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In the southern Atlantic Rainforest remnants between Rio de Janeiro State in Southeast Brazil and Santa Catarina State in South Brazil, there are some 600 species of harvestmen (Opiliones), arachnids that live in caves and humid forests. The number of species is considered high even for this well-known biodiversity hotspot, and most of these species are endemic.

A reconstitution of the evolutionary history of the subfamily Sodreaninae has brought to light an explanation for this peculiar distribution pattern and emergence of new species. Contrary to expectations, the high species diversity is more likely related to ancient geological events, such as mountain range uplift and river formation, than to relatively recent climate fluctuations (i.e., those in the last 20,000 years).

The discovery is based on correlations found between evolutionary data for seven lineages of harvestmen and the influence of geological events that occurred in the region in the last 30 million years. The study was conducted in Brazil by a group of researchers at the University of São Paulo's Bioscience Institute (IB-USP) in partnership with colleagues at the Federal University of Lavras (UFLA) and the Geology Institute (IG) in São Paulo. Its results are published in the journal Molecular Phylogenetics and Evolution.

The research was supported by São Paulo Research Foundation - FAPESP under the aegis of a cooperative agreement between the US National Science Foundation (NSF) and the FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP).

"Curiously, the lineages are far older than the Last Glacial Maximum 20,000 years ago, when ice sheets covered the north of the planet, changing the climate worldwide. From the evidence gleaned in our study, based on genetic analysis of harvestmen alive now, this group began diversifying well before that, about 30 million years ago. This discovery is consistent with the geological evolution of the Ribeira de Iguape and Paraíba do Sul river basins, for example," said Elen Peres, a researcher at IB-USP and first author of the article.

Given the sensitivity of harvestmen and their preference for humid habitats, Peres and her group already surmised that they must have been affected by environmental changes due to climate oscillations in the last 2 million years of the Pleistocene, but the study proved that the speciation of Opiliones occurred much earlier and was caused by even more ancient geological events.

Just as the evolutionary theory developed by Charles Darwin (1809-1882) grew out of his observations of a type of speciation found in the Galapagos, where different islands were home to distinct but related species of finches, in this case, the Brazilian researchers found that the formation of the Ribeira do Iguape Valley separated entire populations, causing different species to emerge over time.

Genetic analysis

"We knew the Atlantic Rainforest remnants in the South and Southeast contained a large and highly peculiar distribution of species belonging to this family of harvestmen, but what's new from this project is that we were able to date their emergence using molecular markers," said Ricardo Pinto-da-Rocha, a professor in IB-USP's Zoology Department and a co-author of the article.

According to the study, the diversification of harvestmen species began with the geological evolution of the Atlantic Rainforest in South and Southeast Brazil, including complex transformations derived from the separation of the African and South American continents during the Upper Cretaceous, which began over 100 million years ago. This event had consequences millions of years later, including mountain range uplift and erosion as well as intense magmatism.

Approximately 60 million years ago, the process culminated in the formation of the Continental Rift of Southeast Brazil, which runs parallel with the coast for 900 km between Curitiba, Southern Brazil, and Niterói, Rio de Janeiro, and is associated with the formation of important rivers, such as the Ribeira do Iguape and Paraíba do Sul.

The article notes that the Paraíba do Sul Valley is 550-400 m above sea level and surrounded by the Serra do Mar and Serra da Mantiqueira ranges, with elevations higher than 2,000 m, constituting geographical barriers.

"The harvestman species appeared at different times between 35 million and 10 million years ago," Pinto-da-Rocha said.

The point of looking for correlations between molecular data, climate and geology was to answer a key question about the Atlantic Rainforest biome, which is how its extraordinary biodiversity came about. "It would be great to know if any specific event or series of events caused the biome's outstandingly rich biodiversity with so many endemic species," said Thadeu Sobral-Souza, a researcher at UFLA and also a co-author of the article.

Most previous research concluded that the biome's biodiversity derived from recent climate events, he added. "Studies have shown that when the climate becomes cooler or warmer, species may become either locally extinct or more widely distributed," he told. "Our study demonstrates that geology was more decisive for species diversity than recent climate oscillations, at least for this group of Opiliones."

Peres agreed. "Higher levels of biodiversity normally correlate with a stable climate, but the climate fluctuations of the Pleistocene occurred between about 2 million and 10,000 years ago, long after the speciation of Opiliones," he said.

New classifications

The genetic analysis also resulted in a new configuration of species in the subfamily Sodreaninae, hitherto analyzed only on the basis of morphology. Molecular analysis showed, for example, that S. sodreana and S. granulata constituted the same species, henceforth called S. sodreana, while S. barbiellinii and S. curupira were found to be closer to the subfamily Progonyleptoidellinae than to Sodreaninae.

"Molecular data for S. barbiellinii and S. curupira showed that the convergence was merely morphological," Pinto-da-Rocha said. "Both species have a kind of appendix that they use to capture food, and were put in the same group when this was discovered 100 years ago. However, we discovered from the genetic analysis that this trait has appeared more than once in different families, and genetically speaking these species are closer to Progonyleptoidellinae."

Quantum mechanics boasts all sorts of strange features, one being quantum superposition - the peculiar circumstance in which particles seem to be in two or more places or states at once. Now, an international group of physicists led by Stevens Institute of Technology, University of Vienna and University of Queensland flip that description on its head, showing that particles are not the only objects that can exist in a state of superposition - so can time itself.

"The sequence of events can become quantum mechanical," said co-author Igor Pikovski, a physicist at the Center for Quantum Science and Engineering at Stevens Institute of Technology. " We looked at quantum temporal order where there is no distinction between one event causing the other or vice versa."

The work, reported in the August 22 issue of Nature Communications, is among the first to reveal the quantum properties of time, whereby the flow of time doesn't observe a straight arrow forward, but one where cause and effect can co-exist both in the forward and backward direction. In the upcoming era of quantum computers, the work holds particular promise: quantum computers that exploit the quantum order of performing operations might beat devices that operate using only fixed sequences.

To show this scenario, Pikovski and colleagues merged two seemingly conflicting theories - quantum mechanics and general relativity - to conduct a Gedanken experiment, a way of using the imagination to investigate the nature of things. The team, consisting of Pikovski, Magdalena Zych, Fabio Costa and Caslav Brukner, started by asking the question, "what would a clock measure if it was influenced by a massive object in a quantum superposition state, i.e. both near and far at the same time?"

According to general relativity, the presence of a massive object slows down the flow of time, such that a clock placed close to a massive object will run slower compared to an identical one that is farther away.

To illustrate what happens, imagine a pair of starships training for a mission. They are asked to fire at each other at a specified time and dodge the fire at another time, whereby each ship knows the exact time when to fire and when to dodge. If either ship fires too early, it will destroy the other, and this establishes an unmistakable time order between the firing events.

However, if a powerful agent could place a sufficiently massive object, say a planet, closer to one ship it would slow down its flow of time. As a result, the ship would dodge the fire too late and would be destroyed.

Quantum mechanics complicates the matter. When placing the planet in a state of superposition near one ship or the other, both can be destroyed or survive at the same time. The sequence of events exists in a state of superposition, such that each starship simultaneously destroys the other.

The authors illustrate for the first time how this quantum scenario can occur and how it can be verified. "Moving planets around is hard," said Pikovski. "But imagining it helped us examine a quantum aspect of time that was previously unknown."

Ew, a cockroach! But it zips off before the swatter appears. Now, researchers have leveraged the bug's superb scurrying skills to create a cleverly simple method to assess and improve locomotion in robots.

Normally, tedious modeling of mechanics, electronics, and information science is required to understand how insects' or robots' moving parts coordinate smoothly to take them places. But in a new study, biomechanics researchers at the Georgia Institute of Technology boiled down the sprints of cockroaches to handy principles and equations they then used to make a test robot amble about better.

The method told the researchers about how each leg operates on its own, how they all come together as a whole, and the harmony or lack thereof in how they do it. Despite bugs' and bots' utterly divergent motion dynamics, the new method worked for both and should work for other robots and animals, too.

The biological robot, the roach, was the far superior runner with neurological signals guiding six impeccably evolved legs. The mechanical robot, a consumer model, had four stubby legs and no nervous system but relied instead for locomotion control on coarse physical forces traveling through its chassis as crude signals to roughly coordinate its clunky gait.

"The robot was much bulkier and could hardly sense its environment. The cockroach had many senses and can adapt better to rough terrain. Bumps as high as its hips wouldn't slow it down at all," said Izaak Neveln, the study's first author, who was a postdoctoral researcher in the lab of Simon Sponberg at Georgia Tech during the study.

Advanced simplicity

The method, or "measure," as the study calls it, transcended these huge differences, which pervade animal-inspired robotics.

"The measure is general (universal) in the sense that it can be used regardless of whether the signals are neural spiking patterns, kinematics, voltages or forces and does not depend on the particular relationship between the signals," the study's authors wrote.

No matter how a bug or a bot functions, the measure's mathematical inputs and outputs are always in the same units. The measure will not always eliminate the need for modeling, but it stands to shorten and guide modeling and avert anguishing missteps.

The authors published the study in the journal Nature Communications in August 2019. The research was funded by the National Science Foundation. Sponberg is an assistant professor in Georgia Tech's School of Physics and in the School of Biological Sciences.

Centralization vs. decentralization

Often a bot or an animal sends many walking signals through a central system to harmonize locomotion, but not all signals are centralized. Even in humans, though locomotion strongly depends on signals from the central nervous system, some neural signals are confined to regions of the body; they are localized signals.

Some insects appear to move with little centralization -- such as stick bugs, also known as walking sticks, whose legs prod about nearly independently. Stick bugs are wonky runners.

"The idea has been that the stick bugs have the more localized control of motion, whereas a cockroach goes very fast and needs to maintain stability, and its motion control is probably more centralized, more clocklike," Neveln said.

Strong centralization of signals generally coordinates locomotion better. It could be code traveling through an elaborate robot's wiring, a cockroach's central neurons synching its legs, or the clunky robot's chassis tilting away from a leg thumping the ground thus putting weight onto an opposing leg. Roboticists need to see through the differences and figure out the interplay of a locomotor's local and central signals.

Cool physics

The new "measure" does this by focusing on an overarching phenomenon in the walking legs, which can be seen as pendula moving back and forth. For great locomotion, they need to synch up in what is called phase-coupling oscillations.

A fun, easy experiment illustrates this physics principle. If a few, say six, metronomes - ticking rhythm pendula that piano teachers use -- are swinging out of sync, and you place them all on a platform that freely sways along with the metronomes' swings, the swings will sync up in unison.

The phases, or directions, of their oscillations are coupling with each other by centralizing their composite mechanical impulses through the platform. This particular example of phase-coupling is mechanical, but it can also be computational or neurological -- like in the roach.

Its legs would be analogous to the swinging metronomes, and central neuromuscular activity analogous to the free-swaying platform. In the roach, not all six legs swing in the same direction.

"Their synchronization is not uniform. Three legs are synchronized in phase with each other -- the front and back legs of one side with the middle leg of the other side -- and those three are synchronized out of phase with the other three," Neveln said. "It's an alternating tripod gait. One tripod of three legs alternates with the other tripod of three legs."

Useless pogoing

And just like pendula, each leg's swings can be graphed as a wave. All the legs' waves can be averaged into an overall roach scurry wave and then developed into more useful math that relates centralization with decentralization and factors like entropy that can throw locomotion control off.

The resulting principles and math benefited the clunky robot, which has strong decentralized signals in its leg motors that react to leg contact with the ground, and centralized control weaker than the stick bug's. The researchers graphed out the robot's movements, too, but they didn't result in the neatly synced group of waves that the cockroach had.

The researchers turned with the principles and math to the clunky robot, which initially was out of sorts -- bucking or hopping uselessly like a pogo stick. Then the scientists strengthened centralized control by re-weighting its chassis to make it move more coherently.

"The metronomes on the platform are mechanical coupling, and our robot coordinates control that way," Neveln said. "You can change the mechanical coupling of the robot by repositioning its weights. We were able to predict the changes this would make by using the measure we developed from the cockroach."

Cockroach surprises

The researchers also wired up specific roach muscles and neurons to observe their syncopations with the scurry waves. Seventeen cockroaches took 2,982 strides to inform the principles and math, and the bugs also sprung surprises on the researchers.

One stuck out: The scientists had thought signaling centralized more when the roach sped up, but instead, both central and local signaling strengthened, perhaps doubling down on the message: Run!

ATLANTA--Targeting specific areas of the measles virus polymerase, a protein complex that copies the viral genome, can effectively fight the measles virus and be used as an approach to developing new antiviral drugs to treat the serious infectious disease, according to a study by the Institute for Biomedical Sciences at Georgia State University published in PLoS Pathogens.

Measles is a highly contagious virus that can lead to serious health complications and death. It begins with a fever, cough, runny nose and red eyes followed by a rash of tiny, red spots that starts at the head and spreads to the rest of the body. Although declared eliminated in the United States in 2000, the Centers for Disease Control and Prevention says the U.S. is experiencing the greatest number of measles cases reported since the early 1990s.

While an effective vaccine exists, there has been a steady decline in the number of people being vaccinated against the measles virus. Most new cases were among unvaccinated individuals, making the development of an effective treatment strategy complementing vaccination a public health priority. There are no antivirals licensed to treat measles. The new study identified a novel protein interface in the polymerase complex that is pivotal for the regulation of polymerase activity, providing a new objective for target-based antiviral drug discovery.

"We have advanced current understanding of the underlying mechanism of viral RNA-dependent RNA polymerase advancement along the encapsidated genome - a poorly understood and not well characterized mechanism - by identifying and characterizing the dynamic interactions between its constituents," said Venice Du Pont, first author of the study and a Ph.D. candidate working in Dr. Richard Plemper's lab in the Institute for Biomedical Sciences.

The study proposes a novel model of dynamic binding and dissociation interacting proteins in the viral polymerase complex, describing how the polymerase negotiates and regulates advancement along the viral genome. This insight has revealed a vulnerability that could be exploited as a target for small-molecule antiviral drugs.

"In recent years, enormous progress has been made to successfully target protein-protein interfaces for therapeutic purpose with chemical fragment libraries," said Dr. Richard K. Plemper, professor in the Institute for Biomedical Sciences and senior author on the study. "The newly identified interface in the paramyxovirus polymerase machinery meets key criteria of a druggable target, and is very likely mechanistically conserved in highly pathogenic paramyxoviruses closely related to measles virus such as the zoonotic Nipah virus, against which we have currently no treatment option."

The study was funded by the National Institutes of Health's National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Cancer Institute and National Eye Institute.

An additional co-author is Dr. Yi Jiang, associate professor in the College of Arts & Sciences' Department of Mathematics and Statistics at Georgia State.

"This work would not have been possible without this effective collaboration across diverse departments," said Plemper, emphasizing how a collegial atmosphere at Georgia State fosters groundbreaking discoveries.

Fasting regimens have gained public and scientific interest in recent years, but fasting shouldn't be dismissed as a fad. In a study published in Cell, Mount Sinai researchers found that fasting reduces inflammation and improves chronic inflammatory diseases without affecting the immune system's response to acute infections.

While acute inflammation is a normal immune process that helps fight off infections, chronic inflammation can have serious consequences for health, including heart disease, diabetes, cancer, multiple sclerosis, and inflammatory bowel diseases.

"Caloric restriction is known to improve inflammatory and autoimmune diseases, but the mechanisms by which reduced caloric intake controls inflammation have been poorly understood," said senior author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai.

Working with human and mouse immune cells, Dr. Merad and colleagues showed that intermittent fasting reduced the release of pro-inflammatory cells called "monocytes" in blood circulation. Further investigations revealed that during periods of fasting, these cells go into "sleep mode" and are less inflammatory than monocytes found in those who were fed.

"Monocytes are highly inflammatory immune cells that can cause serious tissue damage, and the population has seen an increasing amount in their blood circulation as a result of eating habits that humans have acquired in recent centuries," said Dr. Merad.

"Considering the broad spectrum of diseases that are caused by chronic inflammation and the increasing number of patients affected by these diseases, there is an enormous potential in investigating the anti-inflammatory effects of fasting," said first author Stefan Jordan, PhD, a postdoctoral fellow in the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai.

Researchers plan to continue trying to decipher the molecular mechanisms by which fasting improves inflammatory diseases, which could lead to novel preventive therapeutic strategies for the treatment of many human diseases.

Cells can be viewed as natural minicomputers that execute programs encoded in their DNA. In a paper appearing August 22 in the journal Molecular Cell, MIT researchers describe a new technology that uses DNA for information processing and storage in living cells.

Using a system called DOMINO (DNA-based Ordered Memory and Iteration Network Operator), the technology can execute cascades of DNA writing events - where one DNA mutation event triggers another - in response to biological signals. This technology enables the deep interrogation of biology and the use of engineered cells as living computing and recording devices that can process, monitor, and store information occurring within cells and/or their environment.

"We need better strategies to unravel how complex biology works, especially in diseases like cancer where multiple biological events can occur to transform normal cell into diseased ones," says senior author Timothy Lu, an electrical engineer and computer scientist at MIT and the Broad Institute. "With this method we are using DNA as a memory tape to permanently record biological events that are occur in disease. This technology can give us deeper insights into what signals go up and down over time to drive disease development."

The team's DOMINO technology builds on established genome-editing CRISPR tools. Instead of cutting the DNA at a specific location, DOMINO uses a base editing approach to overwrite DNA at particular locations.

With DOMINO, we can write DNA to change the information encoded into different positions, and then read out this information on the fly, like a read-write head in a computer hard drive" says first author Fahim Farzadfard, a postdoctoral fellow and former PhD student in Lu's laboratory who developed the DOMINO concept.

"We can also combine and layer multiple DNA reading and writing events together to build various forms of logic, such as 'AND' and 'OR' operations, which can then be used to create more complex memory and computing operations in living cells."

DOMINO is a modular system made of operator units. Each unit is composed of a base editor (a non-cutting variant of Cas9 fused to a cytidine deaminase) and one guide RNA that binds to its complementary sequence on the genome and recruits the base editor to that sequence. Once recruited, the base editor can introduce cytosine (C) to thymine (T) mutations into the vicinity of the gRNA binding site. The guide RNA in DOMINO operator can be designed in a way that it can bind to its target sequence only after a certain mutation is first introduced into that sequence by a previous event. Thus, for the base editor to make a change, a previous mutation must have been made so that the next mutation can be made. If a particular sequence is mutated, then the next step can happen.

If it is not mutated, then the next step cannot happen. That allows a cascade of writing events that is ultimately 'recorded' as unique mutational signatures in the cell's DNA. These signatures can be read out by DNA sequencing to infer information about the history of events or be read out by other DOMINO operators that couple the information into downstream computations. The team also demonstrated that these DNA signatures can be coupled with a fluorescent reporter, so that DNA writing/editing results in higher fluorescence signal. This allows for continuous monitoring of DNA memory without the need to kill cells for sequencing.

Currently, the team has used the technology to record events on the order of hours. But they are hopeful they can improve the temporal resolution and adapt it for recording cellular events that occur on faster timescales. They also plan on expanding DOMINO's application to highly-parallel computing and recording to process and interrogate more complex biological events.

"This type of biocomputing is an exciting new way of getting and processing information," says Lu. "It is part of a longer-term path to take advantage of the natural memory and computing capabilities in cells." Other applications include using cells as sensors and storage vehicles within the body or in the environment, such as a biosensor to record contamination levels in water. "These designer cells can constantly assess their environment and record information that can be read at a later time," says Lu.

"Biological systems can be thought of as conglomerates of information processing and storage systems, with DNA being one of the many possible media that can be used. The ability to read and write DNA and possibly other biological media could bring us closer to be able to study and program biology in a modular systematic fashion," says Farzadfard.

Researchers at the Paul Scherrer Institute, together with colleagues from the pharmaceutical company F. Hoffmann-La Roche AG, have taken an important step towards the development of an agent against the metastasis of certain cancers. Using the Swiss Light Source, they deciphered the structure of a receptor that plays a crucial role in the migration of cancer cells. This makes it possible to identify agents that could prevent the spread of certain cancer cells via the body's lymphatic system. The researchers have now published their results in the journal Cell.

When cancer cells spread in the body, secondary tumours, called metastases, can develop. These are responsible for around 90 percent of deaths in cancer patients. An important pathway for spreading the cancer cells is through the lymphatic system, which, like the system of blood vessels, runs through the entire body and connects lymph nodes to each other. In the migration of white blood cells through this system, for example to coordinate the defense against pathogens, one special membrane protein, the chemokine receptor 7 (CCR7) plays an important role. It sits in the shell of the cells, the cell membrane, in such a way that it can receive external signals and relay them to the interior. Within the framework of a joint project with the pharmaceutical company F. Hoffmann-La Roche AG (Roche), researchers at the Paul Scherrer Institute (PSI) have for the first time been able to decipher the structure of CCR7 and lay the foundation for the development of a drug that could prevent metastasis in certain prevalent cancer types, such as colorectal cancer.

In the cells of all vertebrates, there are 20 different chemokine receptors that can interact with more than 40 signaling proteins called chemokines. Each of these signaling proteins fits only to very specific receptors. In turn, if one of the signaling proteins binds to a receptor, it triggers processes inside the cell that lead to a specific cellular response to the signal.

CCR7 is one of the receptors that control the movement of cells within the body. As soon as the appropriate signaling protein outside the cell binds to it, a chain reaction in the cell causes the cell to move in the direction of the highest concentration of the signaling protein. The cell follows the track of the chemokine like a hound following a scent. For example, a constant flow of white blood cells, important cells of the body's immune system, is directed to the lymph nodes.

Cancer cells too can take advantage of CCR7 and misuse the cell receptor for their own purposes. The appropriate signaling protein guides them out of the tumour and into the lymphatic system. Furthermore, they spread in the body and eventually form metastases in other tissues. These daughter tumours drastically increase the mortality risk for those affected.

Artificial agents prevent cells from migrating

To increase the survival rate of cancer patients, it is of great medical interest to suppress the metastasis process. That is why PSI researchers have used X-ray crystallography at the Swiss Light Source (SLS) at PSI to decipher the structure of the CCR7 receptor.

This structure served as the basis of the search, in collaboration with Roche, for corresponding active agents. "The right molecule can prevent the signaling protein from coupling to the receptor and causing a reaction in the cell", explains Steffen Brünle, who conducted the study as a postdoctoral researcher in the PSI-FELLOW-II-3i programme and is one of the first authors of the paper. Deciphering the structure of the receptor was a real challenge. "The difficult thing about it was producing them, in the first place, in such a way that we could examine them with X-ray crystallography", says Jörg Standfuss, co-leader of the project and the Time-Resolved Crystallography research group at PSI. In order to speed up the research process, Roche developed its own new protein-modifying technology modules, so-called crystallisation chaperones.

With information about the precise structure of the receptor, they were able to identify a suitable molecule that blocks the receptor and thus prevents a signal from being transmitted into the cell. "Our experiments show that the artificial molecule, inside the cell, binds to the receptor. This keeps the chain reaction that leads to cell migration from getting started", Brünle says.

The value of scientific collaboration

From millions of molecules deposited in a database at Roche, and using the structure of the drug-bound receptor, Roche scientists used computer simulation to search for fitting agents that could be suitable for blocking the signaling protein, and they identified five compounds as possible candidates for further development of potential cancer therapy drugs.

Also, one of the active agents the researchers discovered in their study is already being tested by the pharmaceutical industry, in clinical trials, as a potential drug against metastasis. Previously it had been thought that this agent binds to a different receptor and thus inhibits another function of the cancer cell. This highlights how insights from such studies can be extraordinarily valuable for pharmaceutical research and development.

The researchers have now published their results in the journal Cell.

CAMBRIDGE, MA -- MIT biologists have discovered an unexpected effect of a ketogenic, or fat-rich, diet: They showed that high levels of ketone bodies, molecules produced by the breakdown of fat, help the intestine to maintain a large pool of adult stem cells, which are crucial for keeping the intestinal lining healthy.

The researchers also found that intestinal stem cells produce unusually high levels of ketone bodies even in the absence of a high-fat diet. These ketone bodies activate a well-known signaling pathway called Notch, which has previously been shown to help regulate stem cell differentiation.

"Ketone bodies are one of the first examples of how a metabolite instructs stem cell fate in the intestine," says Omer Yilmaz, the Eisen and Chang Career Development Associate Professor of Biology and a member of MIT's Koch Institute for Integrative Cancer Research. "These ketone bodies, which are normally thought to play a critical role in energy maintenance during times of nutritional stress, engage the Notch pathway to enhance stem cell function. Changes in ketone body levels in different nutritional states or diets enable stem cells to adapt to different physiologies."

In a study of mice, the researchers found that a ketogenic diet gave intestinal stem cells a regenerative boost that made them better able to recover from damage to the intestinal lining, compared to the stem cells of mice on a regular diet.

Yilmaz is the senior author of the study, which appears in the Aug. 22 issue of Cell. MIT postdoc Chia-Wei Cheng is the paper's lead author.

An unexpected role

Adult stem cells, which can differentiate into many different cell types, are found in tissues throughout the body. These stem cells are particularly important in the intestine because the intestinal lining is replaced every few days. Yilmaz' lab has previously shown that fasting enhances stem cell function in aged mice, and that a high-fat diet can stimulate rapid growth of stem cell populations in the intestine.

In this study, the research team wanted to study the possible role of metabolism in the function of intestinal stem cells. By analyzing gene expression data, Cheng discovered that several enzymes involved in the production of ketone bodies are more abundant in intestinal stem cells than in other types of cells.

When a very high-fat diet is consumed, cells use these enzymes to break down fat into ketone bodies, which the body can use for fuel in the absence of carbohydrates. However, because these enzymes are so active in intestinal stem cells, these cells have unusually high ketone body levels even when a normal diet is consumed.

To their surprise, the researchers found that the ketones stimulate the Notch signaling pathway, which is known to be critical for regulating stem cell functions such as regenerating damaged tissue.

"Intestinal stem cells can generate ketone bodies by themselves, and use them to sustain their own stemness through fine-tuning a hardwired developmental pathway that controls cell lineage and fate," Cheng says.

In mice, the researchers showed that a ketogenic diet enhanced this effect, and mice on such a diet were better able to regenerate new intestinal tissue. When the researchers fed the mice a high-sugar diet, they saw the opposite effect: Ketone production and stem cell function both declined.

Stem cell function

The study helps to answer some questions raised by Yilmaz' previous work showing that both fasting and high-fat diets enhance intestinal stem cell function. The new findings suggest that stimulating ketogenesis through any kind of diet that limits carbohydrate intake helps promote stem cell proliferation.

"Ketone bodies become highly induced in the intestine during periods of food deprivation and play an important role in the process of preserving and enhancing stem cell activity," Yilmaz says. "When food isn't readily available, it might be that the intestine needs to preserve stem cell function so that when nutrients become replete, you have a pool of very active stem cells that can go on to repopulate the cells of the intestine."

The findings suggest that a ketogenic diet, which would drive ketone body production in the intestine, might be helpful for repairing damage to the intestinal lining, which can occur in cancer patients receiving radiation or chemotherapy treatments, Yilmaz says.

The researchers now plan to study whether adult stem cells in other types of tissue use ketone bodies to regulate their function. Another key question is whether ketone-induced stem cell activity could be linked to cancer development, because there is evidence that some tumors in the intestines and other tissues arise from stem cells.

"If an intervention drives stem cell proliferation, a population of cells that serve as the origin of some tumors, could such an intervention possibly elevate cancer risk? That's something we want to understand," Yilmaz says. "What role do these ketone bodies play in the early steps of tumor formation, and can driving this pathway too much, either through diet or small molecule mimetics, impact cancer formation? We just don't know the answer to those questions."

Researchers at UC San Francisco and the University of Queensland have discovered a scorpion toxin that targets the "wasabi receptor," a chemical-sensing protein found in nerve cells that's responsible for the sinus-jolting sting of wasabi and the flood of tears associated with chopping onions. Because the toxin triggers a pain response through a previously unknown mechanism, scientists think it can be used as a tool for studying chronic pain and inflammation, and may eventually lead to the development of new kinds of non-opioid pain relievers.

The scientists isolated the toxin, a short protein (or peptide) that they dubbed the "wasabi receptor toxin" (WaTx), from the venom of the Australian Black Rock scorpion. The discovery came as the researchers were conducting a systematic search for compounds in animal venom that could activate, and therefore be used to probe and study, the wasabi receptor -- a sensory protein officially named TRPA1 (pronounced "trip A1") that's embedded in sensory nerve endings throughout the body. When activated, TRPA1 opens to reveal a channel that allows sodium and calcium ions to flow into the cell, which can induce pain and inflammation.

"Think of TRPA1 as the body's 'fire alarm' for chemical irritants in the environment," said John Lin King, a doctoral student in UCSF's Neuroscience Graduate Program and lead author of a study published August 22, 2019 in Cell, which describes the toxin and its surprising mode of action. "When this receptor encounters a potentially harmful compound -- specifically, a class of chemicals known as 'reactive electrophiles,' which can cause significant damage to cells -- it is activated to let you know you're being exposed to something dangerous that you need to remove yourself from."

Cigarette smoke and environmental pollutants, for example, are rich in reactive electrophiles which can trigger TRPA1 in the cells that line the surface of the body's airway, which can induce coughing fits and sustained airway inflammation. The receptor can also be activated by chemicals in pungent foods like wasabi, onions, mustard, ginger and garlic -- compounds that, according to Lin King, may have evolved to discourage animals from eating these plants. WaTx appears to have evolved for the same reason.

Though many animals use venom to paralyze or kill their prey, WaTx seems to serve a purely defensive purpose. Virtually all animals, from worms to humans, have some form of TRPA1. But the researchers found that WaTx can only activate the version found in mammals, which aren't on the menu for Black Rock scorpions, suggesting that the toxin is mainly used to ward off mammalian predators.

"Our results provide a beautiful and striking example of convergent evolution, whereby distantly related life forms -- plants and animals -- have developed defensive strategies that target the same mammalian receptor through completely distinct strategies," said David Julius, PhD, professor and chair of UCSF's Department of Physiology, and senior author of the new study.

But what the researchers found most interesting about WaTx was its mode of action. Though it triggers TRPA1, just as the compounds found in pungent plants do -- and even targets the very same site on that receptor -- the way it activates the receptor was novel and unexpected.

First, WaTx forces its way into the cell, circumventing the standard routes that place strict limits on what's allowed in and out. Most compounds, from tiny ions to large molecules, are either ingested by the cell through a complex process known as "endocytosis," or they gain entry by passing through one of the many protein channels that stud the cell's surface and act as gatekeepers.

But WaTx contains an unusual sequence of amino acids that allows it to simply penetrate the cell's membrane and pass right through to the cell's interior. Few other proteins are capable of the same feat. The most famous example is an HIV protein called Tat, but surprisingly, WaTx contains no sequences similar to those found in Tat or in any other protein that can pass through the cell's membrane.

"It was surprising to find a toxin that can pass directly through membranes. This is unusual for peptide toxins," Lin King said. "But it's also exciting because if you understand how these peptides get across the membrane, you might be able to use them to carry things -- drugs, for example -- into the cell that can't normally get across membranes."

Once inside the cell, WaTx attaches itself to a site on TRPA1 known as the "allosteric nexus," the very same site targeted by pungent plant compounds and environmental irritants like smoke. But that's where the similarities end.

Plant and environmental irritants alter the chemistry of the allosteric nexus, which causes the TRPA1 channel to rapidly flutter open and closed. This allows positively charged sodium and calcium ions to flow into the cell, triggering pain. Though both ions are able to enter when TRPA1 is activated by these irritants, the channel exhibits a strong preference for calcium and lets much more of it into the cell, which leads to inflammation. By contrast, WaTx wedges itself into the allosteric nexus and props the channel open. This abolishes its preference for calcium. As a result, overall ion levels are high enough to trigger a pain response, but calcium levels remain too low to initiate inflammation.

To demonstrate this, the researchers injected either mustard oil, a plant irritant known to activate the wasabi receptor, or WaTx into the paws of mice. With mustard oil, they observed acute pain, hypersensitivity to temperature and touch -- key hallmarks of chronic pain -- and inflammation, as evidenced by significant swelling. But with WaTx, they observed acute pain and pain hypersensitivities, but no swelling.

"When triggered by calcium, nerve cells can release pro-inflammatory signals that tell the immune system that something's wrong and needs to be repaired," Lin King said. "This 'neurogenic inflammation' is one of the key processes that becomes dysregulated in chronic pain. Our results suggest that you can decouple the protective acute pain response from the inflammation that establishes chronic pain. Achieving this goal, if only in principle, has been a longstanding aim in the field."

The researchers believe their findings will lead to a better understanding of acute pain, as well as the link between chronic pain and inflammation, which were previously thought to be experimentally indistinguishable. The findings may even lay the groundwork for the development of new pain drugs.

"The discovery of this toxin provides scientists with a new tool that can be used to probe the molecular mechanisms of pain, in particular, to selectively probe the processes that lead to pain hypersensitivity," Lin King said. "And for those interested in drug discovery, our findings underscore the promise of TRPA1 as a target for new classes of non-opioid analgesics to treat chronic pain."

Washington, D.C. (August 22, 2019) - A new report published in the July issue of the Journal of the American College of Nutrition by pediatrician Dr. Robert D. Murray supports existing scientific data maintaining juice as part of a healthy diet. The report reinforces that claims that 100% juice may be associated with childhood weight gain or negative health outcomes have not been supported by recent scientific research including a number of systematic reviews and meta-analyses.

"Juice has recently been cast in a negative light without scientific evidence to support these claims," said Dr. Robert Murray, pediatric nutritionist and immediate past president of the Ohio Chapter of the American Academy of Pediatrics. "This report encourages parents and other consumers to look at a child's total diet before judging foods or beverages "good" or "bad." Foods should be judged not on individual attributes such as fat or sugar but on their contributions to the diet as a whole."

"Drinking 100% fruit juice has many positive attributes that improve overall diet quality," Dr. Murray stated, "When juice is eliminated from a child's diet, it can have unintended negative nutritional consequences, especially for low-income populations."

National surveys show many Americans have poor quality diets. The report notes that while juices do lack fiber, they retain the majority of the same health-promoting nutrients, bioactives and phytochemicals found in whole fruit. Fruit juice drinkers also have better quality diets, consume more whole fruit, less added sugar and saturated fat and greater amounts of vitamin C, magnesium, potassium, and fiber than non-juice drinkers.

"Over the past three decades, fruit juice consumption has fallen substantially yet the gap has not been filled by the consumption of whole fruit. A combination of whole fruit and juice is the best way for children and adults to meet their daily-recommended fruit servings and improve their overall diet," said Dr. Murray. "Young children are typically the biggest juice drinkers. They are also the only age group in the United States consuming enough servings of fruit."

A team of scientists from School of Engineering at Far Eastern Federal University (FEFU), Institute of Automation and Control Processes, and Institute of Marine Technology Problems of the Far Eastern Department of the Russian Academy of Sciences developed a software module to automatically diagnose defects in sensors and electric drives in various kinds of robots. The system is able to compensate for the detected defects in real time.

Using the software module, a robot can identify constant and variable errors in the signals of its sensors and malfunctions of electromechanical drives and corrects the control signals accordingly. The module eliminates all possible external noise and prevents distortions in sensor signals thus preserving the required levels of operating quality. The new development was presented at the international conference ICCAD'19 that took place in Grenoble, France on July 2-4.

'Even an efficient system might experience issues such as external noise that distorts software signals, malfunctioning sensors, overheated engines, or increased friction due to foreign inclusions. We've developed a range of mathematical controllers, identifiers, and filters that are united under one software module. Using it, a robot can preserve the required accuracy of its work. It can identify the defects and their volumes and, acting just like humans, form signals to compensate for the negative consequences of these defects. At the same time, our module doesn't make the whole control system too complex,' says Professor Vladimir Filaretov, PhD in Technical Sciences, the Head of the Department of Automation and Control at the School of Engineering, Far Eastern Federal University.

Alexander Zuev, assistant professor of the Department of Automation and Control, adds that the methods for the identification and further correction of defects in control signals of mechatronic systems were being intensively developed in the whole world. However, until now the scientists failed to take the dynamics of robots into consideration because it requires complex mathematical transformations. This reduces the quality of diagnostics. Moreover, previously the scientists were able to correct the control signals only in simple machines and only if defects occurred in just one sensor.

'Our mathematical apparatus implemented in the software allows a robot to accurately identify the defects and compensate for their consequences in the presence of numerous external interferences when several sensors malfunction at the same time and the parameters of an electric drive change. The software is universal and can be applied to all types of robots', explains Alexander Zuev.

At the ICCAD'19 conference the team from FEFU also presented a new control principle for smart industrial robots. It lies in the management of software signals on several levels - the executive and the strategic ones. It also takes into account inevitable errors made in the course of manufacture of mechanical robotic parts and provides for the correction of the management program in order to allow the machines to fulfil extra-accurate tasks and preserve high efficiency levels.

The new module is a part of a universal program for smart control of software signals in robots.

Swansea University scientists have reported a new approach to measuring the conductivity between identical carbon nanotubes which could be used to help improve the efficiency of electrical power cables in the future.

The new research is published in the American Chemical Society journal Nano Letters. The paper details how the Swansea University research team, based at the Energy Safety Research Institute (ESRI) working with Rice University researchers, made real physical measurements of carbon nanotubes conductivity.

Carbon nanotubes are tiny molecule with incredible physical properties. These cylindrical molecules are filled with hexagonal carbon atoms that look a little like chicken wire wrapped into a graphene tube and are used to produce lightweight wire. These can be made into strong efficient electrical power cable that have the potential to replace existing metal cables, which often overheat and fail - and can lose about 8% of electricity in transmission and distribution globally.

The new study is a significant step forward as previous studies examining conductivity levels could only use theoretical calculations in their measurements. Another limitation was that theoretical studies looked at nanotubes that were similar in diameter - but in reality the diameters of nanotubes vary and it is this variation that makes theoretical models impossible to prove and leads to real practical issues when measuring conductivity in carbon nanotubes.

ESRI Director, Professor Andrew Barron, who is also professor at Rice University, and his research team noticed that if two carbon nanotubes of different diameter were laid across each other the resistance at the point of contact was higher than if they were similar in diameter. The team passed a large voltage through one of the crossed carbon nanotubes which broke it and the two halves were welded to the probes.

The two halves of the original carbon nanotube could then be handled in such a way that any measurement guaranteed that the diameter and type were the same - since the two carbon nanotubes were actually from the same carbon nanotube. Once this was discovered, the team set about experimentally reproducing measurements that were previously only theoretical.

The team also found that through their practical experiments they were able to prove some key theories:

Varying the angle of overlap between the two halves of the original carbon nanotube shows a variation in electrical conductivity.

Measuring conductivity between two parallel halves of cut carbon nanotube leads to results that are consistent with the theoretical concept of atomic scale registry.

More detail on the experiments can be found in the study abstract.

Professor Barron said; "This is the first time that it has been possible to make experimental measurements to confirm theoretical models. While it is nice to confirm theory with a real experiment, our methodology now opens up a myriad of possibilities for measurements not previously possible. We are looking forward to expanding the basic knowledge of carbon nanotubes that will help us in the production of efficient electrical cabling and a myriad of other technologies in the future."

AUGUST 22, 2019, NEW YORK-- A Ludwig Cancer Research study has uncovered a novel vulnerability in tumors that are driven by a common cancer gene known as MYC. Such cancers, it found, are highly dependent on the cell's machinery for making fats and other lipids.

Led by Chi Van Dang, scientific director of the Ludwig Institute for Cancer Research, and Stanford University researchers Dean Felsher and Richard Zare, the study also identifies a lipid signature associated with MYC-driven cancers. Further, it demonstrates that the cancer cell's predilection for manufacturing lipids rather than importing them as nutrients may be exploited for the development of new therapies for a broad spectrum of malignancies. The paper appears in the current issue of Cell Metabolism.

"Cells that are not growing bring in nutrients from the blood and make some of the other metabolic molecules they need," explains Dang. "But if you're a rapidly replicating cancer cell, you need a much larger supply of the building blocks of cells in order to continue proliferating."

Dang's laboratory previously discovered that MYC's dysregulation in cancer alters cellular metabolism and detailed how this master regulator of gene expression cranks up production of the molecular building blocks of cells, including the components of proteins and DNA. But how precisely oncogenic MYC alters gene expression to drive lipid synthesis was unknown. Lipids are critical constituents of cells: they build the cell's membranes and play an important role in protein function, metabolic reactions and molecular signaling.

In normal cells, a membrane-bound protein named SREBP1 monitors and controls lipid production. When it senses low cholesterol levels in the cell's membranes, SREBP1 moves into the nucleus and activates the expression of genes involved in lipid synthesis.

Postdoctoral researcher Arvin Gouw--who was previously in Dang's lab and is now in Felsher's--and colleagues found that the MYC protein boosts the expression of SREBP1. "What MYC does is put SREBP into overdrive and SREBP jumps onto the genes involved in lipid synthesis," Dang explains. "But we also found that MYC then binds to the same genes as SREBP1, and the two collaborate to push lipid synthesis to even higher levels." The researchers show that MYC controls the gene expression required for almost every stage of lipid synthesis, from the generation of precursor molecules to putting the finishing touches on large, complex lipids.

To further examine the phenomenon, postdoctoral researcher Katy Margulis and colleagues used DESI-MSI--a technology for profiling metabolites in intact tissues developed by Zare's lab--to map how oncogenic MYC alters the lipid content of tumors. Those studies revealed that a species of lipids known as glycerophosphoglycerols is particularly abundant in MYC-driven cancer cells. The researchers even identified a lipid signature associated with such tumors that could be used as a diagnostic marker.

Studies on mice engineered by Felsher's lab to generate, on demand, MYC-driven cancers of the blood, lungs, kidneys and liver revealed that such tumors are highly dependent on fatty acid synthesis. Inhibiting an early step of that process led to the regression of the induced tumors and of MYC-driven human tumors implanted in mice. Together with the identification of a lipid signature and the genes activated by oncogenic MYC, these data provide concrete information for the development of new drugs to treat a broad range of cancers.

"A very diverse expertise was essential to this study," Dang observes. "Bringing these various technologies and knowhow together enabled a deep understanding of something we didn't have great ideas about before, and it illustrates the power of interdisciplinary collaboration."

The findings are particularly notable because MYC is the third most amplified gene in human cancers. Even tumors that are primarily driven by other oncogenes, the researchers show, are susceptible to the inhibition of fatty acid production if they indirectly activate MYC.

Dang, for his part, is now interested in unraveling how cancer cells sense which lipids need to be made and how that information shapes MYC's activation of lipid synthesis.

This study was supported by Ludwig Cancer Research, the U.S. National Institutes of Health and the Stanford Center of Molecular Analysis and Design.

In addition to his Ludwig post, Dang is also a Professor at The Wistar Institute.

Oak Brook, IL - In September's SLAS Discovery cover article, "Using Physicochemical Measurements to Influence Better Compound Design," authors Robert J. Young, Ph.D., Shenaz B. Bunally, Ph.D., and Chris N. Luscombe, Ph.D., (GlaxoSmithKline) outline commonly used physiochemical properties and how they are assessed and measured throughout the drug discovery process, while also explaining the implications of each property that have led to flawed results. This review also offers suggestions on which contemporary methods can be used to improve subpar testing outcomes.

Quantifying the physicochemical make-up of investigational molecules is fundamental to understanding the mechanisms and interactions of drug molecules. In this perspective Bunally, Luscombe and Young introduce key parameters, what they mean and how they are measured and predicted in best practice. The issues with suboptimal properties characterized by excessive lipophilicity and/or poor solubility are varied, ranging from poor outcomes in screening campaigns, promiscuity, limited and/or poorly predictable pharmacokinetic exposure and a greater chance of clinical failure.

High-throughput measurements enable data to be gathered on all experimental compounds, which are then analyzed and established as Structure Property Relationships (SPRs). This should more-rapidly identify both good and bad outliers, which enable enhanced interpretation of results and prioritization of better structures for progression. Increasingly, these data provide the basis for temporal analysis and generation of improved predictive models ? of the descriptors themselves or of more complex models where the descriptors have profound impact.

An introduction to the methods and techniques employed in model building provides background to the basis of modern Predict First cultures. And while the role of artificial intelligence in drug discovery is currently a hot topic and the utility of predicted physical properties is well-established, they're not as widely utilized in drug discovery measurements as they could be. The routine generation of high-throughput measurements, the subsequent evaluation of SPRs and generation of in silico predictive models should expedite this progress through improved quality by design in experimental molecules.

CINCINNATI--The extract of the leaves of Ginkgo biloba, a popular dietary supplement, may offer some therapeutic benefits in fighting Type 2 diabetes, according to a study co-authored by a researcher at the University of Cincinnati (UC) College of Medicine.

"In diabetic rats Ginkgo biloba had a very good effect on the beta cells of Langerhans--cells in the pancreas responsible for insulin secretion--by creating a restorative effect similar to what we see in healthy non-diabetic rats," says Helal Fouad Hetta, PhD, a postdoctoral fellow and scientist in the UC Division of Digestive Diseases. Hetta is also on faculty at Egypt's Assiut University College of Medicine in the Department of Medical Microbiology and Immunology.

The study in animal models by an international team of 13 researchers was published in the journal Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy and is available online. The first author on the research is Ahmed Saleh, PhD, Jazan University in Saudi Arabia.

"The extracts derived from Ginkgo biloba have been frequently used in traditional medicine and have been shown to exhibit antioxidant potency," says Hetta. "Magnetized water, which has been passed through a magnetic field, has also been reported to reduce blood glucose, improve antioxidant status and lipid profiles in diabetic rat models."

In this study, Type 2 Diabetes was induced by feeding rats a high-fat-diet for eight weeks followed by intra-peritoneal injection of a single low dose of streptozotocin, explains Hetta. Forty rats were randomly assigned to four groups: a non-diabetic control group and three diabetic groups. One diabetic group served as a positive control (diabetic), while the other two groups were orally administered with water extract of Ginkgo biloba leaves and magnetized water for four weeks, respectively.

The pancreatic beta cells of diabetic rats are reduced and insulin secretion is curtailed. After having Ginkgo biloba and magnetized water added to their diets, the mass of the pancreatic beta cells and the amount of insulin in these cells was shown to increase markedly, almost back to normal levels, particularly in the Ginkgo biloba-treated group, says Hetta.

In addition, both Ginkgo biloba and magnetized water improved the anti-oxidant status and reduced the oxidative stress associated with type 2 diabetes by down regulation of the two antioxidant enzymes,
glutathione and superoxide dismutase 2, in the pancreatic tissue, says Hetta.

These findings for Ginkgo biloba's impact on Type 2 diabetes are preliminary, says Hetta.

"We still need more evidence about possible benefits for Type 2 diabetes so there is ongoing research," says Hetta. "Our findings need to be tested in human clinical trials of large sample size.

"Gingko biloba is one of the oldest living tree species," says Hetta. "Most Ginkgo products are made with extract prepared from leaves. Most research on Gingko focuses on its effects on dementia and age-related memory impairment such as Alzheimer's disease and pain caused by too little blood flow or claudication. It is commonly available as an oral tablet, extract, capsule or tea. It is not toxic when used in low dosages, but can interact with other medicines."

"I would not recommend eating raw or roasted Ginkgo seeds because they can be poisonous," says Hetta. "It should be taken as a capsule or in tablets if used. Also, if you are currently taking medications please consult with your physicians before considering Ginkgo biloba."

Collaborators on the study include Mamdouh Anwar, Ahmed E. Zayed, Gamal Afifi, Emad Shaheen, and Hassien Alnashiri, all from Jazan University in Saudi Arabia. Additional co-collaborators, all from Assiut University in Egypt include Manal El Sayed Ezz Eldeen, Asmaa MS Gomaa, Mahmoud Abd-Elkareem, Alaa Sayed Abou-Elhamd, Ghada Mohamed and Ahmed M. Kotb.

The work was funded by the Deanship of Scientific Research, Jazan University, Saudi Arabia, Grant # 37/7/00110.

The authors of the study report no conflicts of interest in this work.