Culture

Crop scientists, molecular and computational biologists from two leading St. Petersburg Universities and Federal Centre for Bast Fiber Crops teamed up to sequence and assemble genome of Fusarium oxysporum f.sp. lini, a highly destructive fungal parasite infecting flax.

Fusarium wilt is a plant disease caused by various species of Fusarium fungi. Botanists and plant scientists are aware of approximately 120 species of the parasite, capable of infecting a wide spectrum of crops, such as tomatoes, cucumbers, melons, cabbages, peas, corn, barley, wheat, and many other plants. This study focuses on detailed characterization of F. oxysporum f.sp. lini which infects flax, a major source of textile fibre, seed and flaxseed (linseed) oil in Russia.

"The pathogen has a remarkable resistance to chemical agents and its spores may persist quite comfortably in soil for years. It is a widely accepted opinion in modern crop science that the most promising approach to fight the infection is to breed new resistant varieties,' says Anastasia Samsonova, Professor at the Centre for Genome Bioinformatics at St Petersburg University. "The host and parasite are engaged in an endless "arms race" to survive. Sooner or later, the flax varieties that are currently commercially cultivated may lose their resistance, succumb to the disease completely and become unprofitable to grow. Naturally, this creates a demand for breeding new resistant crops."

The whole genome chromosome-level assembly of the Fusarium oxysporum f.sp. lini was completed in a joint research effort by scientists from St. Petersburg University, Peter the Great St. Petersburg Polytechnic University, and the Centre for Bast Fiber Crops in Torzhok. "The parasite's genome consists of two components; the stable one, which is almost identical in different Fusariums, and the variable part which is mainly responsible for amazing adaptation of the fungus to various plants." says Alexander Kanapin, Professor at the Centre for Genome Bioinformatics at St Petersburg University. "The chromosome-level assembly of the genome is a significant step towards understanding the parasite evolution and adaptation to a particular host."

"Thanks to recent advances in omics technologies and computational biology, and to our fantastic collaborators at the Centre for Bast Fiber Crops, we generated a high quality data resource for comparative studies of Fusarium pathogenic diversity and molecular mechanisms of interaction between the fungus and the host. This will undoubtedly increase the power of integrative systems genetics analyses and thus contribute to the global efforts aimed at elimination of plant disease outbreaks by aiding in engineering of new resistant crops varieties.", explains Maria Samsonova, Head of the Laboratory for Mathematical Biology and Bioinformatics at Peter the Great St Petersburg Polytechnic University.

Further research will address many important questions left unanswered; the team will try to find a genetic determinants of the fungus "taste". In other words, why certain species "enjoys" melons, while the other one "fancies" tomatoes. Knowing parasite's preferences will help to elucidate specific mechanisms of Fusarium adaptation to different hosts and find genes responsible.

To get a better look at the world around them, animals constantly are in motion. Primates and people use complex eye movements to focus their vision (as humans do when reading, for instance); birds, insects, and rodents do the same by moving their heads, and can even estimate distances that way. Yet how these movements play out in the elaborate circuitry of neurons that the brain uses to "see" is largely unknown. And it could be a potential problem area as scientists create artificial neural networks that mimic how vision works in self-driving cars.

To better understand the relationship between movement and vision, a team of Harvard researchers looked at what happens in one of the brain's primary regions for analyzing imagery when animals are free to roam naturally. The results of the study, published Tuesday in the journal Neuron, suggest that image-processing circuits in the primary visual cortex not only are more active when animals move, but that they receive signals from a movement-controlling region of the brain that is independent from the region that processes what the animal is looking at. In fact, the researchers describe two sets of movement-related patterns in the visual cortex that are based on head motion and whether an animal is in the light or the dark.

The movement-related findings were unexpected, since vision tends to be thought of as a feed-forward computation system in which visual information enters through the retina and travels on neural circuits that operate on a one-way path, processing the information piece by piece. What the researchers saw here is more evidence that the visual system has many more feedback components where information can travel in opposite directions than had been thought.

These results offer a nuanced glimpse into how neural activity works in a sensory region of the brain, and add to a growing body of research that is rewriting the textbook model of vision in the brain.

"It was really surprising to see this type of [movement-related] information in the visual cortex because traditionally people have thought of the visual cortex as something that only processes images," said Grigori Guitchounts, a postdoctoral researcher in the Neurobiology Department at Harvard Medical School and the study's lead author. "It was mysterious, at first, why this sensory region would have this representation of the specific types of movements the animal was making."

While the scientists weren't able to definitively say why this happens, they believe it has to do with how the brain perceives what's around it.

"The model explanation for this is that the brain somehow needs to coordinate perception and action," Guitchounts said. "You need to know when a sensory input is caused by your own action as opposed to when it's caused by something out there in the world."

For the study, Guitchounts teamed up with former Department of Molecular and Cellular Biology Professor David Cox, alumnus Javier Masis, M.A. '15, Ph.D. '18, and postdoctoral researcher Steffen B.E. Wolff. The work started in 2017 and wrapped up in 2019 while Guitchounts was a graduate researcher in Cox's lab. A preprint version of the paper published in January.

The typical setup of past experiments on vision worked like this: Animals, like mice or monkeys, were sedated, restrained so their heads were in fixed positions, and then given visual stimuli, like photographs, so researchers could see which neurons in the brain reacted. The approach was pioneered by Harvard scientists David H. Hubel and Torsten N. Wiesel in the 1960s, and in 1981 they won a Nobel Prize in medicine for their efforts. Many experiments since then have followed their model, but it did not illuminate how movement affects the neurons that analyze.

Researchers in this latest experiment wanted to explore that, so they watched 10 rats going about their days and nights. The scientists placed each rat in an enclosure, which doubled as its home, and continuously recorded their head movements. Using implanted electrodes, they measured the brain activity in the primary visual cortex as the rats moved.

Half of the recordings were taken with the lights on. The other half were recorded in total darkness. The researchers wanted to compare what the visual cortex was doing when there was visual input versus when there wasn't. To be sure the room was pitch black, they taped shut any crevice that could let in light, since rats have notoriously good vision at night.

The data showed that on average, neurons in the rats' visual cortices were more active when the animals moved than when they rested, even in the dark. That caught the researchers off guard: In a pitch-black room, there is no visual data to process. This meant that the activity was coming from the motor cortex, not an external image.

The team also noticed that the neural patterns in the visual cortex that were firing during movement differed in the dark and light, meaning they weren't directly connected. Some neurons that were ready to activate in the dark were in a kind of sleep mode in the light.

Using a machine-learning algorithm, the researchers encoded both patterns. That let them not only tell which way a rat was moving its head by just looking at the neural activity in its visual cortex, but also predict the movement several hundred milliseconds before the rat made it.

The researchers confirmed that the movement signals came from the motor area of the brain by focusing on the secondary motor cortex. They surgically destroyed it in several rats, then ran the experiments again. The rats in which this area of the brain was lesioned no longer gave off signals in the visual cortex. However, the researchers were not able to determine if the signal originates in the secondary motor cortex. It could be only where it passes through, they said.

Furthermore, the scientists pointed out some limitations in their findings. For instance, they only measured the movement of the head, and did not measure eye movement. The study is also based on rodents, which are nocturnal. Their visual systems share similarities with humans and primates, but differ in complexity. Still, the paper adds to new lines of research and the findings could potentially be applied to neural networks that control machine vision, like those in autonomous vehicles.

"It's all to better understand how vision actually works," Guitchounts said. "Neuroscience is entering into a new era where we understand that perception and action are intertwined loops. ... There's no action without perception and no perception without action. We have the technology now to measure this."

UNIVERSITY PARK, Pa. -- Fungal spores responsible for bitter rot disease, a common and devastating infection in fruit, do not encounter their host plants by chance. Turns out, they have a symbiotic association with the plant, often living inside its leaves.

The new way of looking at the fungal pathogen, Colletotrichum fioriniae, as a leaf endophyte -- bacterial or fungal microorganisms that colonize healthy plant tissue -- was the outcome of a two-year study conducted by researchers in Penn State's College of Agricultural Sciences.

According to Phillip Martin, a doctoral candidate in plant pathology, the findings, which were published recently in the journal Phytopathology, have important implications for the management of the pathogen in fruit trees.

Colletotrichum fioriniae causes diseases, often called anthracnoses, in more than 100 fruit and vegetable plants, including apple, peach, pear and strawberry. The fungus infects the fruit under warm and wet conditions and causes brown, sunken lesions; occasionally, orange spores will be seen on the surface.

The disease is of concern to the Pennsylvania apple industry, which produces 400 million to 500 million pounds of apples per year. The state ranks fourth in the nation for apple production, per statistics from the U.S. Department of Agriculture.

"The research was based on the idea that if we can determine where the spores are coming from, then maybe we can eliminate the source and break the bitter rot disease cycle," said Martin, who carried out the study under the guidance of Kari Peter, associate research professor of tree-fruit pathology. "Unfortunately, from this perspective, many of the spores come from leaves, including apple leaves, and from trees and shrubs that are everywhere in Pennsylvania."

Previously, the spores in question were thought to originate mostly from diseased fruits and twigs. However, even when infected fruits and twigs were removed from a tree, the disease, while reduced, often still was present, a circumstance that puzzled scientists.

The research, which took place in 2018 and 2019, focused on apples and involved the placement of rain-splash spore traps in orchards at Penn State's Fruit Research and Extension Center, at Hollabaugh Bros. Inc. fruit and vegetable farm, and at a satellite location in Arendtsville, all of which are located in Adams County. Traps also were placed in two forested areas -- comprised mostly of deciduous trees -- near the orchards.

Based on previous research that indicated that Colletotrichum fioriniae could survive on leaves, the team collected more than 1,000 leaves of apple and of 24 forest plant species. The leaves were disinfected to kill fungi on the leaf surface, frozen to kill the leaves and incubated to allow the fungi inside of the leaves to grow out and sporulate.

This test found Colletotrichum fioriniae in more than 30% of leaves sampled, with most spores coming from the forest samples. In orchards that were managed with fungicides, up to 8% of apple leaves were infected with the fungus. In the untreated orchard, Martin said, the spores were abundant, meaning they were found in 15-80% of the leaves. The infections did not seem to be causing any leaf diseases, however.

"While unexpected, these findings did explain why growers struggle with bitter rot even when they remove all diseased fruits and twigs -- the fungus was living in the leaves during the season," Martin said. "The fungus was present in all the tested orchards and could not be traced to infection from a nursery, which makes sense since the initial infections likely are coming from surrounding forests and fence rows."

Since the fungus is abundant in the forest canopy, eradication from nearby areas would be impractical, Martin added. However, the spatial limitations of rain-splash dispersal mean that forests are not regular sources of fungus spread; they likely serve only as primary introduction sources during extreme rain and wind events, after which the fungus becomes established in agricultural areas.

"Our study changes how we think about this fungus," Martin said. "While it may not supply quick fixes, it provides the basis for further research aimed at developing better management techniques, such as selecting resistant cultivars and breeding for genetic resistance."

Peter agreed. "Although it's exciting to understand that Colletotrichum fiorinae's niche in the environment is more sophisticated than we had appreciated, it does make managing bitter rot in apple orchards less straightforward," she said. "As researchers, we can view this is an opportunity to think outside the box and to be creative in figuring out a sustainable bitter rot management strategy."

In the meantime, Martin noted, disease-management tactics stay the same. "We don't believe most spores are overwintering in the leaves," he said. "Growers should continue to remove the infected fruits and twigs to help reduce disease spread season to season."

A special type of aurora, draped east-west across the night sky like a glowing pearl necklace, is helping scientists better understand the science of auroras and their powerful drivers out in space. Known as auroral beads, these lights often show up just before large auroral displays, which are caused by electrical storms in space called substorms. Previously, scientists weren't sure if auroral beads are somehow connected to other auroral displays as a phenomenon in space that precedes substorms, or if they are caused by disturbances closer to Earth's atmosphere.

But powerful new computer models combined with observations from NASA's Time History of Events and Macroscale Interactions during Substorms - THEMIS - mission have provided the first strong evidence of the events in space that lead to the appearance of these beads, and demonstrated the important role they play in our near space environment.

"Now we know for certain that the formation of these beads is part of a process that precedes the triggering of a substorm in space," said Vassilis Angelopoulos, principal investigator of THEMIS at the University of California, Los Angeles. "This is an important new piece of the puzzle."

By providing a broader picture than can be seen with the three THEMIS spacecraft or ground observations alone, the new models have shown that auroral beads are caused by turbulence in the plasma - a fourth state of matter, made up of gaseous and highly conductive charged particles - surrounding Earth. The results, recently published in the journals Geophysical Research Letters and Journal of Geophysical Research: Space Physics, will ultimately help scientists better understand the full range of swirling structures seen in the auroras.

"THEMIS observations have now revealed turbulences in space that cause flows seen lighting up the sky as of single pearls in the glowing auroral necklace," said Evgeny Panov, lead author on one of the new papers and THEMIS scientist at the Space Research Institute of the Austrian Academy of Sciences. "These turbulences in space are initially caused by lighter and more agile electrons, moving with the weight of particles 2000 times heavier, and which theoretically may develop to full-scale auroral substorms."

Mysteries of Auroral Beads Formation

Auroras are created when charged particles from the Sun are trapped in Earth's magnetic environment - the magnetosphere - and are funneled into Earth's upper atmosphere, where collisions cause hydrogen, oxygen, and nitrogen atoms and molecules to glow. By modelling the near-Earth environment on scales from tens of miles to 1.2 million miles, the THEMIS scientists were able to show the details of how auroral beads form.

As streaming clouds of plasma belched by the Sun pass Earth, their interaction with the Earth's magnetic field creates buoyant bubbles of plasma behind Earth. Like a lava lamp, imbalances in the buoyancy between the bubbles and heavier plasma in the magnetosphere creates fingers of plasma 2,500 miles wide that stretch down towards Earth. Signatures of these fingers create the distinct bead-shaped structure in the aurora.

"There's been a realization that, all summed up, these relatively little transient events that happen around the magnetosphere are somehow important," said David Sibeck, THEMIS project scientist at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "We have only recently gotten to the point where computing power is good enough to capture the basic physics in these systems."

Now that scientists understand the auroral beads precede substorms, they want to figure out how, why and when the beads might trigger full-blown substorm. At least in theory, the fingers may tangle magnetic field lines and cause an explosive event known as magnetic reconnection, which is well known to create full-scale substorms and auroras that fill the nightside sky.

New Models Open New Doors

Since its launch in 2007, THEMIS has been taking detailed measurements as it passes through the magnetosphere in order to understand the causes of the substorms that lead to auroras. In its prime mission, THEMIS was able to show that magnetic reconnection is a primary driver of substorms. The new results highlight the importance of structures and phenomenon on smaller scales - those hundreds and thousands of miles across as compared to ones spanning millions of miles.

"In order to understand these features in the aurora, you really need to resolve both global and smaller, local scales. That's why it was so challenging up to now," said Slava Merkin, co-author on one of the new papers and scientist at NASA's Center for Geospace Storms headquartered at Johns Hopkins University Applied Physics Laboratory in Laurel, Maryland. "It requires very sophisticated algorithms and very big supercomputers."

The new computer simulations almost perfectly match THEMIS and ground observations. After the initial success of the new computer models, THEMIS scientists are eager to apply them to other unexplained auroral phenomena. Particularly in explaining small-scale structures, computer models are essential as they can help interpret what happens in between the spaces where the three THEMIS spacecraft pass.

"There's lots of very dynamic, very small-scale structures that people see in the auroras which are hard to connect to the larger picture in space since they happen very quickly and on very small scales," said Kareem Sorathia, lead author on one of the new papers and scientist at NASA's Center for Geospace Storms headquartered at Johns Hopkins Applied Physics Laboratory. "Now that we can use global models to characterize and investigate them, that opens up a lot of new doors."

BOZEMAN -- A Montana State University researcher contributed to a novel project with scientists from around the country and world that sheds light on one of Earth's most important reptile species.

Chris Organ, an assistant teaching professor in the Department of Earth Sciences in MSU's College of Letters and Science, worked with a team from 10 countries and six U.S. states along with Washington D.C.'s Smithsonian Institution to sequence the genome of the tuatara, a reptile Organ refers to as a "living fossil."

"The tuatara isn't a lizard, even though it looks like one. They evolved early among their group of amniotes, animals like lizards, birds and mammals," said Organ. "The group never really diversified much, so the tuatara is very similar anatomically to fossils that we see that go back 200 million years. The question that remains is, if the anatomy of the animal hasn't evolved very much, what about the genome?"

The project marks the first time the tuatara genome, which is roughly twice the size of a human genome, has ever been sequenced, which illuminates not only how the unique species evolved, but also offers some insights into human genetic lineage as well. Organ brought a paleontological perspective to the international team, helping to compare the genome of the animals living today to their prehistoric ancestors. The paper, "The tuatara genome reveals ancient features of amniote evolution," appeared in the scientific journal Nature on Aug. 5.

Lead author Neil Gemmell from the University of Otago in New Zealand said sequencing the genome allows scientists to learn just where the tuatara fits in the tree of life.

"If we consider a tree, with species diverging over time and splitting off into groups such as reptiles, birds and mammals, we can finally see with some certainty where the tuatara sits," Gemmell said. The sequencing of the tuatara genome places it on the same branch of the tree of life as snakes and lizards up until about 250 million years ago, when the tuatara's branch, the genus Sphenodon, split from the class branch squamata, the branch that includes snakes and lizards. The tuatara has been genetically unique ever since.

Tuatara are native only to the islands of New Zealand, and because of that they have experienced very little habitat change during their long evolutionary existence, said Organ. Rodents, as a counterexample, exist all over the world. They have adapted over time to survive in a multitude of habitats with varying weather, predators, threats and food sources. Tuatara have been exposed to very few such speciation events, meaning they have seen a remarkably slow pace of evolutionary change.

Coupled with a long lifespan -- a tuatara can live for more than 100 years -- this consistent habitat means tuatara have seen very slow evolutionary rates.

Tuatara predate modern snakes and lizards by around 100 million years, said Organ. They also do not use genetic sex chromosomes to determine the sex of offspring, instead determining sex based on the temperature of their surroundings. This makes them particularly sensitive to changing habitats or a warming climate, which could unbalance the male-to-female ratio and lead to significant declines in population.

The tuatara is also a culturally significant animal to the Maori native people of New Zealand, said Gemmell. The research team worked closely with indigenous communities in New Zealand as well as the New Zealand Institute for Plant and Food Research, the Ngatiwai Trust Board and the New Zealand Department of Conservation to explore how these novel insights into the tuatara could aid in its preservation in New Zealand.

In addition to having an unusually large genome for an amniote, the tuatara also bears unique, never-before-identified genetic elements discovered through this research. Through narrowing down what makes the tuatara unique, the team hopes to discover the root of the species' longevity and to identify the best way to preserve this unique reptile.

"Sequencing a genome is like piecing together a page of text using only sentence fragments," said Organ. "But because the tuatara genome is so large and has changed over time, it's like trying to piece together 'War and Peace,' and in a different dialect. Since the tuatara is so distantly related to anything that's alive today, we have genomic 'sentences' that don't overlap clearly, and that makes compiling this genome something new and exciting."

If you want to enhance a locust to be used as a bomb-sniffing bug, there are a few technical challenges that need solving before sending it into the field.

Is there some way to direct the locust -- to tell it where to go to do its sniffing? And because the locusts can't speak (yet), is there a way to read the brain of these cyborg bugs to know what they're smelling?

For that matter, can locusts even smell explosives?

Yes and yes to the first two questions. Previous research from Washington University in St. Louis has demonstrated both the ability to control the locusts and the ability to read their brains, so to speak, to discern what it is they are smelling. And now, thanks to new research from the McKelvey School of Engineering, the third question has been settled.

The answer, again: 'yes.'

In a pre-proof published online Aug. 6 in the journal Biosensors and Bioelectronics: X, researchers showed how they were able to hijack a locust's olfactory system to both detect and discriminate between different explosive scents -- all within a few hundred milliseconds of exposure.

They were also able to optimize a previously developed biorobotic sensing system that could detect the locusts' firing neurons and convey that information in a way that told researchers about the smells the locusts were sensing.

"We didn't know if they'd be able to smell or pinpoint the explosives because they don't have any meaningful ecological significance," said Barani Raman, professor of biomedical engineering. "It was possible that they didn't care about any of the cues that were meaningful to us in this particular case."

Previous work in Raman's lab led to the discovery that the locust olfactory system could be decoded as an 'or-of-ands' logical operation. This allowed researchers to determine what a locust was smelling in different contexts.

With this knowledge, the researchers were able to look for similar patterns when they exposed locusts to vapors from TNT, DNT, RDX, PETN and ammonium nitrate -- a chemically diverse set of explosives. "Most surprisingly," Raman said, "we could clearly see the neurons responded differently to TNT and DNT, as well as these other explosive chemical vapors."

With that crucial piece of data, Raman said, "We were ready to get to work. We were optimized."

Now they knew that the locusts could detect and discriminate between different explosives, but in order to seek out a bomb, a locust would have to know from which direction the odor emanated. Enter the "odor box and locust mobile."

"You know when you're close to the coffee shop, the coffee smell is stronger, and when you're farther away, you smell it less? That's what we were looking at," Raman said. The explosive vapors were injected via a hole in the box where the locust sat in a tiny vehicle. As the locust was driven around and sniffed different concentrations of vapors, researchers studied its odor-related brain activity.

The signals in the bugs' brains reflected those differences in vapor concentration.

The next step was to optimize the system for transmitting the locusts' brain activity. The team, which included Shantanu Chakrabartty, the Clifford W. Murphy Professor in the Preston M. Green Department of Electrical & Systems Engineering, and Srikanth Singamaneni, the Lilyan & E. Lisle Hughes Professor in the Department of Mechanical Engineering & Materials Science, focused the breadth of their expertise on the tiny locust.

In order to do the least harm to the locusts, and to keep them stable in order to accurately record their neural activity, the team came up with a new surgical procedure to attach electrodes that didn't hinder the locusts' movement. With their new instrumentation in place, the neuronal activity of a locust exposed to an explosive smell was resolved into a discernible odor-specific pattern within 500 milliseconds.

"Now we can implant the electrodes, seal the locust and transport them to mobile environments," Raman said. One day, that environment might be one in which Homeland Security is searching for explosives.

The idea isn't as strange as it might first sound, Raman said.

"This is not that different from in the old days, when coal miners used canaries," he said. "People use pigs for finding truffles. It's a similar approach -- using a biological organism -- this is just a bit more sophisticated."

Results from an international clinical trial found that men with advanced prostate cancer who have mutated BRCA1/BRCA2 genes can be treated successfully with a targeted therapy known as rucaparib, resulting in recent FDA approval.

Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. Metastatic, castrate-resistant prostate cancer (mCRPC) is an incurable form of prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels. Researchers are looking for new treatment options to use for mCRPC.

Rucaparib (trademarked as Rubraca®) is one of a new class of anticancer drugs called poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors, which work by targeting cancer cells that have a defect in how they repair damage to their DNA. PARP inhibitors are already successfully used to treat ovarian cancers and some inherited forms of breast and pancreatic cancer.

"There is a critical need for personalized medicines to effectively treat advanced prostate cancer," said Akash Patnaik, MD, PhD, national authority on prostate cancer research at the University of Chicago Medicine and one of the study authors, who presented the findings from this study at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology in San Francisco in February 2020. "Approximately 12% of advanced prostate cancer patients have tumors that harbor a BRCA1 or BRCA2 alteration. We have arrived at an exciting inflection point in the field, as we now have the first FDA approved targeted therapy that can effectively treat a genetically defined subset of mCRPC patients, with poor prognosis and worse clinical outcomes on conventional treatments."

The TRITON2 phase II study investigated whether or not rucaparib can safely and effectively treat men with mCRPC who are predisposed to prostate cancer because of their genetic profile. Men whose cancer had progressed after completing hormone therapy and chemotherapy were eligible to participate. The University of Chicago Medicine Comprehensive Cancer Center was the second lead site internationally to enroll patients to this practice-changing study.

Patnaik and colleagues from cancer centers in the U.S. and across the world enrolled 115 patients whose genetic screening revealed abnormalities in their BRCA genes. The patients then received 600 mg of rucaparib twice a day. The objective response rate was 41%. Over half of the patients (53.9%) had improvements in their prostate-specific antigen (PSA) levels.

The researchers noted that in addition to demonstrating a significant anti-cancer response in mCRPC patients that had progressed on two prior lines of therapy, the rucaparib treatment had a manageable safety profile consistent with that reported in other solid tumor types, with the most common side effect reported being anemia.

Based on the initial efficacy and safety results from TRITON2, the FDA granted accelerated approval for rucaparib in mCRPC patients with BRCA1/2 mutations on May 15, 2020. Results from TRITON2 have been previously presented to the medical community at the European Society for Medical Oncology (ESMO) Annual Congress (October 19-23, 2018, and September 27-October 1, 2019), the American Society of Clinical Oncology (ASCO) Annual Meeting (May 31-June 4, 2019), and the ASCO Genitourinary Cancers Symposium (February 13-15, 2020).

A publication summarizing the TRITON2 results was published today at the Journal of Clinical Oncology. "In a separate publication, we have demonstrated that additional non-BRCA1/2 mutations within the DNA repair pathway in mCRPC patients could confer sensitivity or resistance to PARP inhibitor rucaparib," Patnaik said. "We still have a lot more to learn about which patients with additional genetically defined alterations in the DNA repair pathway will benefit most from this therapy."

He continued, "Studies are underway within our laboratory and clinical trials to test combinations of PARP inhibitors with other conventional or experimental therapies to substantially increase the fraction of mCRPC patients that respond to PARP inhibitors. Based on these investigations, we are optimistic about the development of additional personalized treatment options for our mCRPC patients."

The synthetic drug ebselen can bind to both the catalytic region and a previously unknown distant site on the SARS-CoV-2 virus' main protease, according to a molecular simulation analysis of the drug's interactions with this enzyme. The results suggest that ebselen could be a potential treatment for COVID-19, if future work can confirm its ability to inhibit the activity of the viral protease, which is involved in viral gene expression and replication. While current virtual screening campaigns primarily focus on drugs that target the catalytic site of the SARS-CoV-2 main protease, the findings highlight another binding site that may provide an effective target for other drugs previously written off as ineffective. Since researchers typically require years to design and develop drugs for widespread use, repurposing previously approved pharmaceuticals is considered an essential strategy to quickly combat the current global pandemic. Recently, computational-experimental screenings identified several existing drugs, including ebselen, that may work to inhibit the virus' main protease. However, the molecular mechanisms by which this drug interacts with the main protease had yet to be understood. To investigate this interaction, Cintia Menendez and colleagues performed molecular simulations, identifying sites at which the drug and the main protease interact while evaluating the effect of different binding sites on molecular stiffness and strain. They found that ebselen appears to target both a binding site within the catalytic region and another between binding site domains II and III. Menendez et al. suggest that future experiments will be necessary to validate these findings, especially concerning the distant binding site.

Scientists have identified a small molecule that inhibits multiple different viruses, including SARS-CoV-2, in tissue culture and in mice by targeting the same signaling pathway. By identifying a host cell pathway that a wide variety of viruses rely on for successful infection, the findings suggest a possible target for broad-spectrum antiviral drugs. Novel viruses - including SARS-CoV-2, HIV, Zika virus, and avian influenza A - can present unique challenges for researchers, since interactions between viruses and their hosts often drive evolutionary changes that diversify both the viruses and hosts' responses. To keep ahead of this arms race, scientists have sought evolutionarily conserved mechanisms, common to many host-virus interactions, that can offer sweeping solutions. To investigate whether the TGF-β signaling pathway could serve as a target for antiviral therapies against numerous viruses, Shuofeng Yuan and colleagues performed screens of previously identified inhibitors of the pathway. They found that one such compound, the small molecule N-(p-Amylcinnamoyl)anthranilic acid (or ACA), successfully inhibited influenza A, MERS-CoV, SARS-CoV-2, HIV, adenovirus, and two picornaviruses, both in tissue culture and in mice. They also found that ACA achieved this by blocking the interaction of AP2M1, a subunit of the AP2 adaptor complex that is known to interact with the TGF-β pathway, with an amino acid sequence present in many viral proteins. Blocking this host-virus protein interaction interfered with proper subcellular localization of virus components, thereby inhibiting a productive infection. These findings point to a target and a possible broad-spectrum therapy to treat viral outbreaks, including the current COVID-19 pandemic.

Supercomputers around the world work around the clock on research problems. In principle, even novel materials can be simulated in computers in order to calculate their magnetic and thermal properties as well as their phase transitions. The gold standard for this kind of modelling is known as the quantum Monte Carlo method.

Wave-Particle Dualism

However, this method has an intrinsic problem: due to the physical wave-particle dualism of quantum systems, each particle in a solid-state compound not only possesses particle-like properties such as mass and momentum, but also wave-like properties such as phase. Interference causes the "waves" to be superposed on each other, so that they either amplify (add) or cancel (subtract) each other locally. This makes the calculations extremely complex. It is referred to the sign problem of the quantum Monte Carlo method.

Minimisation of the problem

"The calculation of quantum material characteristics costs about one million hours of CPU on mainframe computers every day", says Prof. Jens Eisert, who heads the joint research group at Freie Universität Berlin and the HZB. "This is a very considerable proportion of the total available computing time." Together with his team, the theoretical physicist has now developed a mathematical procedure by which the computational cost of the sign problem can be greatly reduced. "We show that solid-state systems can be viewed from very different perspectives. The sign problem plays a different role in these different perspectives. It is then a matter of dealing with the solid-state system in such a way that the sign problem is minimised", explains Dominik Hangleiter, first author of the study that has now been published in Science Advances.

From simple spin systems to more complex ones

For simple solid-state systems with spins, which form what are known as Heisenberg ladders, this approach has enabled the team to considerably reduce the computational time for the sign problem. However, the mathematical tool can also be applied to more complex spin systems and promises faster calculation of their properties.

"This provides us with a new method for accelerated development of materials with special spin properties", says Eisert. These types of materials could find application in future IT technologies for which data must be processed and stored with considerably less expenditure of energy.

Children with autism born to mothers who had immune conditions during their pregnancy are more likely to have behavioral and emotional problems, a UC Davis Health study has found. The study examined maternal immune history as a predictor of symptoms in children with autism.

"We tested the ability of maternal immune history to predict ASD symptoms and the possible role that the sex of the offspring plays," said Paul Ashwood, professor of microbiology and immunology and faculty member at the UC Davis MIND Institute.

Published Aug. 14 in Translational Psychiatry, the study found that offspring sex may interact with maternal immune conditions to influence outcomes, particularly in terms of a child's cognition.

Maternal immunity conditions and autism

Maternal immune conditions are caused by a dysfunction of the mother's immune system. They include allergies, asthma, autoimmune diseases, autoinflammatory syndromes and immunological deficiency syndromes. Previous studies have shown that maternal immune conditions are more prevalent in mothers of children with autism spectrum disorder (ASD).

The researchers enrolled 363 mothers and their children (252 males and 111 females) from the Autism Phenome Project (APP) and Girls with Autism Imaging of Neurodevelopment (GAIN) study at the UC Davis MIND Institute. The median age of the children was three years.

The researchers measured the children's autism severity and assessed a set of behavioral and emotional problems such as aggression and anxiety. They also measured the children's development and cognitive functioning.

The study found that around 27% of the mothers had immune conditions during their pregnancy. Of these mothers, 64% reported a history of asthma, the most common immune condition. Other frequent conditions included Hashimoto's thyroiditis (hypothyroidism), Raynaud's disease (blood circulation disease), alopecia (hair loss), psoriasis (skin disease) and rheumatoid arthritis (joint tissue inflammation).

The study also found that maternal immune conditions are associated with increased behavioral and emotional problems but not reduced cognitive functioning in children with autism.

Does the sex of the offspring interact with the influence of maternal immune conditions on autism symptoms?

According to the Centers for Disease Control and Prevention (CDC), ASD is four times more common among boys than among girls.

"Our study explored whether offspring sex interacts with the presence of maternal immune conditions to influence behavioral outcomes in children," said Ashwood. "Maternal immune conditions may be one environmental factor which contributes to the higher male prevalence seen in ASD."

The study found that a history of maternal immune conditions was more common in male children with ASD (31%) compared to female (18%). Specifically, asthma was twice as common in mothers of male children with ASD than in mothers of female children with ASD.

The study also showed that in cases of ASD where maternal immune conditions are present, female offspring are less likely to be susceptible to adverse cognitive outcomes in response to maternal inflammation than male offspring.

"This critical finding links offspring sex and maternal immune conditions to autism," said Ashwood. "It provides more evidence that male offspring are at higher risk of adverse outcomes due to maternal immunity activation compared to female offspring."

Future studies would include identifying the type, severity and gestational timing of immune conditions, and then examining offspring outcomes over time.

Oak Ridge National Laboratory researchers have developed artificial intelligence software for powder bed 3D printers that assesses the quality of parts in real time, without the need for expensive characterization equipment.

The software, named Peregrine, supports the advanced manufacturing "digital thread" being developed at ORNL that collects and analyzes data through every step of the manufacturing process, from design to feedstock selection to the print build to material testing.

"Capturing that information creates a digital 'clone' for each part, providing a trove of data from the raw material to the operational component," said Vincent Paquit, who leads advanced manufacturing data analytics research as part of ORNL's Imaging, Signals and Machine Learning group. "We then use that data to qualify the part and to inform future builds across multiple part geometries and with multiple materials, achieving new levels of automation and manufacturing quality assurance."

The digital thread supports the factory of the future in which custom parts are conceived using computer-aided design, or CAD, and then produced by self-correcting 3D printers via an advanced communications network, with less cost, time, energy and materials compared with conventional production. The concept requires a process control method to ensure that every part rolling off printers is ready to install in essential applications like cars, airplanes, and energy facilities.

To devise a control method for surface-visible defects that would work on multiple printer models, ORNL researchers created a novel convolutional neural network -- a computer vision technique that mimics the human brain in quickly analyzing images captured from cameras installed on the printers. The Peregrine software uses a custom algorithm that processes pixel values of images, taking into account the composition of edges, lines, corners and textures. If Peregrine detects an anomaly that may affect the quality of the part, it automatically alerts operators so adjustments can be made.

The software is well suited to powder bed printers. These printers distribute a fine layer of powder over a build plate, with the material then melted and fused using a laser or electron beam. Binder jetting systems rely on a liquid binding agent rather than heat to fuse powdered materials.

The systems print layer by layer, guided by the CAD blueprint, and are popular for the production of metal parts.
However, during the printing process, problems such as uneven distribution of the powder or binding agent, spatters, insufficient heat, and some porosities can result in defects at the surface of each layer. Some of those issues may happen in such a very short timeframe that they may go undetected by conventional techniques.

"One of the fundamental challenges for additive manufacturing is that you're caring about things that occur on length-scales of tens of microns and happening in microseconds, and caring about that for days or even weeks of build time," said ORNL's Luke Scime, principal investigator for Peregrine. "Because a flaw can form at any one of those points at any one of those times, it becomes a challenge to understand the process and to qualify a part."

Peregrine is being tested on multiple printers at ORNL, including as part of the Transformational Challenge Reactor (TCR) Demonstration Program that is pursuing the world's first additively manufactured nuclear reactor. TCR is leveraging ORNL's rich history in nuclear science and engineering, materials science and advanced manufacturing to develop a microreactor with newer materials in less time at a lower cost, ensuring the future of this important carbon-free energy source.

"For TCR in particular, you could have a scenario in which the regulator will want detailed data on how a part was manufactured, and we can provide specs with the database built using Peregrine," Scime said.

"Establishing correlations between these signatures collected during manufacturing and performance during operation will be the most data-rich and informed process for qualifying critical nuclear reactor components," said Kurt Terrani, TCR program director. "The fact that it may be accomplished during manufacturing to eliminate the long and costly conventional qualification process is the other obvious benefit."

ORNL researchers stress that by making the Peregrine software machine-agnostic -- able to be installed on any powder bed system -- printer manufacturers can save development time while offering an improved product to industry. Peregrine produces a common image database that can be transferred to each new machine to train new neural networks quickly, and it runs on a single high-powered laptop or desktop. Standard cameras were used in the research, ranging in most cases from 4 to 20 megapixels and installed so they produce images of the print bed at each layer. The software has been tested successfully on seven powder bed printers at ORNL so far, including electron beam melting, laser powder bed, and binder jetting, as detailed in the journal Additive Manufacturing.

"Anything we can do to help operators and designers know what works and what doesn't helps with the confidence that the part will be okay for use," Scime said. "When you have a 3D map of every pixel where the network thinks there is an anomaly and what it thinks the problem is, it opens up a whole world of understanding of the build process."

As the monitoring system has evolved, Scime said researchers are able to combine the image data with data from other sources such as the printer's log files, the laser systems and operator notes, allowing parts to be uniquely identified and statistics from all parts tracked and evaluated.

The AI software was developed at the Manufacturing Demonstration Facility at ORNL, a U.S. Department of Energy user facility that works closely with industry to develop, test and refine nearly every type of modern advanced manufacturing technology.

"There's no place else like the MDF where this machine-agnostic algorithm could have been developed, simply because we have so many machines and so many builds going on all the time in the course of our research," Scime said. "Access to data is key. Here, we have the ability to place sensors easily and the technicians to make sure everything works and that we're getting our data. With the variety of scientific expertise available here, it's been easy to find experts to help with all the challenges involved."

In other process control work, MDF researchers are developing methods to monitor for defects on the subsurface of builds and to detect porosity that may form in deeper layers, including the use of photodiodes and high-speed cameras.

"We've been doing welding for hundreds of years, but additive has only been around for a couple of decades and we don't know what the problems look like in some cases," Scime said. "Machine learning techniques allow us to collect and analyze a lot of data quickly. We can then identify those problems and gain the knowledge we need to better understand and prevent anomalies."

BIRMINGHAM, Ala. - Why is the COVID-19 virus deadly, while many other coronaviruses are fairly innocuous and just cause colds?

A team of University of Alabama at Birmingham and Polish researchers propose an answer -- the COVID-19 virus acts as a microRNA "sponge." This action modulates host microRNA levels in ways that aid viral replication and stymies the host immune response.

This testable hypothesis results from analysis of current literature and a bioinformatic study of the COVID-19 virus and six other coronaviruses. It is published as a perspective in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

Human microRNAs, or miRNAs, are short, non-coding RNAs with about 22 bases. They act to regulate gene expression by their complementary pairing with specific messenger RNAs of the cell. That pairing silences the messenger RNA, preventing it from being translated into a protein. Thus, miRNAs are a fine-tuned controller of cell metabolism or the cell's response to stress and adverse challenges, like infection by a virus.

The miRNAs are only about 0.01 percent of total human cell and tissue RNA, while replicating viral RNA of a virus like the COVID-19 virus may reach 50 percent of the total cellular RNA. So, the UAB and Polish researchers say, if the COVID-19 virus has binding sites for specific miRNAs -- and these sites are different from the binding sites for miRNAs found on coronaviruses that cause colds -- the more pathogenic COVID-19 virus may selectively sponge up certain miRNAs to dysregulate the cell in ways that make it a dangerous human coronavirus.

The sponge idea is not novel. Viral RNA sponges have been shown capable of removing host miRNA by the Epstein-Barr virus, and sponge activity has also been shown for the herpes and hepatitis C viruses.

There were two human coronaviruses prior to the COVID-19 virus -- whose formal name is SARS-CoV-2 -- that foreshadowed the devastating consequences of the COVID-19 virus. The first was the severe acute respiratory coronavirus, or SARS virus, in 2002; the second was the Middle East respiratory syndrome coronavirus, or MERS virus, in 2012. Neither had the high infectivity of the COVID-19 virus; but both were dangerous, causing 774 and 866 deaths, respectively, according to the National Institutes of Health.

In the present study, the researchers used computer-aided bioinformatic analysis to find potential miRNA target sites for 896 mature human miRNA sequences on seven different coronavirus genomes. These genomes included the three pathogenic coronaviruses -- the SARS, MERS and COVID-19 viruses -- and four non-pathogenic coronaviruses.

The researchers found that the number of target sites was elevated in the pathogenic viruses compared to the non-pathogenic strains. Furthermore, they found that pathogenic human coronaviruses attracted sets of miRNAs that differ from the non-pathogenic human coronaviruses. In particular, a set of 28 miRNAs were unique for the COVID-19 virus; the SARS and MERS viruses had their own unique sets of 21 and 24 miRNAs, respectively.

Focusing on the 28 unique miRNAs for the COVID-19 virus, the researchers found that the majority of these miRNAs are well expressed in bronchial epithelial cells, and their dysregulation has been reported in human lung pathologies that include lung cancers, chronic obstructive pulmonary disease, cystic fibrosis and tuberculosis. Furthermore, many of the miRNAs have been proposed to act as tumor suppressors that target the pathways for programmed cell death, or apoptosis, that are supposed to make a cell kill itself when infected, mutated or stressed in other ways. Reduction of those miRNAs has been associated with poor cancer prognosis.

"Hence, the COVID-19 virus -- by its potential reduction of the host's miRNA pool -- may promote infected cell survival and thus continuity of its replication cycle," the researchers said.

The authors gave a detailed explanation of how the virus replicates inside an infected cell, including how the cell assists protein folding and how the virus begins assembly in the cell's endoplasmic reticulum and Golgi system. They also described many of the cellular proteins involved in these steps. This viral replication is known to produce stress and can provoke an unfolded protein response that causes a cell to undergo programmed death.

"Taken together," the researchers said, "the viral strategies to increase the endoplasmic reticulum membranes and endoplasmic reticulum folding capacity and block unfolded protein response-associated translational attenuation, inflammatory responses and apoptosis are critical components for virus production."

The authors then showed, by citing literature, that nine of the specific cellular miRNAs that potentially are sponged by the COVID-19 virus could help achieve those viral needs.

"The host miRNAs potentially controlled by the pathogenic human coronaviruses may be the key to gaining control over a very limited and specific set of miRNAs targets," they said. The researchers used computer-assisted gene ontology programs to find the genes and cellular pathways affected by the pathogenic human coronaviruses, and by the COVID-19 virus in particular.

The pathways they found "further supports the hypothesis that pathogenic human coronaviruses -- including the COVID-19 virus -- utilize the host miRNAs to adjust cellular processes in order to facilitate their viral protein production."

"Our hypothesis will require validations," they said, "starting with the assessment of these miRNA levels in infected tissues and ending with restoring the host miRNA balance with miRNA analogs. Furthermore, completely understanding how viruses take advantage of the endoplasmic reticulum and unfolded protein response pathway may also lead to the novel therapeutic strategies."

This hypothesis by the UAB and Polish researchers, who all contributed equally to the paper, may explain some other biological oddities of the COVID-19 virus.

One is the varying susceptibilities to infection seen among patients, including a more severe morbidity and mortality for older patients. There may be individual differences among patient miRNA profiles, they said, and one "recent study has suggested that COVID-19 virulence in aged patients may be due to a lower abundance of miRNAs, and this may be a contributing factor in disease severity."

Another biological question is how the virus co-exists in its normal animal source -- bats. "Notably," the researchers said, "a recent study proposed that bats, considered as host of origin for the COVID-19 virus, have tolerance to potentially deadly viruses because of specific miRNAs."

The European Union aims to achieve climate neutrality by 2050 and is relying largely on renewable electricity to reach this goal. The implementation of this energy transition is the subject of heated debate: A continental-scale system that concentrates energy generation infrastructure in the most suitable locations would provide the most affordable solution but many citizens favour smaller, more dispersed supply networks. A new study prepared by researchers in Potsdam and Zurich shows that the implementation of such systems would not incur significant additional costs.

The researchers examined the technical feasibility and economic viability of renewable electricity generation at the continental, national, and regional levels. The study aimed to learn whether smaller electricity supply systems are indeed significantly more expensive than a continental-scale system, explains lead author Tim Tröndle (Institute for Advanced Sustainability Studies, Potsdam/ETH Zurich): "Proponents of a continental system argue that large-scale solutions are more affordable, enable suppliers to balance fluctuations, and facilitate the efficient use of resources regardless of their location. While these advantages are undeniable, political interests and public acceptance play a significant role in shaping the energy transition. As a result, proper consideration must also be given to smaller systems."

Smaller scale systems incur a cost penalty of less than 20%

Modelling conducted as part of the study confirmed that the most affordable solution would involve the creation of an interconnected European grid to distribute electricity generated at locations across Europe with the best solar and wind resources. But the cost penalties incurred by smaller systems remain low if suppliers are able to balance fluctuations in electricity generation across countries and regions. In this case, grid operators can cooperate with partners at the national and regional levels to balance fluctuations by sharing electricity with neighbouring grids rather than deploying costly storage technologies or curtailing electricity generation from wind and solar plants.

The creation of a well performing European energy market could reduce cost penalties incurred by small-scale systems to below 20 percent compared with a continental supply system. According to the authors, this finding supports current efforts to establish a European electricity market and expand the network of cross-border interconnectors linking national systems, which help to balance fluctuations.

Infrastructure requirements vary significantly

According to the study, the location of electricity generation infrastructure does not significantly affect the cost of a completely renewable electricity supply. "However, location significantly impacts infrastructure choices, especially with respect to the question of whether more generation or transmission infrastructure is required. In light of this, the preferred size of power generation systems should be clarified quickly in order to accelerate the energy transition," recommends co-author Johan Lilliestam (IASS Potsdam/University of Potsdam). Several solutions are feasible, ranging from a more continental system in which electricity generation is concentrated in the best locations through to numerous smaller, local systems in which electricity is generated close to consumers.

Even as studies have shown that the uneven distribution of urban heat islands, urban tree canopy cover, and urban environmental hazards, for example, are strongly dictated by structural racism and classism in cities, relatively few studies have addressed the varied contributions of social factors like race to ecological heterogeneity in cities. Here, Christopher J. Schell and colleagues integrate findings from ecology, evolution, and the social sciences to underscore such relationships. Their findings, they say, are necessary to conserve biodiversity, improve human health, and promote justice in nature and society. They start with a well-known hypothesis called the luxury effect - which suggests that urban biodiversity, and plant diversity in particular, is positively correlated with neighborhood wealth. A direct effect of the luxury effect is that poorer-income neighborhoods usually have less tree cover - and thus more heat. These neighborhoods are also typically located closer to pollution sources. "Work on heat islands and pollution support the idea that inequality in neighborhood wealth leads not only to a diversity of environmental hazards," the authors say, "but that these hazards compound to create unique, challenging environmental patches." They also cite research that has shown that neighborhood racial composition can be a stronger predictor of urban socio-ecological patterns than wealth. Neighborhoods that were "redlined" decades ago - by a policy that segregated urban residential neighborhoods principally by race - have on average 21 percent less tree canopy, for example. Knowing where these cities are could help to identify and predict geographic regions with compounding anthropogenic disturbances that require more sustained stewardship, the authors say. "Our capacity to understand urban ecosystems and non-human organisms necessitates a more thorough integration of the natural and social parameters of our cities," Schell and colleagues write. "We cannot generalize human behavior in urban ecosystems without dealing with systemic racism and other inequities."