  The lake is centered at 193°E, 81°S, a flat area that does not exhibit any peculiar topographic characteristics but is surrounded by higher ground, except on its eastern side, where there is a depression.

                              https://en.wikipedia.org/wiki/Life_on_Mars

Vertical Turbines: the Future of Wind Power?

The now-familiar sight of traditional propeller wind turbines could be replaced in the future with wind farms containing more compact and efficient vertical turbines.

From: Oxford Brookes University

April 26, 2021 -- New research from Oxford Brookes University[in Headington, UK] has found that the vertical turbine design is far more efficient than traditional turbines in large scale wind farms, and when set in pairs the vertical turbines increase each other’s performance by up to 15%.

A research team from the School of Engineering, Computing and Mathematics (ECM) at Oxford Brookes led by Professor Iakovos Tzanakis conducted an in-depth study using more than 11,500 hours of computer simulation to show that wind farms can perform more efficiently by substituting the traditional propeller type Horizontal Axis Wind Turbines (HAWTs), for compact Vertical Axis Wind Turbines (VAWTs). 

Vertical turbines are more efficient than traditional windmill turbines

The research demonstrates for the first time at a realistic scale, the potential of large scale VAWTs to outcompete current HAWT wind farm turbines. 

VAWTs spin around an axis vertical to the ground, and they exhibit the opposite behaviour of the well-known propeller design (HAWTs). The research found that VAWTs increase each other’s performance when arranged in grid formations. Positioning wind turbines to maximise outputs is critical to the design of wind farms.

Professor Tzanakis comments “This study evidences that the future of wind farms should be vertical. Vertical axis wind farm turbines can be designed to be much closer together, increasing their efficiency and ultimately lowering the prices of electricity. In the long run, VAWTs can help accelerate the green transition of our energy systems, so that more clean and sustainable energy comes from renewable sources.” 

With the UK’s wind energy capacity expected to almost double by 2030, the findings are a stepping stone towards designing more efficient wind farms, understanding large scale wind energy harvesting techniques and ultimately improving the renewable energy technology to more quickly replace fossil fuels as sources of energy. 

Cost effective way to meet wind power targets

According to the Global Wind Report 2021, the world needs to be installing wind power three times faster over the next decade, in order to meet net zero targets and avoid the worst impacts of climate change.

Lead author of the report and Bachelor of Engineering graduate Joachim Toftegaard Hansen commented: “Modern wind farms are one of the most efficient ways to generate green energy, however, they have one major flaw: as the wind approaches the front row of turbines, turbulence will be generated downstream. The turbulence is detrimental to the performance of the subsequent rows. 

“In other words, the front row will convert about half the kinetic energy of the wind into electricity, whereas for the back row, that number is down to 25-30%. Each turbine costs more than £2 million/MW. As an engineer, it naturally occurred to me that there must be a more cost-effective way.”

The study is the first to comprehensively analyse many aspects of wind turbine performance, with regards to array angle, direction of rotation, turbine spacing, and number of rotors. It is also the first research to investigate whether the performance improvements hold true for three VAWT turbines set in a series.

Dr Mahak co-author of the article and Senior Lecturer in ECM comments: “The importance of using computational methods in understanding flow physics can’t be underestimated. These types of design and enhancement studies are a fraction of the cost compared to the huge experimental test facilities. This is particularly important at the initial design phase and is extremely useful for the industries trying to achieve maximum design efficiency and power output.”

https://www.brookes.ac.uk/about-brookes/news/vertical-turbines-could-be-the-future-for-wind-farms/

Experimental Drug Fights Alzheimer's Disease

Removing 'garbage' from brain cells improves memory in mice

From:  Albert Einstein College of Medicine

April 22, 2021 -- The drug works by reinvigorating a cellular cleaning mechanism that gets rid of unwanted proteins by digesting and recycling them.  The study was published online today in the journal Cell.

"Discoveries in mice don't always translate to humans, especially in Alzheimer's disease," said co-study leader Ana Maria Cuervo, M.D., Ph.D., the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, professor of developmental and molecular biology, and co-director of the Institute for Aging Research at Einstein. "But we were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer's in mice also occurs in people with the disease, suggesting that our drug may also work in humans." In the 1990s, Dr. Cuervo discovered the existence of this cell-cleaning process, known as chaperone-mediated autophagy (CMA) and has published 200 papers on its role in health and disease.

CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate into insoluble clumps that damage cells. In fact, Alzheimer's and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients' brains. The Cell paper reveals a dynamic interplay between CMA and Alzheimer's disease, with loss of CMA in neurons contributing to Alzheimer's and vice versa. The findings suggest that drugs for revving up CMA may offer hope for treating neurodegenerative diseases.

Establishing CMA's Link to Alzheimer's

Dr. Cuervo's team first looked at whether impaired CMA contributes to Alzheimer's. To do so, they genetically engineered a mouse to have excitatory brain neurons that lacked CMA. The absence of CMA in one type of brain cell was enough to cause short-term memory loss, impaired walking, and other problems often found in rodent models of Alzheimer's disease. In addition, the absence of CMA profoundly disrupted proteostasis -- the cells' ability to regulate the proteins they contain. Normally soluble proteins had shifted to being insoluble and at risk for clumping into toxic aggregates.

Dr. Cuervo suspected the converse was also true: that early Alzheimer's impairs CMA. So she and her colleagues studied a mouse model of early Alzheimer's in which brain neurons were made to produce defective copies of the protein tau. Evidence indicates that abnormal copies of tau clump together to form neurofibrillary tangles that contribute to Alzheimer's. The research team focused on CMA activity within neurons of the hippocampus -- the brain region crucial for memory and learning. They found that CMA activity in those neurons was significantly reduced compared to control animals.

What about early Alzheimer's in people -- does it block CMA too? To find out, the researchers looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer's patients and from a comparison group of healthy individuals. The sequencing data revealed CMA's activity level in patients' brain tissue. Sure enough, CMA activity was somewhat inhibited in people who had been in the early stages of Alzheimer's, followed by much greater CMA inhibition in the brains of people with advanced Alzheimer's.

"By the time people reach the age of 70 or 80, CMA activity has usually decreased by about 30% compared to when they were younger," said Dr. Cuervo. "Most peoples' brains can compensate for this decline. But if you add neurodegenerative disease to the mix, the effect on the normal protein makeup of brain neurons can be devastating. Our study shows that CMA deficiency interacts synergistically with Alzheimer's pathology to greatly accelerate disease progression."

A New Drug Cleans Neurons and Reverses Symptoms

In an encouraging finding, Dr. Cuervo and her team developed a novel drug that shows potential for treating Alzheimer's. "We know that CMA is capable of digesting defective tau and other proteins," said Dr. Cuervo. "But the sheer amount of defective protein in Alzheimer's and other neurodegenerative diseases overwhelms CMA and essentially cripples it. Our drug revitalizes CMA efficiency by boosting levels of a key CMA component."

In CMA, proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells' lysosomes -- membrane-bound organelles filled with enzymes, which digest and recycle waste material. To successfully get their cargo into lysosomes, however, chaperones must first "dock" the material onto a protein receptor called LAMP2A that sprouts from the membranes of lysosomes. The more LAMP2A receptors on lysosomes, the greater the level of CMA activity possible. The new drug, called CA, works by increasing the number of those LAMP2A receptors.

"You produce the same amount of LAMP2A receptors throughout life," said Dr. Cuervo. "But those receptors deteriorate more quickly as you age, so older people tend to have less of them available for delivering unwanted proteins into lysosomes. CA restores LAMP2A to youthful levels, enabling CMA to get rid of tau and other defective proteins so they can't form those toxic protein clumps." (Also this month, Dr. Cuervo's team reported in Nature Communications that, for the first time, they had isolated lysosomes from the brains of Alzheimer's disease patients and observed that reduction in the number of LAMP2 receptors causes loss of CMA in humans, just as it does in animal models of Alzheimer's.)

The researchers tested CA in two different mouse models of Alzheimer's disease. In both disease mouse models, oral doses of CA administered over 4 to 6 months led to improvements in memory, depression, and anxiety that made the treated animals resemble or closely resemble healthy, control mice. Walking ability significantly improved in the animal model in which it was a problem. And in brain neurons of both animal models, the drug significantly reduced levels of tau protein and protein clumps compared with untreated animals.

"Importantly, animals in both models were already showing symptoms of disease, and their neurons were clogged with toxic proteins before the drugs were administered," said Dr. Cuervo. "This means that the drug may help preserve neuron function even in the later stages of disease. We were also very excited that the drug significantly reduced gliosis -- the inflammation and scarring of cells surrounding brain neurons. Gliosis is associated with toxic proteins and is known to play a major role in perpetuating and worsening neurodegenerative diseases."

Treatment with CA did not appear to harm other organs even when given daily for extended periods of time. The drug was designed by Evripidis Gavathiotis, Ph.D.,, professor of biochemistry and of medicine and a co-leader of the study.

Drs. Cuervo and Gavathiotis have teamed up with Life Biosciences of Boston, Mass., to found Selphagy Therapeutics, which is currently developing CA and related compounds for treating Alzheimer's and other neurodegenerative diseases.

The study is titled, "Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome." The study's other co-leader and first author is Mathieu Bourdenx, Ph.D., a postdoctoral fellow in Dr. Cuervo's lab and also a junior researcher at the Institute of Neurodegenerative Diseases, University of Bordeaux, France. Additional Einstein authors include: Adrián Martín-Segura, Aurora Scrivo, Susmita Kaushik, Ph.D., Inmaculada Tasset, Ph.D., Antonio Diaz and Yves R. Juste.

Other contributors include: Jose A. Rodriguez-Navarro (formerly at Einstein) at Hospital Universitario Ramón y Cajal, Madrid, Spain, Nadia J. Storm (formerly at Einstein) at University of Copenhagen, Denmark, Qisheng Xin (formerly at Einstein), Erica Stevenson, Nevan Krogan and Danielle L. Swaney both at University of California at San Francisco, CA, Enrique Luengo at Universidad Autonoma de Madrid, Madrid, Spain, Cristina Clement, Ph.D., and Laura Santambrogio, M.D., Ph.D., both at Weill Cornell Medicine, New York, NY, Se Joon Choi, Ph.D., Eugene V. Mosharov and David Sulzer, Ph.D., all at Columbia University Medical Center, New York, NY and Fiona Grueninger, Ph.D., and Ludovic Collin both at Roche Pharma, Switzerland.

https://www.sciencedaily.com/releases/2021/04/210422150402.htm

New Polymer Mimics Cartilage

Inspired by nature, research developed a new load-bearing material

From: University of Leeds

April 22, 2021 -- Engineers have developed a material that mimics human cartilage – the body’s shock absorbing and lubrication system, and it could herald the development of a new generation of lightweight bearings.

Cartilage is a soft fibrous tissue found around joints which provides protection from the compressive loading generated by walking, running or lifting. It also provides a protective, lubricating layer allowing bones to pass over one another in a frictionless way.

For years, scientists have been trying to create a synthetic material with the properties of cartilage. To date, they have had mixed results. 

But in a paper published in the journal Applied Polymer Materials, researchers at the University of Leeds and Imperial College London have announced that they have created a material that functions like cartilage. 

The research team believes a cartilage-like material would have a wide-range of uses across engineering.

Nature's cushion 

Cartilage is a bi-phasic porous material, meaning it exists in solid and fluid phases. It switches to its fluid phase by absorbing a viscous substance produced in the joints called synovial fluid. This fluid not only lubricates the joints but when held in the porous matrix of the cartilage, it provides a hydroelastic cushion against compressive forces.

Because the cartilage is porous, the synovial fluid eventually drains away and as it does, it helps dissipate the energy forces travelling through the body, protecting joints from wear and tear and impact injuries. At this point the cartilage returns to its sold phase, ready for the cycle to be repeated.

Many potential applications' 

Dr Siavash Soltanahmadi, Research Fellow in the School of Mechanical Engineering at Leeds, who led the research, said: “Scientists and engineers have been trying for years to develop a material that has the amazing properties of cartilage. 

"We have now developed a material for engineering applications that mimics some of the most important properties found in cartilage, and it has only been possible because we have found a way to mimic the way nature does it.

“There are many applications in engineering for a synthetic material that is soft but can withstand heavy loading with minimum wear and tear, such as in bearings. There is potential across engineering for a material that behaves like cartilage.” 

Earlier attempts at developing a synthetic cartilage system have focused on the use of hydrogels, materials that absorb water. Hydrogels are good at reducing friction but perform poorly when under compressive force. 

One of the problems is that it takes time for the hydrogel to return to its normal shape after it has been compressed.

The researchers have overcome this problem by creating a synthetic porous material made of a hydrogel held in a matrix of polydimethylsiloxane or PDMS - a silicone-based polymer. The matrix keeps the shape of the hydrogel.  

The hydrogel also provided a lubricating layer. 

In the paper, the scientists report that the load-bearing behaviour of the hydrogel held in the PDMS matrix was 14 to 19 times greater than the hydrogel on its own. The equilibrium elastic modulus of the composite was 452 kPa at a strain range of 10%-30%, close to the values reported for the modulus of cartilage tested.

Water as an effective lubricant 

The scientists believe future applications of a new material based on the function of cartilage could challenge many traditional oil-lubricated engineering systems.

Dr Michael Bryant, Associate Professor in the School of Mechanical Engineering, who supervised the research, said: “The ability to use water as an effective lubricant has many applications from energy generation to medical devices. However this often requires a different approach when compared to traditional engineering systems which often use oil-based lubricants and hard-surface coatings.

“This project has helped us to better understand these requirements and develop new tools to address this need.” 

https://www.leeds.ac.uk/news/article/4807/inspired_by_nature_the_research_to_develop_a_new_load-bearing_material