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Serious conditions, including sepsis, stem from inflammation in the body, and there is a lack of effective medication for sepsis. A chromosomal protein called high-mobility group box 1 (HMGB1), secreted by immune and dying cells, binds to a specific cellular receptor--named receptor for advanced glycation end-products (RAGE)--and triggers the process of inflammation in the body. Through a computer software-based docking study with a structural similarity-based strategy, scientists from Japan, led by senior researcher Prof Sei-ichi Tanuma from Tokyo University of Science (TUS), discovered that the popular anticonvulsant drug papaverine blocks the binding of HMGB1 to this receptor. This kind of "drug repositioning" can be used to find other merits for existing drugs whose safety profiles are known. This novel approach used for the first time here is unique to TUS and is described in the paper published in Biochemical and Biophysical Research Communications. Prof Tanuma states, "Our research group has been trying to identify compounds, preferably based on existing drugs, that block the binding of irritants to cellular receptors. We want to find novel drugs to treat inflammation-based conditions."

Inflammation is the body's response to injury or irritation. Although it is technically an "immune response," acute and chronic inflammation is associated with serious conditions and diseases like sepsis, rheumatoid arthritis, diabetes, Alzheimer's disease, and even cancer. One of the many molecular-level processes underlying inflammation is the binding of a RAGE, to a "ligand" (e.g., HMGB1, amyloid β) or irritant. The chromosomal protein HMGB1, which is secreted by immune and dying cells, specifically binds to RAGE and triggers the production of molecules that promote inflammation. These molecules are called pro-inflammatory cytokines (PICs), and this entire cellular mechanism has been implicated in the onset of the diseases and conditions mentioned above. Sepsis, which is a manifestation of acute infection and inflammation, is a particularly serious concern. Septic shock results in fatal multi-organ dysfunction, and there is still a want of effective drugs to treat septic shock.

This means that molecules that can block the interaction between HMGB1 and RAGE could be a novel class of therapeutics for treating such conditions, especially sepsis. However, it easily takes more than 10 years to get new drugs screened, evaluated, and approved. The concept of "drug repositioning" can be used to overcome this problem. Drug repositioning basically means finding new merits for existing drugs that have known safety profiles. This approach was the basis of this high-profile study done by Prof Tanuma and his colleagues.

The scientists first designed a unique cyclic "peptide" (small protein) called Pepb2 to mimic the RAGE-binding domain of HMGB1, using their computer software called "COSMOS." They found that Pepb2 competed with HMGB1 to bind to RAGE, and thus "competitively inhibited" the HMGB1-RAGE interaction. Then, they screened for Pepb2 mimetic compounds (compounds that are structurally similar to Pepb2) in the DrugBank library. They found that papaverine, a popular vasodilating and anticonvulsant drug extracted from poppy seeds, was structurally similar to Pepb2.

In the laboratory, the researchers then found that papaverine directly blocks the binding of HMGB1 to RAGE and consequently lowers the production of PICs such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This proves that papaverine prevents irritants from binding to their receptors and thus suppresses inflammation. Prof Tanuma and colleagues also found that papaverine considerably reduced death rates in model mice with induced sepsis. Prof Tanuma summarizes this research by saying, "This in silico drug design approach, to find novel effects of papaverine, is a unique strategy employed for the first time only by TUS researchers."

In another related study that was also headed by Prof Tanuma, the scientists found that papaverine canceled out the tumor-promoting effects of HMGB1 in tumor microenvironment. They also found that papaverine suppressed the growth and migration of cancer cells. This study, published in PLOS ONE, showed that papaverine may also specifically be a potential anticancer drug.

These findings about papaverine could be a breakthrough in the treatment of diseases like Alzheimer's, diabetes, and cancer, and even sepsis, which is a critical issue in geriatric medicine and emergency medicine. Prof Tanuma concludes, "Drug repositioning using the in silico drug discovery approach used in our research can repurpose existing drugs into novel therapeutic agents. Also, because the cost of 'designing' a novel drug is saved, such approaches can also radically reduce the cost of medical treatment. The next step is to understand the degree to which papaverine blocks HMGB1-RAGE interaction in the human body. We are now trying to optimize the structure of papaverine to design a more 'effective' drug for the future."

Mixing microbes with carbon nanomaterials could help the transition to renewable energy. KAUST research shows microbes and nanomaterials can be used together to form a biohybrid material that performs well as an electrocatalyst. The material could be used in the solar-powered production of carbon-free fuels and several other green-energy applications.

At the heart of many clean energy technologies is a process called the oxygen-evolution reaction (OER). In the case of solar-fuel production, for example, the OER enables the use of solar electricity to split water molecules into oxygen and hydrogen, producing clean hydrogen that can be used as a fuel. Currently, rare and expensive metals are used as OER electrocatalysts. But graphene-based biohybrid materials could make an inexpensive, eco-friendly alternative, Pascal Saikaly and his team have shown.

Graphene--a sheet of carbon that is just a single layer of atoms thick--and closely related reduced graphene oxide are highly conductive, mechanically robust and widely available. However, they only become active catalysts once they have been doped with other elements, such as sulfur, iron, nitrogen or copper.

"Usually graphene-based OER catalysts are developed by chemical methods, which require rigorous reaction conditions, such as high temperature and copious toxic chemicals," explains Shafeer Kalathil, Saikaly's former postdoc. A more environmentally friendly alternative is to use microbes to decorate the surface of the reduced graphene oxide. "We used the electric bacterium Geobacter sulfurreducens because it is nonpathogenic, rich in iron-containing proteins and abundant in nature," explains Kalathil.

When the team mixed the bacterium and the graphene oxide under oxygen-free conditions, the bacterial cells adhere to the surface and produce iron-rich proteins to interact biochemically with the graphene oxide as part of their natural metabolism. As a result, the reduced graphene oxide ends up decorated with iron, copper and sulfur; thereby, becoming a highly efficient OER electrocatalyst.

"The elements contributed by the bacterium transformed the catalytically inert graphene into a highly electrocatalytic one," says Kalathil. "The biohybrid material's OER activity outperformed the benchmark expensive metal-based OER catalysts," he adds. The bonus is the environmentally friendly method the team used to make it.

Saikaly and his team are now working on large-scale production and commercialization of this biohybrid catalyst and developing other types of biohybrid catalyst for other important electro-catalytic reactions, such as hydrogen-evolution reaction and carbon-dioxide reduction.

EAST LANSING, Mich. - Racial disparity in special education is growing, and it's more complex than previously thought. New research from Michigan State University examined how often black and Hispanic students are identified as needing special education compared to white students, leading to new findings on disproportionality and racial gaps.

"When it comes to special education demographics, people generally believe that minority students are put into special ed programs more frequently than white students, and if you look just at the raw numbers, that's generally true," said Scott Imberman, MSU professor of economics and lead author. "But this doesn't consider background factors, particularly health, which can determine a lot about a child. When looking at numbers and data more closely, what many think about this racial disproportionality gets turned on its head."

The research findings, published by the National Bureau of Economic Research, or NBER, revealed that black and Hispanic students are put into special education more often in white schools. But, they are much less likely to be identified as needing special education in schools that are mostly minority, where they are surrounded by students of the same race. Additionally, black and Hispanic students are put into special education programs less frequently than white students who have similar health backgrounds.

For example, a black student in fourth grade attending a school that was more than 90 percent minority was 6 percentage points less likely to be identified for special education than a similar white student. At the same time, if a student attends a mostly white school, he or she is 3 percentage points more likely to be identified than a similar white student.

To uncover these racial gaps, Imberman - along with MSU co-author Todd Elder, David Figlio from Northwestern University and Claudia Persico from American University - analyzed birth and education records for all 869,000 children born in Florida between 1992 and 2002. Imberman explained that prior special education research did not examine health data, which is a critical piece of information because it reveals traits well before the children go to school that could lead to a child to needing special education.

"Birth records show details about a child's weight and any congenital abnormalities or birth complications, like if the baby needed ventilation or suffered from fetal alcohol syndrome," Imberman said. "Newborn health issues oftentimes lead to a child needing special ed services later on. With this data, we generated a prediction of a special education needs for healthy white students that we used as our baseline when comparing black and Hispanic students."

Beyond being the first to use health data, this research also is the first to link students' special education needs with a school's racial demographics. This revealed that special education rates weren't necessarily about a student's race - but rather about how that student's race compares to the school's racial makeup, Imberman said.

"Our findings suggest that schools are more likely to incorrectly say a student has disabilities when he or she is racially different from the student body as a whole," Imberman said.

Imberman said that policies related to disproportionality in special education, such as the Individuals with Disabilities and Education Act, may need to be reexamined so that students who need special education services are getting them.

"Overall, we need a better understanding of how we can overcome these disproportionalities for students," he said. "In order to tackle bigger issues like income inequality and wealth later in life, we need to understand what students are going through early on - particularly in education systems."

Microbiologists at Ludwig-Maximilians-Universitaet (LMU) in Munich have shown that Toxoplasma gondii, the parasite that is responsible for toxoplasmosis, utilizes at least two modes of locomotion during its infection cycle.

Toxoplasma gondii - the microorganism that causes toxoplasmosis - is a highly successful parasite, which can invade and establish a persistent infection in most cell types found in mammals. As a rule, this cosmopolitan parasite causes relatively innocuous infections in humans. But in immunocompromised individuals the infection can become chronic, while in pregnant women the organism can induce miscarriage or malformation of the fetus. "Up to now, the general consensus among researchers was that the parasite's motility is dependent on the actomyosin cytoskeleton, which is made up of actin filaments with which myosins interact as motor proteins to generate force," explains Markus Meissner, Professor of Experimental Parasitology at LMU. In a study carried out together with colleagues at the Wellcome Center for Integrative Parasitology at the University of Glasgow, which appears in the online journal PLoS Biology, Meissner's group now describes a previously unrecognized mode of motility in T. gondii.

T. gondii belongs to the Apicomplexa, the group of obligate intracellular pathogens to which the causative agents of malaria belong. The infectious form, or tachyzoite, is a teardrop-like cell, which changes its morphology following successful invasion of host cells. The new study was prompted by the observation that the parasite is capable of infecting cells even when the motor proteins of its specialized 'glideosome' have been disabled. The LMU-UoG team went on to show that the extracellular T. gondii tachyzoite are capable of recycling material secreted from its apical tip into the membrane at its posterior pole. The researchers made use of this observation to study the motility of the unicellular parasites with the aid of fluorescently labelled molecules. "We demonstrated that T. gondii secretes membrane material as vesicles at the apical pole of the cell, which are then reincorporated into the cell membrane at the posterior pole by a process called endocytosis. This secretion-endocytosis cycle generates a fountain-like flow of membrane material, which contributes to propel the parasite along the substrate. "The endocytic uptake mechanism appears to be fundamentally different from that found in other eukaryotic cells, including the parasite's host cells," says Meissner. The next step will be to elucidate the mechanisms that underlie this type of motility and identify possible points of attack for potential therapies that can effectively prevent chronic infections.

Toggling between viewing entertainment and social media lessens a person's ability to escape reality and enjoy a show, according to a new University of Connecticut study.

Researchers studied an experience that has become increasingly common: More than half of television viewers aged 18 to 24 use a second screen web-connected device for engaging on social media to discuss what they are watching, according to previous research.

The new study, conducted by a team in the Department of Communication and published in the Journal of Broadcasting & Electronic Media, found the most significant impact of two-screen experience was on viewers' ability to "transport" into the narrative and become immersed in the televised story.

"Despite its popularity, live-tweeting has potential pitfalls on audience experience," says Saraswathi Bellur, assistant professor in communication, who collaborated on the study with Suji Park, UConn Ph.D., and Xiaowen Xu and Brenda Rourke, doctoral candidates.

For the study, researchers separated 230 college students into two groups. One group watched the television show "Friends" while tweeting; the other group watched the same show without tweeting. Those tweeting were asked to send at least five messages during the half-hour broadcast.

Afterward, both groups completed a survey about the experience.

Compared to those engaged in media multitasking, participants consuming only one medium were more likely to experience "transportation" into the content and, in turn, more intensified emotions.

Given the prevalence of television shows that actively initiate social media conversations among viewers by promoting conversations, more research needs to be done, say the authors.

East Timor's origin is shrouded in myth. The Southeast Asian island is said to have formed from "Grandfather Crocodile." That is why many who live on East Timor revere the animal who they believe established the island. A doctoral candidate of the Faculty of Environment and Natural Resources at the University of Freiburg, Sebastian Brackhane, investigated the challenges the belief poses for wildlife management. He has published an article about the cultural status of saltwater crocodiles in East Timor in the journal "Human Dimensions of Wildlife."

"The cultural status of crocodiles can be traced back to the creation myth of East Timor. Once, a little boy rescued a crocodile. He and the crocodile became friends and they travelled the sea together. After the crocodile died, the island of East Timor formed from his body," explains Brackhane. In many East Timorese communities, this belief continues to coexist alongside Catholicism. The special relationship between humans and animals is demonstrated in various ways. "There are rituals for saltwater crocodiles that involve the sacrification of other animals such as pigs. At the national level, a soccer team and East Timor's biggest telecommunication company use crocodiles as logos." And the reptiles are not just worshipped, since 2000, they have also been protected by law.

The study used stakeholder interviews to gain a better understanding of the cultural belief around crocodiles in East Timor. The information is crucial to develop options for wildlife management, because East Timor is subject to severe human-crocodile conflict, which Brackhane revealed in an earlier study from 2018. The number of saltwater crocodile attacks on people has increased in recent years. Successful crocodile management must integrate the local stakeholder´s beliefs based around the special cultural status of crocodiles. Raising public awareness may help on the short term: The local crocodile task force has put up warning signs around crocodile habitat and provides workshops for local fishermen. On the long term, Brackhane describes two potential measures to solve the problem: "Crocodiles could be captured in areas where human and crocodile activities often overlap and then be removed to enclosures. Important crocodile habitat for nesting could become protected areas with limited access for humans. However, all activities in the water, especially traditional fishing, will continue to pose a risk in the future."

By energizing precursor molecules using a tiny, high-energy supersonic jet of inert gas, researchers have dramatically accelerated the fabrication of nanometer scale structures. The rapid additive manufacturing technique also allows them to produce structures with high aspect ratios. Now, a theory developed to describe the technique could lead to new applications for additive nanomanufacturing and new nanoscale materials.

Based on focused electron beam deposition, the technique allows structures to be fabricated from gas-phase precursors at rates approaching what could be expected in the liquid phase - all without raising the temperature of substrates. That could lead to manufacturing of the nanometer-scale structures at rates that could make them practical for use in magnetic memory, high-frequency antennas, quantum communication devices, spintronics and atomic-scale resonators.

"We are controlling matter on the atomic scale to bring about new modes of additive manufacturing," said Andrei Fedorov, a professor in the George W. Woodruff School of Mechanical Engineering at the Georgia Institute of Technology. "This new science could bring about additive manufacturing applications that might otherwise be impossible. The resulting new technology will open up new dimensions for additive manufacturing at the atomic scale."

The work grew out of frustration with trying to create small structures using the electron beams, which can be just a few nanometers in diameter. The research was supported by the U.S. Department of Energy's Office of Science, and was reported May 28 in the journal Physical Chemistry Chemical Physics.

"When we went to the lab to use nanofabrication with focused electron beams, which are the size of a few nanometers, we could not grow structures that were just a few nanometers. They grew to be 50 or 100 nanometers," Fedorov explained. "And it also took a long time to produce the structures, which meant that, without improvements, we'd never be able to produce them at high volume."

Fedorov and collaborators Matthew Henry and Songkil Kim realized the reactions producing the structures were slow, and tied to the thermodynamic state of the substrate on which they are being grown. They decided to add some energy to the process to speed things up - as much as a hundred times faster.

The result was the invention of a micro-capillary injector just a few micrometers in diameter that could introduce tiny jets of gaseous molecules into the deposition chamber to activate the precursors for the nanometer-scale structures. Partly because the jet is entering a vacuum chamber, the gas accelerates to supersonic speeds. Energy from the supersonic jet excites the precursor molecules that are adsorbed to the substrate.

"This energetic thermal state allows the electrons from the beam to much more easily break chemical bonds, and as a result, structures grow much faster," Fedorov said. "All of this amplification, both the molecule transport and the rate of reaction, are exponential, meaning a small change can lead to a dramatic increase in outcome."

That much has been observed experimentally, but to understand how to control the process and expand its applications, the researchers wanted to create a theory for what they were seeing. They used nano-scale thermometric techniques to measure the temperature of the adsorbed atoms - also known as adatoms - subjected to the jet, and used that information to help understand the basic physics at work.

"Once we have a model, it essentially becomes a design tool," Fedorov said. "With this understanding and the capabilities we have demonstrated, we can expand them to other fields such as directed self-assembly, epitaxial growth and other areas. This could enable a whole host of new capabilities to use this kind of direct-write nanofabrication."

Development of the model and understanding of the first-principles physics behind it could also allow other researchers to find new applications.

"With this, you can have almost the same order of magnitude growth rate as you'd have with liquid phase precursors, but still have access to the richness of possible precursors, the ability to manipulate alloying, and all the experience that has been developed over the years with gas phase deposition," Fedorov said. "This technology will allow us to do things at a scale that is meaningful from a practical standpoint and cost-effective."

The ability to rapidly produce small, three-dimensional structures could open up a range of new applications.

"If you can adapt additive direct-write techniques, this could bring a lot of unique capabilities for magnetic memory, superconducting materials, quantum devices, 3D electronic circuitry, and many more things," he said. "These structures are currently very hard to make using conventional methods."

Beyond using the jets to accelerate deposition of precursor materials already on the substrate, the researchers have also created hybrid jets that contain both high-energy inert gas and precursor gases, which allow not only dramatic acceleration of nanostructure growth but also precisely control the material composition during growth. In future work, the researchers plan to use these hybrid approaches to enable formation of nanostructures with phase and topology that cannot be achieved by any existing nanofabrication techniques.

Spotted owl populations are in decline all along the West Coast, and as climate change increases the risk of large and destructive wildfires in the region, these iconic animals face the real threat of losing even more of their forest habitat.

Rather than attempting to preserve the owl's remaining habitat exactly as is, wildfire management -- through prescribed burning and restoration thinning -- could help save the species, argues a new paper by fire ecologists and wildlife biologists and appearing today (July 2 ) in the journal Frontiers in Ecology and the Environment.

The paper compares the plight of the owl with that of another iconic threatened species, the red-cockaded woodpecker, which has made significant comebacks in recent years -- thanks, in part, to active forest management in the Southern pine forests that the woodpecker calls home. Though the habitat needs of the two birds are different, both occupy forests that once harbored frequent blazes before fire suppression became the norm.

"In the South, the Endangered Species Act has been used as a vehicle to empower forest restoration through prescribed burning and restoration thinning, and the outcome for the red-cockaded woodpecker has been positive and enduring," said Scott Stephens, a professor of environmental science, policy and management at the University of California, Berkeley, and lead author on the study.

"In the West, it's just totally the opposite," Stephens added. "Even though both places physically have strong connections to frequent fire, the feeling here is that the best thing to do is to try to protect what we have and not allow the return of frequent fire -- but that's really difficult when you have unbridled fires just ripping through the landscape."

A tale of two birds

Spotted owls make their homes in the dense forests of the Western and Southwestern U.S., feeding on flying squirrels and woodrats and nesting in broken-off treetops or tree hollows. Red-cockaded woodpeckers, meanwhile, reside in pine stands in the Southeastern U.S., provisioning nests from nest boxes or hollowed-out cavities in living pine trees and eating insects pried from under tree bark.

Development and logging have robbed both species of much of their former habitat, and their populations have both taken a hit: Partners in Flight estimates the global breeding population of spotted owls to be at 15,000 individuals.

What habitat remains is now largely protected under the Endangered Species Act -- but when it comes to fire and forest management, the act has been interpreted in dramatically different ways in the two regions, said paper co-author Leda Kobziar, associate clinical professor of wildland fire science at the University of Idaho.

"In the South, the act is interpreted to support active management through forest thinning and prescribed burning, and in the West, it is interpreted to exclude most fires and active management from protected areas surrounding spotted owl nests," Kobziar said.

One critical difference is the degree to which active management in red-cockaded woodpecker habitat provides complementary benefits. "In the South, active management is known to reduce wildfire hazards, and it benefits local economies, along with a host of other fire-dependent species. In the West, those complementary benefits are less well-defined," Kobziar said.

Another part of the reason for the discrepancy is perceived differences in the habitat preferences of the two birds, Kobziar explains. Red-cockaded woodpeckers live in more open, mature pine forests that result when low-intensity natural or prescribed burns limit the development of a forest midstory, where woodpecker predators take cover. Meanwhile, spotted owls generally prefer the dense, multi-layered forests that grow when fire is excluded.

However, suppressing all fires in order to encourage growth of these dense canopies also creates conditions that are ripe for large, severe wildfires that can take out not just the smaller trees, but entire forests, obliterating swaths of owl habitat in the process. The 2014 King Fire, for example, tore through regions of the Eldorado National Forest that were home to a long-term study of the California spotted owl and caused the bird's largest population decline in the 23-year history of the study.

"A key question to be asking is: Where would owl habitats be with more characteristic fire regimes, and could we tailor landscape conditions where these habitats are less vulnerable and more supportive of today's wildfires?" said co-author Paul Hessburg, a research landscape ecologist with the U.S. Forest Service Pacific Northwest Research Station.

The solution would mean, "essentially creating less habitat in order to have more in the long run," he said.

Fighting fire with fire

Before European settlement, many small to medium sized wildfires burned through the forests of the Southeastern and Western U.S., sparked by lightning or intentionally lit by native peoples to produce food, clear land or drive game. These fires would gobble up the dead wood, seedlings and saplings that made up the forest understory, while leaving taller, older trees standing and marked with fire scars recorded in their growth rings that fire ecologists use to track the frequency of historical fires.

In the mountainous landscape of the West, these fires didn't strike uniformly everywhere, to the potential benefit of the owls, Hessburg said. "If I took you back in the way-back machine 200 years ago, you would have seen that fire regimes in the Cascade Mountains differed very much by topographic setting," Hessburg said. "Ridgetops and south slopes would often get pounded with lightning and fires, and so tree cover would be sparse. But in shaded and cool valley bottoms and north slopes, you would see complex layered forests, and some of these would have been incredible owl habitats."

Targeted restoration thinning and prescribed burning on ridgetops and dry southern slopes where fire used to be a frequent visitor, while leaving valley bottoms and northern slopes to develop into complex forest, could be a way to discourage large wildfires from ripping through vast landscapes, while maintaining owl habitat in a more fire-protected context.

New evidence also hints that owls may not be so dependent on dense understory canopies as once thought, the paper notes. Recent findings indicate that other aspects of forest structure, particularly the presence of large, old, tall trees, may be more important to the owls. These findings hint that prescribed burning and restoration thinning to reduce the size and severity of wildfires may not be damaging to owl habitat, even in the short term.

"We're treating the habitat as if we know precisely what habitat characteristics are preferred. It might be that these birds are tolerant of a broader range of characteristics that would enable things like fuels reduction to protect them from high-intensity wildfires," Kobziar said.

"The South has melded fire and rare species management in a holistic way, but in the West, we're doing one or the other -- (in) most places (where) we do forest restoration, we are trying to avoid owls," Stephens said. "But the King Fire showed that owls and their habitats are vulnerable to large wildfires. More restoration thinning and prescribed burning could help us keep the habitat that we have now, modify it and actually make it more sustainable in the future."

OKLAHOMA CITY - Women with ovarian cancer who have undergone four or more rounds of chemotherapy typically haven't had much hope that another treatment option will lengthen their lives in a meaningful way. However, a new research study shows tremendous promise for a drug called niraparib to extend life when all options have been exhausted.

Gynecologic oncologist Kathleen Moore, M.D., associate director of clinical research at the Stephenson Cancer Center at OU Medicine, is the lead author for the study, which was published in The Lancet Oncology, the world's leading cancer journal. The study reveals especially good news for patients with ovarian cancer who do not have a mutation of their BRCA gene, as well as those who have received multiple chemotherapy treatments. Because the study showed a longer survival time for those patients, it lends support for an expansion of the use of niraparib, a PARP inhibitor that targets cancer cells without affecting normal cells.

"This is another piece of the puzzle that helps our patients live longer," Moore said. "There haven't been a lot of studies done on patients without BRCA mutations who have received four, five, six or more lines of chemotherapy. That's who this trial sought to study. Until we can cure patients, we are doing our best to find treatments that buy them meaningful periods of time, until we can provide them with the next effective line of therapy."

Because women with BRCA-associated cancers respond best to PARP inhibitors, they have been the most heavily studied group and led to the first indications for using the drugs in treating ovarian cancer. However, only about 25 percent of women with ovarian cancer have a BRCA mutation either in their tumor or blood, and there is a high unmet need for effective therapies for the 75 percent of women who do not have BRCA mutations, Moore said.

Ironically, having a BRCA mutation means that the patient's cancer will respond better to chemotherapy and to a PARP inhibitor like niraparib. Women with BRCA mutations have something called homologous recombination deficiency - which means that when their cancer cells make mistakes in the process of dividing, they have trouble repairing those mistakes. PARP inhibitors like niraparib make repairing those mistakes even harder, which equates to treatment being able to kill cancer cells more efficiently.

However, women with BRCA mutations aren't the only cancer patients who have homologous recombination deficiency. Up to 25 percent of women without a BRCA mutation can also develop the condition, meaning they, too, can benefit from taking a PARP inhibitor.

The study further categorized patients into those who were resistant to platinum-based chemotherapy and those who showed some response to it. Among women who responded to their last chemotherapy treatment, 27 percent responded well to niraparib and averaged 9.2 months until the disease grew or spread. Participants in the study had an overall survival time of more than 20 months, which is quite remarkable in this late line of therapy, Moore said.

"We don't normally see response rates of more than 10 percent in women who have had four, five and six chemotherapy treatments," she said. "So a 27 percent response, especially given that these were not all women with BRCA mutations, was a nice signal that these patients can still benefit from PARP inhibitor use."

Even among women whose cancers were resistant to their last chemotherapy treatment, niraparib still extended their lives. Thirty-three percent of women in that category benefited from the drug for at least four months.

"Those additional months are important," Moore said. "They are never enough, but several months of disease stabilization is better than none. They can get people to Christmas or to see a new grandchild or to another milestone. Then, if they are stabilized and feeling better, they might be able to take another drug or go on a clinical trial."

Research studies also are important for expanding the types of patients who can receive a drug like niraparib, Moore said. Per FDA regulations, the only way that women without a BRCA mutation can currently receive niraparib is to respond favorably to platinum-based chemotherapy, then go on the drug as maintenance.

"We think this data supports the expansion of niraparib to be more inclusive of patients. PARP inhibitors work best in women with BRCA mutations, but they can still work well in women without the mutation. Niraparib really makes sense for a much broader population," said Moore, who holds the Virginia Kerley Cade Endowed Chair in Cancer Developmental Therapeutics, funded by the Presbyterian Health Foundation.

Understanding the structure and metabolism of cells and living organisms is essential for the development of new drugs and diagnostics. The availability of chemical tools that allow scientists to edit biomolecules, like proteins, with atom-level resolution have greatly contributed to the progress of chemical biology.

Proteins are macromolecules constructed from a set of twenty chemically different amino acids. One key approach to modify proteins is to react with the sulfur atom in the amino acid cysteine. However, current methods are still problematic in terms of efficiency, selectivity, and stability of the final product (the "adduct").

Now, the labs of Jérôme Waser and Beat Fierz at EPFL's Institute of Chemical Sciences and Engineering have developed a new method for modifying cysteines on peptides and proteins. The method uses a group of highly reactive organic molecules, the ethynylbenziodoxolones (EBXs). What makes EBXs highly reactive is that they contain an iodine atom bound to three substituent groups. This non-natural situation leads to high reactivity in these so-called "hypervalent iodine" reagents.

For the first time, the researchers were able to generate a simple biomolecule-EBX adduct while keeping their reactive iodine group in the final molecule. The reaction can be easily performed by a non-expert under standard physiological conditions.

The end product are protein-hypervalent iodine reagent chimeras that can act as dual attachment points for two new chemical groups, opening up new opportunities for the study of biological processes.

"One new functionality can be introduced via 'click-chemistry', a well-established reaction in chemical biology," says Waser. "Using a palladium catalys, another selective modification can be achieved at the reactive iodine atom- what we would call a 'biorthogonal' functionality, as it does not exist in nature." Introducing such exotic reactive groups into biomolecules is currently one of the most important tools in chemical biology, as it allows the study of biological processes without interfering with them.

The scientists demonstrated the potential of the method by introducing a diverse set of chemical groups into biomolecules. For example, the scientists used the dual handle to attach a fluorescent dye and a photoprotecting group into a neuropeptide simultaneously. Combining them improves the dye's photostability, and enables high-resolution, single-molecule imaging of molecular interactions.

Beyond peptides, they further modified small proteins, and even large protein-DNA complexes, so-called nucleosomes. As nucleosomes organize the genome, labeling them with fluorescent dyes can help track them to decipher how nature regulates gene expression.

"What we developed here is a new method for modifying proteins based on fundamental studies of chemical reactivity," says Fierz. "We have already used it to modify of histones, and carried out fluorescence experiments on living cells. With these examples, we have set the foundation for a better understanding of biological processes."

Plant leaves have a natural superpower -- they're designed with water repelling characteristics. Called a superhydrophobic surface, this trait allows leaves to cleanse themselves from dust particles. Inspired by such natural designs, a team of researchers at Texas A&M University has developed an innovative way to control the hydrophobicity of a surface to benefit to the biomedical field.

Researchers in Dr. Akhilesh K. Gaharwar's lab in the Department of Biomedical Engineering have developed a "lotus effect" by incorporating atomic defects in nanomaterials, which could have widespread applications in the biomedical field including biosensing, lab-on-a-chip, blood-repellent, anti-fouling and self-cleaning applications.

Superhydrophobic materials are used extensively for self-cleaning characteristic of devices. However, current materials require alteration to the chemistry or topography of the surface to work. This limits the use of superhydrophobic materials.

"Designing hydrophobic surfaces and controlling the wetting behavior has long been of great interest, as it plays crucial role in accomplishing self-cleaning ability," Gaharwar said. "However, there are limited biocompatible approach to control the wetting behavior of the surface as desired in several biomedical and biotechnological applications."

The Texas A&M design adopts a 'nanoflower-like' assembly of two-dimensional (2D) atomic layers to protect the surface from wetting. The team recently released a study published in Chemical Communications. 2D nanomaterials are an ultrathin class of nanomaterials and have received considerable attention in research. Gaharwar's lab used 2D molybdenum disulfide (MoS2), a new class of 2D nanomaterials that has shown enormous potential in nanoelectronics, optical sensors, renewable energy sources, catalysis and lubrication, but has not been investigated for biomedical applications. This innovative approach demonstrates applications of this unique class of materials to the biomedical industry.

"These 2D nanomaterials with their hexagonal packed layer repel water adherence, however, a missing atom from the top layer can allow easy access to water molecules by the next layer of atoms underneath making it transit from hydrophobic to hydrophilic," said lead author of the study, Dr. Manish Jaiswal, a senior research associate in Gaharwar's lab.

This innovative technique opens many doors for expanded applications in several scientific and technological areas. The superhydrophobic coating can be easily applied over various substrates such as glass, tissue paper, rubber or silica using the solvent evaporation method. These superhydrophobic coatings have wide-spread applications, not only in developing self-cleaning surfaces in nanoelectronics devices, but also for biomedical applications. Specifically, the study demonstrated that blood and cell culture media containing proteins do not adhere to the surface, which is very promising. In addition, the team is currently exploring the potential applications of controlled hydrophobicity in stem cell fate.

Secondary progressive multiple sclerosis (MS) is a relentless disease. Over time, patients experience worsening physical, mental and mood-related symptoms. And yet, even as their symptoms progress, the brain white matter lesions found on a patient's MRI scans often remain unchanged. Suspecting that changes in the grey matter regions of the brain may be playing a critical role in the disease's progression, investigators from Brigham and Women's Hospital conducted an initial study assessing the differences in the activity of microglial cells in the grey matter regions of healthy volunteers versus those with MS. Using a novel tracer molecule known as [F-18]PBR06 and Positron Emission Tomography (PET) imaging, the team detected widespread and abnormal activation of microglia in MS patients and a link to brain atrophy, physical disability, and progressive MS. The team's findings are published in the July 2019 issue of Neurology: Neuroimmunology & Neuroinflammation, an official journal of the American Academy of Neurology.

"There's more to multiple sclerosis than white matter lesions," said corresponding author Tarun Singhal, MD, a neurologist at the Ann Romney Center for Neurologic Diseases at the Brigham. "There's evidence of inflammation in the brain's grey matter, not just the white matter. Here we have a technique to detect it and a path to develop this technique for use in the clinic in looking for early signs of progression and the effects of treatments."

Currently, there are several disease-modifying drugs on the market to help patients with relapsing remitting MS experience fewer and less severe relapses, but few drugs exist for patients with secondary progressive MS. Investigations to develop new drugs are underway, but many questions remain about the underlying biology of the disease and how it progresses.

The new study leverages the novel radioisotope, [F-18]PBR06, a tracer that targets a specific protein (TSPO) found in activated microglia, key immune cells found in the brain. Many other research projects use C-11, an isotope with a much shorter half-life. But, unlike C-11, the F-18 tracer has a significantly longer half-life and a higher potential to be used in the clinic.

For the pilot study, investigators evaluated results for 12 patients with MS -- seven with relapsing remitting MS and five with secondary progressive MS -- and compared it with healthy controls using the F-18 tracer. They found more grey matter microglial activation in the MS patients as compared to healthy controls, particularly in hippocampus, parahippocampus, cingulate gyrus and amygdala regions of the brain. These regions of the brain are known to influence critical processes, including emotion, memory and cognition, all of which may be affected in MS patients. Brain structures in the deep grey matter, particularly the thalamus, showed higher microglial activation in secondary progressive MS than in the relapsing remitting MS patients and healthy controls. This correlated significantly with physical disability and brain atrophy.

The authors note that the pilot study is small and its findings will require additional confirmation in larger studies with a longitudinal design, but it offers the first assessment of [F-18]PBR06 PET for grey matter changes in MS, demonstrating the potential value of this technique.

"Unless we can measure the progress of a disease accurately, our ability to treat that disease remains limited," said Singhal. "When a patient tells us that their symptoms are worsening, we want to have a technology that can reflect that, or better yet, predict the progression before it is clinically obvious. This technique may have the potential to do that and give us critical insights into neurodegeneration and its relationship with neuroinflammation."

RIVERSIDE, Calif. -- A research team at the University of California, Riverside, has found that electronic cigarettes, often targeted to youth and pregnant women, produce a stress response in neural stem cells, which are critical cells in the brain.

Present throughout life, stem cells become specialized cells with more specific functions, such as brain cells, blood cells, or bone. Far more sensitive to stress than the specialized cells they become, stem cells provide a model to study exposure to toxicants, such as cigarette smoke.

Electronic cigarettes, or ECs, are nicotine-delivery devices that aerosolize nicotine and flavor chemicals through heating. Researchers do not yet understand how the chemicals in ECs might affect neural stem cells, particularly their mitochondria -- organelles that serve as the cell's powerhouses and are critical in regulating cell health.

Using cultured mouse neural stem cells, the UC Riverside researchers identified the mechanism underlying EC-induced stem cell toxicity as "stress-induced mitochondrial hyperfusion," or SIMH.

"SIMH is a protective, survival response," said Prue Talbot, a professor in the Department of Molecular, Cell and Systems Biology who led the research. "Our data show that exposure of stem cells to e-liquids, aerosols, or nicotine produces a response that leads to SIMH."

The study, performed on Vuse, a leading EC brand, appears in iScience, an open-access journal from Cell Press.

"Although originally introduced as safer, ECs, such as Vuse and JUUL, are not harmless," said Atena Zahedi, the first author of the research paper who received her doctoral degree in bioengineering this year. "Even short-term exposure can stress cells in a manner that may lead, with chronic use, to cell death or disease. Our observations are likely to pertain to any product containing nicotine."

Zahedi, the recipient of a 2019-20 UC President's Postdoctoral Fellowship, explained that during SIMH, round punctate mitochondria fuse together to form long hyperfused networks in order to rescue each other -- making them less vulnerable to degradation.

"The high levels of nicotine in ECs lead to a nicotine flooding of special receptors in the neural stem cell membrane," Zahedi said. "Nicotine binds to these receptors, causing them to open up.  Calcium and other ions begin to enter the cell. Eventually, a calcium overload follows."

Zahedi explained that too much calcium in the mitochondria is harmful. The mitochondria then swell, changing their morphology and function. They can even rupture and leak molecules that lead to cell death.

"If the nicotine stress persists, SIMH collapses, the neural stem cells get damaged and could eventually die," Zahedi said. "If that happens, no more specialized cells -- astrocytes and neurons, for example -- can be produced from stem cells."

Zahedi added that damaged stem cell mitochondria could accelerate aging and lead to neurodegenerative diseases. Neural stem cells can get exposed to nicotine through the olfactory route, she explained. Users inhale the fumes, which can travel through the olfactory tracks to reach the brain.

Talbot and Zahedi stress that youth and pregnant women need to pay especially close attention to their results.

"Their brains are in a critical developmental stage," said Talbot, the director of the UCR Stem Cell Center. "Nicotine exposure during prenatal or adolescent development can affect the brain in multiple ways that may impair memory, learning, and cognition. Furthermore, addiction and dependence on nicotine in youth are pressing concerns. It's worth stressing that it is nicotine that is doing damage to neural stem cells and their mitochondria. We should be concerned about this, given that nicotine is now widely available in ECs and their refill fluids."

Brazil's leatherback turtles are making a "gentle recovery" after 30 years of conservation efforts, new research shows.

Scientists studied nesting sites in the state of Espírito Santo in eastern Brazil - the only place in the south-west Atlantic where leatherbacks regularly nest.

Data on this small population from 1988-2017 showed the average number of nests rose from 25.6 in the first five years of the period to 89.8 in the final five years.

The researchers, from the University of Exeter and Brazilian sea turtle conservation programme TAMAR-ICMBio, believe local conservation efforts have contributed to this increase.

But they say conservation of this population is still a concern due to climate change, pollution, coastal development and "bycatch" (accidental catch by humans fishing).

"The numbers vary year by year, but overall we have seen an increase in the number of leatherback nests in Espírito Santo," said Dr Liliana Poggio Colman, of the Centre for Ecology and Conservation on the Exeter's Penryn Campus in Cornwall.

"This gentle recovery is probably due, at least in part, to local conservation efforts started by Projeto TAMAR in the 1980s.

"Our study revealed a significant decrease in the size of the turtles breeding on these beaches, suggesting that new females are joining the breeding population."

Dr Poggio Colman, who had a scholarship from the programme Science Without Borders, funded by the Brazilian government, added: "We are encouraged by what we have found, but this is a small population - fewer than 20 nesting females per year, each laying several clutches - so their conservation will remain a concern."

Throughout the study period, nests were concentrated in the southern part of the 100-mile (160km) study area, with the protection of core nesting areas being key for the effective conservation of this population.

Professor Brendan Godley, who was one of Dr Poggio Colman's PhD supervisors, added: "It was a great pleasure to help facilitate this collaborative work in Brazil.

"By chance, the team was in the field when a major spill of waste mining material impacted in the area in 2015. Average hatching success has, however, remained fairly steady at about 66%."

In the time it takes for an Amazon Prime delivery to arrive, cells damaged by chemotherapy can almost completely fix their most important DNA. That is the case in the livers of mice at least, according to a new study.

A team of researchers led by Nobel laureate Aziz Sancar found that DNA damaged by the widely used chemotherapy drug cisplatin is mostly good as new in noncancerous tissue within two circadian cycles, or two days. The results published in the Journal of Biological Chemistry could inform the development of chronochemotherapies -- strategies aimed at administering chemotherapy drugs at times that maximize tumor damage while minimizing side effects.

Cisplatin is a frontline drug for numerous cancers, but it often is accompanied by serious side effects including kidney, liver and peripheral nerve injury. Since cisplatin kills cells, cancerous or otherwise, by damaging their DNA, Sancar and his team aimed to uncover the pattern of DNA repair in healthy cells, which could reveal when it might be best to administer cisplatin. In normal cells, the circadian clock drives the rhythm of DNA repair, but this is not the case in tumors.

"Most cancers do not have a functional clock and so, basically any time that it's good for the normal tissue, you can hit the cancer," said Sancar, professor of biochemistry and biophysics at the University of North Carolina School of Medicine.

In an earlier study, Sancar's team provided a first look at DNA repair across the genome of whole animals (mice in this case), uncovering two mechanisms of circadian-controlled DNA repair.

They found that for some genes, transcription -- during which damaged DNA is recognized and patched up -- was rhythmic and controlled by the circadian clock. The pattern of transcription was specific to each gene, with repair peaking at different times of day. For the remaining DNA that was not transcribed, repair was less efficient but also clock-controlled, and maximum repair occurred between 4 p.m. and 6 p.m., Sancar said.

They examined DNA two hours after injecting cisplatin in this previous experiment, but in their new work in JBC, Sancar's team wanted to study the recovery of DNA following administration of cisplatin on a more clinically relevant time scale.

"We recapitulate what has been done in patients because in patients you give cisplatin (intravenously) at either weekly, 10-day or two-week intervals. So you give one dose and then let the patient recover for a week or so and then give the second dose. And so we wanted to know what happens over those long periods," Sancar said.

The team used a technique developed in their lab, known as XR-seq, to capture and sequence fragments of damaged DNA from mice injected with cisplatin. Over the course of 70 days, they produced maps displaying where and when DNA was fixed at the resolution of a single nucleotide.

They found that the DNA of transcribed genes was just about fully mended in two circadian cycles, Sancar said. Restoration of these genes composed the majority of repair during the first 48 hours but afterward, repair of nontranscribed DNA became dominant and proceeded for weeks.

The remaining damage in nontranscribed DNA is not harmful in normal cells that aren't replicating, Sancar said. But for cancer cells which divide uncontrollably, this damage could lead to cell death.

This new information about the timetable of DNA repair could eventually aid the design of successful chronochemotherapies, but before this information is considered in the clinic, further experiments are needed, Sancar said.

Sancar himself is already at work with oncologists, evaluating new cisplatin regimens in mice implanted with human tumors to find a treatment that reduces toxicity in normal tissue while hitting cancer hard.