Protecting the Brain from Hypoxia

Serendipitous discovery could lead to treatment for strokes, cardiac arrest

From: Massachusetts General Hospital

May 28, 2021 -- Lack of oxygen, which is harmful to the brain, causes hydrogen sulfide 'sewer gas' to accumulate in the brain. The brains of lab animals repeatedly exposed to hydrogen sulfide became tolerant to the gas and lack of oxygen. Researchers identified the mechanism that induces this tolerance, which could lead to new treatments for brain injuries caused by oxygen deprivation.

In a surprising discovery, researchers at Massachusetts General Hospital (MGH) identified a mechanism that protects the brain from the effects of hypoxia, a potentially lethal deprivation of oxygen. This serendipitous finding, which they report in Nature Communications, could aid in the development of therapies for strokes, as well as brain injury that can result from cardiac arrest, among other conditions.

However, this study began with a very different objective, explains senior author Fumito Ichinose, MD, PhD, an attending physician in the Department of Anesthesia, Critical Care and Pain Medicine at MGH, and principal investigator in the Anesthesia Center for Critical Care Research. One area of focus for Ichinose and his team is developing techniques for inducing suspended animation, that is, putting a human's vital functions on temporary hold, with the ability to "reawaken" them later. This state of being would be similar to what bears and other animals experience during hibernation. Ichinose believes that the ability to safely induce suspended animation could have valuable medical applications, such as pausing the life processes of a patient with an incurable disease until an effective therapy is found. It could also allow humans to travel long distances in space (which has frequently been depicted in science fiction).

A 2005 study found that inhaling a gas called hydrogen sulfide caused mice to enter a state of suspended animation. Hydrogen sulfide, which has the odor of rotten eggs, is sometimes called "sewer gas." Oxygen deprivation in a mammal's brain leads to increased production of hydrogen sulfide. As this gas accumulates in the tissue, hydrogen sulfide can halt energy metabolism in neurons and cause them to die. Oxygen deprivation is a hallmark of ischemic stroke, the most common type of stroke, and other injuries to the brain.

In the Nature Communications study, Ichinose and his team initially set out to learn what happens when mice are exposed to hydrogen sulfide repeatedly, over an extended period. At first, the mice entered a suspended-animation-like state -- their body temperatures dropped and they were immobile. "But, to our surprise, the mice very quickly became tolerant to the effects of inhaling hydrogen sulfide," says Ichinose. "By the fifth day, they acted normally and were no longer affected by hydrogen sulfide."

Interestingly, the mice that became tolerant to hydrogen sulfide were also able to tolerate severe hypoxia. What protected these mice from hypoxia? Ichinose's group suspected that enzymes in the brain that metabolize sulfide might be responsible. They found that levels of one enzyme, called sulfide:quinone oxidoreductase (SQOR), rose in the brains of mice when they breathed hydrogen sulfide several days in a row. They hypothesized that SQOR plays a part in resistance to hypoxia.

There was strong evidence for this hypothesis in nature. For example, female mammals are known to be more resistant than males to the effects of hypoxia -- and the former have higher levels of SQOR. When SQOR levels are artificially reduced in females, they become more vulnerable to hypoxia. (Estrogen may be responsible for the observed increase in SQOR, since protection from the adverse effects of hypoxia is lost when a female mammal's estrogen-producing ovaries are removed.) Moreover, some hibernating animals, such as the thirteen-lined ground squirrel, are highly tolerant of hypoxia, which allows them to survive as their bodies' metabolism slows down during the winter. A typical ground squirrel's brain has 100 times more SQOR than that of a similar-sized rat. However, when Ichinose and colleagues "turned off" expression of SQOR in the squirrels' brains, their protection against the effects of hypoxia vanished.

Meanwhile, when Ichinose and colleagues artificially increased SQOR levels in the brains of mice, "they developed a robust defense against hypoxia," explains Ichinose. His team increased the level of SQOR using gene therapy, an approach that is technically complex and not practical at this point. On the other hand, Ichinose and his colleagues demonstrated that "scavenging" sulfide, by using an experiment drug called SS-20, reduced levels of the gas, thereby sparing the brains of mice when they were deprived of oxygen.

Human brains have very low levels of SQOR, meaning that even a modest accumulation of hydrogen sulfide can be harmful, says Ichinose. "We hope that someday we'll have drugs that could work like SQOR in the body," he says, noting that his lab is studying SS-20 and several other candidates. Such medications could be used to treat ischemic strokes, as well as patients who have suffered cardiac arrest, which can lead to hypoxia. Ichinose's lab is also investigating how hydrogen sulfide affects other parts of the body. For example, hydrogen sulfide is known to accumulate in other conditions, such as certain types of Leigh syndrome, a rare but severe neurological disorder that usually leads to early death. "For some patients," says Ichinose, "treatment with a sulfide scavenger might be lifesaving."

The lead author of the study is Eizo Marutani, MD, an investigator in MGH's Department of Anesthesia Critical Care and Pain Medicine and an instructor at Harvard Medical School (HMS). Ichinose is also the William Thomas Green Morton Professor of Anaesthesia at HMS.

https://www.sciencedaily.com/releases/2021/05/210525160848.htm

Coming: Cheaper Solar Panels

Study of promising photovoltaic material leads to discovery of a new state of matter

May 26, 2006 -- Researchers at McGill University have gained new insight into the workings of perovskites, a semiconductor material that shows great promise for making high-efficiency, low-cost solar cells and a range of other optical and electronic devices.

Perovskites have drawn attention over the past decade because of their ability to act as semiconductors even when there are defects in the material’s crystal structure. This makes perovskites special because getting most other semiconductors to work well requires stringent and costly manufacturing techniques to produce crystals that are as defect-free as possible. In what amounts to the discovery of a new state of matter, the McGill team has made a step forward in unlocking the mystery of how perovskites pull off this trick.

“Historically, people have been using bulk semiconductors that are perfect crystals. And now, all of a sudden, this imperfect, soft crystal starts to work for semiconductor applications, from photovoltaics to LEDs,” explains senior author Patanjali Kambhampati, an associate professor in the Department of Chemistry at McGill. “That's the starting point for our research: how can something that’s defective work in a perfect way?”

Quantum dots, but not as we know them

In a paper published May 26 in Physical Review Research, the researchers reveal that a phenomenon known as quantum confinement occurs within bulk perovskite crystals. Until now, quantum confinement had only been observed in particles a few nanometres in size – the quantum dots of flatscreen TV fame being one much-vaunted example. When particles are this small, their physical dimensions constrain the movement of electrons in a way that gives the particles distinctly different properties from larger pieces of the same material – properties that can be fine-tuned to produce useful effects such as the emission of light in precise colours.

Using a technique known as state-resolved pump/probe spectroscopy, the researchers have shown a similar type of confinement occurs in bulk caesium lead bromide perovskite crystals. In other words, their experiments have uncovered quantum dot-like behaviour taking place in pieces of perovskite significantly larger than quantum dots.

Surprising result leads to unexpected discovery

The work builds on earlier research which established that perovskites, while appearing to be a solid substance to the naked eye, have certain characteristics more commonly associated with liquids. At the heart of this liquid-solid duality is an atomic lattice able to distort in response to the presence of free electrons. Kambhampati draws a comparison to a trampoline absorbing the impact of a rock thrown into its centre. Just as the trampoline will eventually bring the rock to a standstill, the distortion of the perovskite crystal lattice – a phenomenon known as polaron formation – is understood to have a stabilizing effect on the electron.

While the trampoline analogy would suggest a gradual dissipation of energy consistent with a system moving from an excited state back to a more stable one, the pump/probe spectroscopy data in fact revealed the opposite. To the researchers’ surprise, their measurements showed an overall increase in energy in the aftermath of polaron formation.

“The fact that the energy was raised shows a new quantum mechanical effect, quantum confinement like a quantum dot,” Kambhampati says, explaining that, at the size scale of electrons, the rock in the trampoline is an exciton, the bound pairing of an electron with the space it leaves behind when it is in an excited state.

“What the polaron does is confine everything into a spatially well-defined area. One of the things our group was able to show is that the polaron mixes with an exciton to form what looks like a quantum dot. In a sense, it’s like a liquid quantum dot, which is something we call a quantum drop. We hope that exploring the behavior of these quantum drops will give rise to a better understanding of how to engineer defect-tolerant optoelectronic materials.”

https://www.mcgill.ca/science/channels/news/study-promising-photovoltaic-material-leads-discovery-new-state-matter-331213

Is “Wokeness” Actually “Sleepiness”?

In a devastating opinion essay in today’s New York Times, Thomas B. Edsall dares to posit that the academic and intellectual concept of wokeness is “kryptonite” for the modern Democratic party.

It is not a short essay, but it is profoundly thought provoking.  See https://www.nytimes.com/2021/05/26/opinion/democrats-republicans-wokeness-cancel-culture.html

Certain Exercises Help Young Children with Math

Young children who practice visual working memory and reasoning tasks improve their math skills more than children who focus on spatial rotation exercises, according to a large study by researchers at Karolinska Institutet in Sweden.

From: Karolinska Institutet

May 20, 2021 -- The findings support the notion that training spatial cognition can enhance academic performance and that when it comes to math, the type of training matters. The study is published in the journal Nature Human Behaviour.

"In this large, randomized study we found that when it comes to enhancing mathematical learning in young children, the type of cognitive training performed plays a significant role," says corresponding author Torkel Klingberg, professor in the Department of Neuroscience, Karolinska Institutet. "It is an important finding because it provides strong evidence that cognitive training transfers to an ability that is different from the one you practiced."

Numerous studies have linked spatial ability -- that is the capacity to understand and remember dimensional relations among objects -- to performance in science, technology, engineering and mathematics. As a result, some employers in these fields use spatial ability tests to vet candidates during the hiring process. This has also fueled an interest in spatial cognition training, which focuses on improving one's ability to memorize and manipulate various shapes and objects and spot patterns in recurring sequences. Some schools today include spatial exercises as part of their tutoring.

However, previous studies assessing the effect of spatial training on academic performance have had mixed results, with some showing significant improvement and others no effect at all. Thus, there is a need for large, randomized studies to determine if and to what extent spatial cognition training actually improves performance.

In this study, more than 17,000 Swedish schoolchildren between the ages of six and eight completed cognitive training via an app for either 20 or 33 minutes per day over the course of seven weeks. In the first week, the children were given identical exercises, after which they were randomly split into one of five training plans. In all groups, children spent about half of their time on mathematical number line tasks. The remaining time was randomly allotted to different proportions of cognitive training in the form of rotation tasks (2D mental rotation and tangram puzzle), visual working memory tasks or non-verbal reasoning tasks (see examples below for details). The children's math performance was tested in the first, fifth and seventh week.

The researchers found that all groups improved on mathematical performance, but that reasoning training had the largest positive impact followed by working memory tasks. Both reasoning and memory training significantly outperformed rotation training when it came to mathematical improvement. They also observed that the benefits of cognitive training could differ threefold between individuals. That could explain differences in results from some previous studies seeing as individual characteristics of study participants tend to impact the results.

The researchers note there were some limitations to the study, including the lack of a passive control group that would allow for an estimation of the absolute effect size. Also, this study did not include a group of students who received math training only.

"While it is likely that for any given test, training on that particular skill is the most time-effective way to improve test results, our study offers a proof of principle that spatial cognitive training transfers to academic abilities," Torkel Klingberg says. "Given the wide range of areas associated with spatial cognition, it is possible that training transfers to multiple areas and we believe this should be included in any calculation by teachers and policymakers of how time-efficient spatial training is relative to training for a particular test."

The researchers have received funding by the Swedish Research Council. Torkel Klingberg holds an unpaid position as chief scientific officer for Cognition Matters, the non-profit foundation that owns the cognition training app Vektor that was used in this study.

Examples of training tasks in the study

• In a number line task, a person is asked to identify the right position of a number on a line bound by a start and an end point. Difficulty is typically moderated by removing spatial cues, for example ticks on the number line, and progress to include mathematical problems such as addition, subtraction and division.
• In a visual working memory task, a person is asked to recollect visual objects. In this study, the children reproduced a sequence of dots on a grid by touching the screen. Difficulty was increased by adding more items.
• In a non-verbal reasoning task, a person is asked to complete sequences of spatial patterns. In this study, the children were asked to choose the correct image to fill a blank space based on previous sequences. Difficulty was increased by adding new dimensions such as colors, shapes and dots.
• In a rotation task, a person is asked to figure out what an object would look like if rotated. In this study, the children were asked to rotate a 2D object to fit various angles. Difficulty was moderated by increasing the angle of the rotation or the complexity of the object being rotated.

       https://www.sciencedaily.com/releases/2021/05/210520133755.htm

Safer Next-generation Nuclear Reactors

Computational researchers develop advanced model, the pebble bed reactor

From: Texas A&M College of Engineering

By Laura Simmons

May 20, 2021 -- When one of the largest modern earthquakes struck Japan on March 11, 2011, the nuclear reactors at Fukushima-Daiichi automatically shut down, as designed. The emergency systems, which would have helped maintain the necessary cooling of the core, were destroyed by the subsequent tsunami. Because the reactor could no longer cool itself, the core overheated, resulting in a severe nuclear meltdown, the likes of which haven’t been seen since the Chernobyl disaster in 1986.  

 Since then, reactors have improved exponentially in terms of safety, sustainability and efficiency. Unlike the light-water reactors at Fukushima, which had liquid coolant and uranium fuel, the current generation of reactors has a variety of coolant options, including molten-salt mixtures, supercritical water and even gases like helium.

Dr. Jean Ragusa and Dr. Mauricio Eduardo Tano Retamales from the Department of Nuclear Engineering at Texas A&M University have been studying a new fourth-generation reactor, pebble bed reactors. Pebble-bed reactors use spherical fuel elements (known as pebbles) and a fluid coolant (usually a gas).

“There are about 40,000 fuel pebbles in such a reactor,” said Ragusa. “Think of the reactor as a really big bucket with 40,000 tennis balls inside.”

During an accident, as the gas in the reactor core begins to heat up, the cold air from below begins to rise, a process known as natural convection cooling. Additionally, the fuel pebbles are made from pyrolytic carbon and tristructural-isotropic particles, making them resistant to temperatures as high as 3,000 degrees Fahrenheit. As a very-high-temperature reactor (VHTR), pebble-bed reactors can be cooled down by passive natural circulation, making it theoretically impossible for an accident like Fukushima to occur.

However, during normal operation, a high-speed flow cools the pebbles. This flow creates movement around and between the fuel pebbles, similar to the way a gust of wind changes the trajectory of a tennis ball. How do you account for the friction between the pebbles and the influence of that friction in the cooling process?

This is the question that Ragusa and Tano aimed to answer in their most recent publication  in the journal Nuclear Technology titled “Coupled Computational Fluid Dynamics–Discrete Element Method Study of Bypass Flows in a Pebble-Bed Reactor.”

“We solved for the location of these ‘tennis balls’ using the Discrete Element Method, where we account for the flow-induced motion and friction between all the tennis balls,” said Tano. “The coupled model is then tested against thermal measurements in the SANA experiment.” 

The SANA experiment was conducted in the early 1990s and measured how the mechanisms in a reactor interchange when transmitting heat from the center of the cylinder to the outer part. This experiment allowed Tano and Ragusa to have a standard to which they could validate their models.

As a result, their teams developed a coupled Computational Fluid Dynamics-Discrete Element Methods model for studying the flow over a pebble bed. This model can now be applied to all high-temperature pebble-bed reactors and is the first computational model of its kind to do so. It’s very-high-accuracy tools such as this that allow vendors to develop better reactors. 

“The computational models we create help us more accurately assess different physical phenomena in the reactor,” said Tano. “As a result, reactors can operate at a higher margin, theoretically producing more power while increasing the safety of the reactor. We do the same thing with our models for molten-salt reactors for the Department of Energy.” 

As artificial intelligence continues to advance, its applications to computational modeling and simulation grow. “We’re in a very exciting time for the field,” said Ragusa. “And we encourage any prospective students who are interested in computational modeling to reach out, because this field will hopefully be around for a long time.”

https://engineering.tamu.edu/news/2021/05/nuen-computational-researchers-develop-advanced-model-to-improve-safety-of-next-generation-reactors.html

Challenging the Standard Model of Cancer

New atavistic model shows role of ancient genes in the spread of cancer

From:  ARIZONA STATE UNIVERSITY

May 20, 2021 -- In spite of decades of research, cancer remains an enigma. Conventional wisdom holds that cancer is driven by random mutations that create aberrant cells that run amok in the body.

In a new paper published this week in the journal BioEssays, Arizona and Australian researchers challenge this model by proposing that cancer is a type of genetic throwback, that progresses via a series of reversions to ancestral forms of life. In contrast with the conventional model, the distinctive capabilities of cancer cells are not primarily generated by mutations, the researchers claim, but are pre-existent and latent in normal cells.

Regents' Professor Paul Davies, director of Arizona State University's Beyond Center for Fundamental Concepts in Science and Kimberly Bussey, cancer geneticist and bioinformatician from the Precision Medicine Program at Midwestern University, Glendale, Ariz., teamed up with Charles Lineweaver and Anneke Blackburn at the Australian National University (ANU) in Canberra to refine what they call the Serial Atavism Model (SAM) of cancer. This model suggests that cancer occurs through multiple steps that resurrect ancient cellular functions.

Such functions are retained by evolution for specific purposes such as embryo development and wound healing, and are usually turned off in the adult form of complex organisms. But they can be turned back on if something compromises the organism's regulatory controls. It is the resulting resurrection steps, or atavistic reversions, that are mostly responsible for the ability of cancer cells to survive, proliferate, resist therapy and metastasize, the researchers said.

Davies and Bussey are also members of ASU's Arizona Cancer Evolution Center (ACE) which seeks to understand cancer, not just in humans, but across all complex species, in the light of evolutionary processes.

"Cancer research has been transformed in recent years by comparing genetic sequences across thousands of species to determine gene ages," Davies said. Just as geologists can date rock strata, so geneticists can date genes, a technique known as phylostratigraphy.

"The atavistic model predicts that the genes needed for cancer's abilities are mostly ancient - in some cases little changed over billions of years," Davies added.

Lineweaver explained, "In biology, nothing makes sense except in the light of evolution, and in the case of cancer nothing makes sense except in the light of the deep evolutionary changes that occurred as we became multicellular organisms."

"The atavistic model of cancer has gained increasing traction around the world," added Bussey. "In part, this is because it makes many predictions that can be tested by phylostratigraphy, unlike the conventional somatic mutation theory."

Blackburn, a cancer biologist in ANU's John Curtin School of Medical Research, agreed.

"Appreciation of the importance of gene ages is growing among oncologists and cancer biologists," she said. "Now we need to use this insight to develop novel therapeutic strategies. A better understanding of cancer can lead to better therapeutic outcomes."

                  https://www.eurekalert.org/pub_releases/2021-05/asu-cts051921.php

Researchers Find New Form of Carbon

And that new arrangement is not graphene: researchers in Germany and Finland discover new type of atomically thin carbon material

From:  Aalto University

May 20, 2021 -- Carbon exists in various forms. In addition to diamond and graphite, there are recently discovered forms with astonishing properties. For example graphene, with a thickness of just one atomic layer, is the thinnest known material, and its unusual properties make it an extremely exciting candidate for applications like future electronics and high-tech engineering. In graphene, each carbon atom is linked to three neighbours, forming hexagons arranged in a honeycomb network. Theoretical studies have shown that carbon atoms can also arrange in other flat network patterns, while still binding to three neighbours, but none of these predicted networks had been realized until now.

Researchers at the University of Marburg in Germany and Aalto University in Finland have now discovered a new carbon network, which is atomically thin like graphene, but is made up of squares, hexagons, and octagons forming an ordered lattice. They confirmed the unique structure of the network using high-resolution scanning probe microscopy and interestingly found that its electronic properties are very different from those of graphene.

In contrast to graphene and other forms of carbon, the new Biphenylene network — as the new material is named —has metallic properties. Narrow stripes of the network, only 21 atoms wide, already behave like a metal, while graphene is a semiconductor at this size. “These stripes could be used as conducting wires in future carbon-based electronic devices.” said professor Michael Gottfried, at University of Marburg, who leads the team that developed the idea. The lead author of the study, Qitang Fan from Marburg continues, “This novel carbon network may also serve as a superior anode material in lithium-ion batteries, with a larger lithium storage capacity compared to that of the current graphene-based materials.”

The team at Aalto University helped image the material and decipher its properties. The group of Professor Peter Liljeroth carried out the high-resolution microscopy that showed the structure of the material, while researchers led by Professor Adam Foster used computer simulations and analysis to understand the exciting electrical properties of the material.

The new material is made by assembling carbon-containing molecules on an extremely smooth gold surface. These molecules first form chains, which consist of linked hexagons, and a subsequent reaction connects these chains together to form the squares and octagons. An important feature of the chains is that they are chiral, which means that they exist in two mirroring types, like left and right hands. Only chains of the same type aggregate on the gold surface, forming well-ordered assemblies, before they connect. This is critical for the formation of the new carbon material, because the reaction between two different types of chains leads only to graphene. “The new idea is to use molecular precursors that are tweaked to yield biphenylene instead of graphene” explains Linghao Yan, who carried out the high-resolution microscopy experiments at Aalto University.

For now, the teams work to produce larger sheets of the material, so that its application potential can be further explored. However, “We are confident that this new synthesis method will lead to the discovery of other novel carbon networks.” said Professor Liljeroth.

               https://www.aalto.fi/en/news/a-new-form-of-carbon