Culture

Chemists from Far Eastern Federal University's School of Natural Sciences (SNS FEFU) developed a new method to synthesize biologically active derivatives of fascaplysin -- cytotoxic pigment of a sea sponge. For the first time, they got a sufficient amount of 3-bromofascaplysin and 3,10-dibromofascaplysin, which were known before but were not available for study. Basing on these compounds, scientists synthesized 14-bromoreticulatate and 14-bromoreticulatine -- the derivatives of the reticulatine alkaloids. The resulting article is published in Marine Drugs.

The joint study of scientists from the Far Eastern branch of the Russian Academy of Sciences and University Medical Center Hamburg-Eppendorf has shown that 14-bromoreticulatine -- obtained for the first time in FEFU -- selectively affects Pseudomonas Aeruginosa bacterium, resistant to many types of antibiotics. Also, the new compound has a moderate cytotoxic activity resulting in the death of skin cancer, rectal cancer, and prostate cancer cells.

3,10-Dibromofascaplysin can suppress human prostate cancer cell's metabolism at sevenfold lower concentrations than those that lead to their cell membranes destruction. The substance has a wide range of potential applications to selective treatment of malignant tumor, without an adverse effect on the healthy cells.

&laquoIt is important that due to the modification of the original alkaloid structure, we were able to register the variety of its mechanisms of action at greatly different concentrations. This opens up possibilities to create new antitumor drugs with selective action based on fascaplysin. Modern anti-cancer drugs have this important property implemented not sufficiently -- it determines their high toxicity for the organism as a whole. Next drug generation will not affect the patients' quality of life that bad", said Maxim Zhidkov one of the authors of the study, associate professor of organic chemistry in SNS FEFU.

The author refined that it is too early to talk about the developing of a new drug. Scientists hope to synthesize a new series of fascaplysin derivatives based on the results of the study and to test their action in mice. The results of prospective experiments will reveal how close the researchers came to a new effective drug.

The vast part of the research related to the synthesis of target compounds was carried out by Polina Smirnova -- a Ph.D. student of the Department of organic chemistry in SNS FEFU. Scientists from G.B. Elyakov Pacific Institute of Bioorganic Chemistry of the Far Eastern Branch of the Russian Academy of Sciences, Federal Scientific Center of the East Asia Terrestrial Biodiversity of the Far Eastern Branch of the Russian Academy of Sciences and University Medical Center Hamburg-Eppendorf are among other participants of the study.

Fascaplysin was first extracted from the sea sponge Fascaplysinopsis sp. in 1988 and has been intensively studied ever since. This compound has a wide range of biological activity -- it strongly suppresses the growth of various types of tumor cells and has antibacterial, antifungal and even analgesic effects. However, the fascaplysin's high toxicity to healthy cells limits its use as a drug.

Earlier, FEFU scientists have shown that fascaplysin derivatives stimulate the death of glioblastoma multiforme cells -- the most aggressive type of brain cancer.

HOUSTON - (Nov. 14, 2019) - A microscopic polymer in the form of a common kitchen implement could give industry exquisite control over coatings.

Bottlebrush copolymers have long been a topic of study for Rafael Verduzco, a chemical and biomolecular engineer at Rice University's Brown School of Engineering. Now, he and his collaborators have developed models and methods to refine surface coatings to make them, for instance, more waterproof or more conductive.

The researchers discovered that bottlebrushes mixed with linear polymers tend to migrate to the top and bottom of a thin film as it dries. These films, as coatings, are ubiquitous in products, for instance as waterproof layers to keep metals from rusting or fabrics from staining.

When the migration happens, the linear polymers hold the center while the bottlebrushes are drawn to the air above or the substrate below. This, Verduzco said, effectively decouples the properties of the bulk coating from its exposed surfaces.

Computational models and experiments showed that variations in the bottlebrush itself could be used to control surface characteristics.

Bottlebrush polymers remain challenging to make in bulk, Verduzco said, but their potential uses are vast. Applications could include drug delivery via functionalized bottlebrushes that form micelles, lubricants, soft elastomers, anti-fouling filters and surfaces that heal themselves, he said.

The details appear in the American Chemical Society journal Macromolecules.

The Rice lab, with help from peers at the University of Tennessee, Knoxville; Oak Ridge National Laboratory and the University of Houston, characterized various bottlebrushes made of polystyrene and poly(methyl methacrylate) (aka PMMA) while studying what causes the polymers to migrate.

Resembling their macro kitchen cousins (as well as certain flowers), bottlebrushes consist of small polymer chains that radiate outward from a linear polymer rod. The bottlebrushes self-assemble in a solution, which can be manipulated to adjust their properties.

Coatings are ubiquitous, Verduzco said. "If we didn't have the right coatings, our materials would degrade quickly," he said. "They would react in ways we don't want them to. So coating a surface is usually a separate process; you make something and then you have to find a way to deposit a coating on top of it.

"What we're looking at is a kind of universal additive, a molecule you can blend with whatever you're making that will spontaneously go to the surface or the interface," he said. "That's how we ended up using bottlebrushes."

Bottlebrushes can be tuned by varying the number of side chains, their length or the length of the backbone polymer, Verduzco said. The side chains themselves can be of mixed type, and small molecules or proteins can be added to their end groups.

"The chemistry of these materials is advanced sufficiently that you can pretty much put just about any kind of polymer as one of these bristles on the side chain," he said. "You can put them in different order."

The researchers found entropic and enthalpic thermodynamics drove bottlebrushes almost completely away from the interior of the films and toward the interfaces as they dried. Even where linear polymers were designed to pair with the surface interface, the bottlebrushes still rose to the exposed surface.

Verduzco noted the findings were made possible by the time of flight-secondary ion mass spectrometer acquired by Rice in 2018 through a National Science Foundation grant. The spectrometer allowed the researchers to characterize not only the surface of coatings by bombarding them with ions, but also how coatings changed as microscopic layers were removed from the top down.

CHAPEL HILL — University of North Carolina Lineberger Comprehensive Cancer Center researchers have discovered a promising method to identify aggressive breast cancer tumors that will respond to drugs that unleash the immune system against cancer.

The U.S. Food and Drug Administration recently approved a treatment that combines an immunotherapy drug and chemotherapy for triple negative breast cancer, but not all cases of this aggressive form of breast cancer responded in clinical studies.

UNC Lineberger researchers discovered biological clues that could help identify which tumors might respond to the combination treatment.

Their findings, published in the journal Cell, were drawn from studies in mice and an analysis of data from six clinical trials. If confirmed in future studies, the insights could help guide patients to the right treatments, sparing them from those that are not effective. It also could lead to an approach to make the drugs work in cancers that don't initially respond.

"Potentially, we have a new biomarker to be used to figure out which triple negative breast cancer patients should be receiving immunotherapies," said UNC Lineberger's Charles M. Perou, PhD, the May Goldman Shaw Distinguished Professor in the UNC School of Medicine departments of genetics and pathology.

Triple negative breast cancer lacks three receptors used to guide therapy in breast cancer patients: the estrogen receptor, progesterone receptor, and HER2/ERBB2 protein. It accounts for approximately 12 percent of invasive breast cancer cases in the United States, and is more likely to affect younger women, as well as black women and people who have a BRCA1 mutation. Without these three treatment options, doctors typically have used chemotherapy, which bluntly attacks rapidly dividing cells in the body, but that can be effective for many patients with triple negative breast cancer.

The FDA approved the use of an immunotherapy drug, atezolizumab, in combination with chemotherapy for patients with triple negative breast cancer that has metastasized, or spread out of the breast. It was the first time the FDA had approved a treatment that included an immunotherapy for breast cancer.

Atezolizumab is a checkpoint inhibitor, a type of immunotherapy that "releases the brakes" on certain immune cells called T cells, freeing them to find and attack cancer cells. These treatments have been groundbreaking for patients with advanced melanoma, the deadliest form of skin cancer, and other cancers.

A New England Journal of Medicine study reported that the combined atezolizumab-chemotherapy regimen produced prolonged progression-free survival for some patients with triple negative breast cancer that tested positive for the PD-L1 protein. Forty-one percent of patients were PD-L1 positive, and not all of these tumors responded to the combination therapy.

To study why some triple negative breast cancers respond to immunotherapy and others do not, Perou and his colleagues created multiple mouse model of triple negative breast cancer to define the biological features of breast tumors that do respond to the treatment.

In order to answer this question, the mouse models had to respond to immunotherapies - which existing models did not. They genetically modified existing models so that they contained a high number of so-called "tumor antigens" - irregular proteins in the tumor that can trigger the immune system - so the altered models were highly responsive to immune treatments.

They then used genetic tools to analyze the biological features of the tumors that responded, and uncovered a "signature" of response using gene expression data.

The signature revealed clues about what could be causing the immunotherapies to work: The patients whose cancer responded to treatment had a coordinated immune response to the cancer that involved multiple types of immune cells, including both T-cells, which can directly attack and kill tumors, and B cells, which make antibodies that may also attack tumors.

"The biomarker signifies a coordinated effort of the adaptive immune system," Perou said.

Researchers also showed that the gene expression pattern worked for identifying immunotherapy responses in their mouse models as well as in analysis of data from human clinical trials. They showed they could potentially use it to identify breast cancers that will respond to chemotherapy, HER2-positive breast cancers that will respond to trastuzumab, and importantly, human melanomas that will respond to immunotherapies.

"There are many types of immune cells, and they need to work together to mount an effective immune response, and this biomarker shows when B cells and T cells are working together," Perou said. "And whenever we see that, it predicts a better response--whether it to be immune therapy in melanoma, HER2 targeting therapy in breast cancer patients or chemotherapy in triple negative breast cancer patients."

They believe the finding could identify both patients who would benefit from the therapy, and also those who wouldn't.

He added that they also want to use their findings to discover new ways to boost treatment responses.

"Our work going forward right now is to look for ways to leverage B cells to improve treatment plans and regimens for breast cancer patients," said Dan Hollern, PhD, the first author of the study and a postdoctoral research associate at UNC Lineberger. "We definitely need to be looking at ways to activate B cells more effectively with our therapies."

Researchers say they also plan to study the biomarker in further studies in order to continue to evaluate the signature in patients with triple negative breast cancer who are receiving the immunotherapy combination.

Feelings of neighborhood pride, interactions with tourists and a community's laws can all influence how neighbors feel about short-term vacation rentals.

These interactions can change from neighborhood to neighborhood and can offer insight into how to craft local ordinances governing these types of vacation rentals, according to a newly published study conducted at the University of Georgia.

Short-term vacation rentals--more commonly known as companies such as Airbnb, VRBO or HomeAway--can have polarizing effects in communities, says Emily Yeager, now an assistant professor at East Carolina University who conducted the study as a doctoral student in UGA's Warnell School of Forestry and Natural Resources. Her paper, which was released late last month in the Journal of Travel Research, studied resident attitudes toward short-term vacation rentals in Savannah, Georgia.

"Through resident surveys, we found evidence of what we call psychological empowerment, or how proud you are of your community because short-term vacation rentals are in it," said Yeager. "In other words, imagine you are proud of your neighborhood because people want to come visit and stay there. People are excited and think, 'This is what we have to offer.' But it's very spatially nuanced."

Yeager chose Savannah for her study because it has long been a tourist destination. Since the rise of short-term vacation rentals, it has adjusted local ordinances to reflect changes wrought by the industry. Short-term rentals are allowed in certain neighborhoods, offering a variety of experiences for both residents and guests.

These interactions, says Yeager, have influenced residents' overall attitudes toward short-term vacation rentals.

"For example, the Northwest portion of the city has a high concentration of bars and carriage tours. If you asked people who lived in this area's historic districts, they are proud to have Airbnbs in the neighborhood, but the answer is less positive than in the Southwest corridor," said Yeager. "On the other hand, the Starland District is a new district that's developed in the Southwest portion of the vacation rental zones. There's an art scene and boutique coffee shops, and if you asked people there if they were proud, it's a lot different. They are very excited about vacation rentals."

Yeager conducted the study in 2016 and 2017, just before Savannah developed new regulations for short-term vacation rentals. At the time, residents were concerned with the density of rentals and the effect they had on the neighborhood--Yeager called some of them "ghost neighborhoods" because of the lack of permanent residents.

Bridget Lidy, director of planning and urban design for Savannah, said new regulations put in place since 2017 addressed some of the angst residents had toward short-term vacation rentals, but a follow-up survey, similar to what Yeager conducted, would be needed to know for sure. "The regulations are much more stringent than what they were before, but we have to walk a fine line," relating to property rights, she said.

Yeager's study was unique in that it was the first to look at the support or opposition of residents toward short-term vacation rentals. Research typically investigates resident attitudes toward tourism in general, but not yet for short-term rentals, said Bynum Boley, an associate professor in Warnell who served as Yeager's advisor.

Because tourists are embedded in neighborhoods when using services such as Airbnb or VRBO, they have a different kind of interaction with residents than those who stay in a hotel, where tourists are usually sequestered in their own part of town.

"It's an interesting finding that psychological empowerment had a direct relationship on support," said Boley. "If residents felt their neighborhood was on show, and if they felt visitors were there because their neighborhood had some sort of unique cultural or architectural value, then they are likely to support short-term vacation rentals."

"Additionally, the more short-term vacation rentals bring a community together, the more residents support it," he added. "But a big fear is that they could create some type of ghost neighborhood, where nobody lives there anymore. So, if one perceives short-term vacation rentals as tearing a community apart, then they are going to be opposed to it."

Ultimately, Yeager said she wants the study to be useful to communities as they move forward with their own regulations. Hosts and neighbors can be considered positive ambassadors for the community, and perception--whether it's on the street or via social media channels--can have a large impact. Especially when tourism is a large part of a community's income.

"If a community is thinking about regulating something like this, it might be important to look at channels of communications that aren't managed by the city," Yeager added. "For example, some online forums were additional resources to find opinions about short-term vacation rentals, and these were the same people attending city-hosted workshops. But you'd never hear the stories that were shared online."

A new study from researchers at the Johns Hopkins Bloomberg School of Public Health found that in several cities and counties the proportion of high-schoolers who have ever used heroin or misused prescription opioids is much higher than the national average.

The study found that about one in every five white or Latina high school girls in Duval County, Florida, which includes Jacksonville, have misused prescription opioids, while more than 10 percent of Latino high school boys in Duval County and black high school boys in Baltimore, Maryland, have used heroin at least once.

The data used in the study were from 21 cities or counties--20 of which had survey data on heroin use, and 20 of which had survey data on non-medical use of prescription opioids. National data from the U.S. Centers for Disease Control and Prevention show that two percent of U.S. high-schoolers report having used heroin at least once.

The findings, published online in the journal Drug and Alcohol Dependence, are based on survey data gathered in 2017 under the CDC's Youth Risk Behavior Surveillance System, which includes school-based surveys of U.S. students in grades 9 to 12.

"These figures show that as part of the effort to address the opioid crisis, our public health planning and interventions should consider the needs of young people who have been caught up in the epidemic," says study senior author Renee M. Johnson, PhD, MPH, associate professor in the Bloomberg School's Department of Mental Health.

The opioid epidemic in the U.S. began about 20 years ago and has been fueled by the misuse of medical opioids such as oxycodone and fentanyl as well as by heroin use. There were more than 70,000 drug overdose deaths in the U.S. in 2017--about 70 percent of them opioid-related--compared to fewer than 17,000 overdose deaths in 1999.

Results from the study also indicate that some urban areas have much more prevalent heroin use. For example, among ninth to twelfth graders, 12.3 percent of Latino male students in Duval County, Florida, including Jacksonville; 10.9 percent of black male students in Baltimore; and 8.6 percent of black male students in Miami-Dade County reported having used heroin at least once. Overall, male high school students were much more likely than their female schoolmates to have tried heroin.

"Our findings illustrate the complexities of the opioid epidemic, with some cities and subgroups reporting elevated levels of adolescent heroin use also reporting elevated levels of non-medical prescription opioid use while others did not," says Abenaa A. Jones, PhD, a postdoctoral fellow at the Bloomberg School and the paper's first author.

Surprisingly, the highest figures for non-medical prescription opioid use were among high school girls--Latina and white female students in Duval County, Florida (21.3 and 19.9 percent, respectively), and Latina female students in Shelby County, Tennessee, which includes the city of Memphis (18.3 percent). Among the surveyed male students, 17.9 percent of black male students in Chicago, and 17.6 percent of Latino male students and 17.1 percent of black male students in Cleveland reported having misused medical opioids. The CDC's nationwide figures also show that lifetime prescription-opioid misuse is more prevalent among girls (14.4 percent) than boys (13.4 percent).

"It is unusual in drug use prevalence studies to see girls using at the same or even higher rates than boys," Jones says. "These data speak to the importance of ensuring substance use disorder treatment services address the unique needs of girls."

The results on the whole suggest that heroin and medical-opioid misuse among high-schoolers is concentrated at much higher-than-average levels in some cities and counties--places which, Johnson says, clearly demonstrate a need for adequate services directed toward treatment for opioid use among adolescents.

"There is evidence from some of our team's ongoing research that at present the services just aren't there for young people, even in cities where heroin and medical-opioid misuse is a long-standing problem," Johnson says. "We need to think more about treatment for this group--and of course aim for prevention."

New Rochelle, NY, November 14, 2019--A novel method uses subcellular fractionation to quantify label-free antisense oligonucleotides (AONs)- designed to silence targeted genes - that have crossed into the nucleus of a cell, where they can exert their effects. Researchers used this method to correlate nuclear entry of several AON molecules with target gene knockdown and they report their results in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc. publishers. Click here to read the full-text open access article for free on the Nucleic Acid Therapeutics website.

Troels Koch and colleagues from Roche Innovation Center Copenhagen, Hørsholm, Denmark coauthored the article entitled "Nuclear and Cytoplasmatic Quantification of Unconjugated, Label-Free Locked Nucleic Acid Oligonucleotides." Their method combines three main techniques: subcellular fractionation; nucleus counting; and Locked Nucleic Acid (LNA) sandwich Enzyme-Linked Immunosorbent Assay (ELISA) to determine the absolute numbers of AONs in nuclei. These unconjugated LNA oligonucleotides lack any labels that could alter their distribution in the cell. The researchers showed that increased nuclear entry was proportional to increased target gene knockdown, but depending on the compound and the target, other factors could impact the target transcript level reduction.

"As we anticipate the increase in oligonucleotide-based therapeutics, we must acknowledge it is one thing to know how many oligonucleotides are administered to the patient, it is quite another to know how many accumulate in the target cell nuclear fraction," says Executive Editor Graham C. Parker, PhD, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI.

Some of the most biologically active molecules, including synthetic drugs, contain a central, nitrogen-containing chemical structure called an isoquinuclidine. This core has a three-dimensional shape which means it has the potential to interact more favourably with enzymes and proteins than flat, two-dimensional molecules. Unfortunately methods to make isoquinuclidines and the related dehyrdoisoquinuclidines suffer from a number of drawbacks which make it more difficult for scientists to discover new medicinal compounds. A team of researchers led by Prof. Frank Glorius at the University of Münster (Germany) have now published a new method of enabling this reaction. The study was published in the journal Chem.

Background and method:

Several methods for the preparation of three-dimensional core structures involve the addition of another molecule across a flat structure. The internal bonds of both molecules are reorganised to create new bonds between them in a transformation called a cycloaddition. In the case of isoquinuclidines, there is a high energy barrier to this chemical reaction since the flat starting molecule, a so-called pyridine, is very stable. This means that simple heating of the reaction is not enough to allow it to occur.

In the newly developed method, a special "photocatalyst" is able to transfer light energy from blue LEDs to excite a carbon-carbon double bond containing starting material to a high energy state. The excited molecule is then capable of addition into a nearby pyridine to give a dehydroisoquinuclidine. The scientists disclosed 44 examples of these compounds, which could afterwards be transformed into isoquinuclidines and other useful structures.

A highlight of the research is the recyclability of the photocatalyst, which can be used more than ten times without any decrease in its activity. The scientists also carried out experiments to understand the mechanistic details of how the reaction works, supported by computational calculations.

"We hope that the work will inspire other chemists to explore the area of so-called 'energy-transfer catalysis' and that easier access to these valuable molecules will accelerate the development of new drug molecules," says Dr. Jiajia Ma, first author of the study.

A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appears today in the journal Developmental Cell.

Patients with rare genetic mutations shed light on how Zika virus causes microcephaly

"The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Children's Hospital," said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The fruit fly helps clarify the mystery

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts - brain cell precursors - and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.

"To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans," said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.

Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.

Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

"When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions," said Link.

Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

The Zika connection

"Linking our findings to Zika virus-associated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection," Link said.

"For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly," Bellen said.

"Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets."

Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.

The 270 million hectares of native vegetation preserved by rural landowners (Legal Reserves and unprotected areas) yield Brazil the equivalent of some USD 1.5 trillion per year in ecosystem services, such as crop pollination, pest control, water security, rain production and soil quality maintenance.

The calculation is part of a paper published in the journal Perspectives in Ecology and Conservation and endorsed by 407 scientist signatories, including 371 researchers affiliated with 79 Brazilian institutions.

"The paper is meant to show that preserving native vegetation isn't an obstacle to social and economic development but part of the solution. It's one of the drivers of sustainable development in Brazil and diverges from what was done in Europe 500 years ago, when the level of environmental awareness was different," said Jean Paul Metzger, professor of landscape ecology and conservation at the University of São Paulo's Institute of Biosciences (IB-USP) and first author of the paper.

The above amount derives from research and analysis conducted to compute the value of ecosystem services and apply it to the 270 million hectares of native vegetation in Brazil's biomes. These estimates are consolidated and have been used for years by experts in the field, including the UN Intergovernmental Science Policy Platform on Biodiversity and Ecosystem Services (IPBES).

"It's an important paper because it presents sound information that can be used to refute the arguments of those who want to change the Brazilian Forest Code and do away with the Legal Reserve requirement," said Carlos Joly, one of the paper's scientist signatories.

Joly is a member of the steering committee for the São Paulo Research Foundation - FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP).

According to Joly, it is important to bear in mind the distinction between a "Legal Reserve" (RL) and a "Permanent Conservation Area" (APP) in Brazilian law. They are complementary, he stressed. "The one can't replace the other. The Legal Reserve is crucial to maintain or restore environmental services. It's essential not only for biodiversity but also for soil protection and permeability, aquifer replenishment, water source conservation, carbon storage, and the maintenance of pollinator populations, a matter of interest to farmers and the landowners themselves," Joly said.

Brazilian law requires rural landowners to leave forest cover intact on a certain percentage of their property varying from 80% in the Amazon to 35% in the transitional area between the Amazon and Cerrado and 20% in other biomes, including the Atlantic Rainforest, Caatinga, Cerrado, Pantanal and Pampa. All such areas currently correspond to almost one-third of Brazil's native vegetation.

"Brazil conserves a great deal, protecting over 60% of its vegetation cover, and has strict legislation. It's ranked 30th by the World Bank, behind Sweden and Finland, which protect approximately 70%. However, we must call attention to the fact that conservation isn't bad," Metzger said.

The paper was written in response to a bill put before the Brazilian Senate in 2019 (Projeto de Lei 2362). The proponents have since withdrawn the bill, which would have weakened the Legal Reserve requirement or eliminated it altogether. A Portuguese-language translation of the paper will be taken to Congress and presented to members of both houses as well as technical staff.

If the bill had been passed, it could have led to the loss of 270 million hectares of native vegetation - 167 million hectares in Legal Reserve areas - which would have been added to the 103 million hectares not currently protected by the Native Vegetation Protection Law (known as the New Forest Code) either as Legal Reserve areas or as APPs (because they are not on river banks, hilltops, or hillsides or in other ecosystems considered to be sensitive).

Financial loss

One of the arguments provided by the authors of the paper refers to the impact of pollinators on coffee yields. "A study performed by our group showed that coffee bean production is much higher when bees are present and that this represents a gain of BRL 2 billion to BRL 6 billion per year for Brazil. Without the work done by bees, coffee production would fall by 20%," Metzger said.

However, pollination services take place only in areas close to natural vegetation, typically within a radius of under 300 meters, and require the creation of interfaces between crops and native vegetation.

"It's important to bear in mind that ecosystems need to be balanced. You only lose if you clear an area of bush to plant soybeans and end up without these services. That's the whole point of the Legal Reserve requirement," said Paulo Artaxo, a member of the steering committee of the FAPESP Research Program on Global Climate Change (RPGCC) and a scientist signatory to the paper.

"Farmers sometimes take a short-term view that focuses on three or four years of personal profit, but the nation is left with an enormous losses. This mindset should go. The paper makes that very clear."

Worcester, Mass. - November 14, 2019 - Researchers at Worcester Polytechnic Institute (WPI) are developing a sensor the size of a Band-Aid that will measure a baby's blood oxygen levels, a vital indication of the lungs' effectiveness and whether the baby's tissue is receiving adequate oxygen supply. Unlike current systems used in hospitals, this miniaturized wearable device will be flexible and stretchable, wireless, inexpensive, and mobile--possibly allowing the child to leave the hospital and be monitored remotely.

Ulkuhan Guler, assistant professor of electrical and computer engineering and director of WPI's Integrated Circuits and Systems Lab, is leading the project focused on enabling sick, hospitalized babies to be untethered from wired sensors, so they can more easily and frequently be examined, held, and even allowed to go home. Guler and her team have developed a miniature oxygen monitor for babies, which measures blood gases diffusing through the skin and reports the data wirelessly.

"Extended stays in the hospital are costly and can be a strain on families," said Guler. "And studies have shown that babies' health improves when they are with their families. Our goal with this affordable, mobile device is to give doctors more flexibility in monitoring their patients both in the hospital and at home."

Typically, measuring oxygen molecule levels transcutaneously involves using a system with an approximately 5-pound monitor plugged into an electrical outlet, and sensors that generally are wired to the monitor. Guler's healthcare device will use wireless power transfer. It also will be connected to the Internet wirelessly so an alarm on a monitor in a doctor's office or smartphone app would notify medical personnel and family members if the baby's oxygen level begins to drop.

The device is designed to measure PO2, or the partial pressure of oxygen, which indicates the amount of oxygen dissolved in the blood--a more accurate indicator of respiratory health than a simple oxygen saturation measurement, which can be easily taken with a pulse oximetry device gently clamped on a finger. And measuring the PO2 level via a noninvasive device attached on the skin is as accurate as a blood test.

The wearable baby oxygen monitor also would be useful for adults, especially people with severe asthma and seniors with COPD, or Chronic Obstructive Pulmonary Disease, which is an incurable, progressive lung disease and the third leading cause of death in the United States, according to the Centers for Disease Control and Prevention. Guler will modify the wearable for adults, and create a related smartphone app, in another phase of her research.

Guler is collaborating with Pratap Rao, associate professor of mechanical engineering at WPI, and Lawrence Rhein, MD, chair of the department of pediatrics and an associate professor at the University of Massachusetts Medical School. Ian Costanzo and Devdip Sen, both graduate students in electrical and computer engineering at WPI, also are working with Guler to create a chip that will eventually act as the heart for the wearable device.

"The concept of the technology is that if we have more accessible data for a person of any age, we'll be able to better take care of these patients," said Rhein, who has been advising Guler on what's needed in a hospital and home setting. "The idea of noninvasive, untethered, accessible data collection opens up a whole new world of care."

The chip, designed to work inside the wearable oxygen monitor, activates the optical sensors, captures analogue signals from the sensor, handles power management, and contains required circuitry. Guler and the team have custom designed the individual circuits, such as signal capturing circuits and driver circuits for optical based read-out circuits. In the next phase of the research project, they plan to equip the chip with more circuitries to digitize the analogue signals, transmit the captured and digitized data, and create power from a wireless link. At that point, it will be a complete system on the chip.

In an interdepartmental collaboration, Guler and Rao are creating miniaturized thin and flexible sensors for the wearable healthcare devices so they will be comfortable and secure on the babies while they're moving.

A 2008 federal parity law succeeded in expanding Medicaid acceptance by treatment facilities for substance use disorders (SUDs), according to a study by University of Massachusetts Amherst researchers.

What remains unclear is the extent to which this enhanced coverage has led to more people receiving SUD treatment. In 2016, less than 20% of the estimated 21 million people with substance use disorders received any treatment for it, according to the Substance Abuse and Mental Health Services Administration.

"How to increase Medicaid acceptance by SUD treatment facilities is very complicated," says Kimberley Geissler, lead author of the observational study published in the journal Medical Care. "That's the main takeaway."

Geissler and UMass Amherst colleague and co-author Elizabeth Evans, a public health researcher, conclude that the post-parity increase in SUD treatment coverage "may result in significant expansions in access to care for those enrolled in Medicaid."

Congress passed the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act in 2008 to require equal coverage of treatment for mental illness and addiction. The law went into effect in 2010, but little has been known about its impact on treatment for SUD, notes Geissler, assistant professor of health policy management in the School of Public Health and Health Sciences.

"The goal of parity was to make insurance coverage of mental health treatment and substance use treatment on par with insurance coverage for physical health," she says.

Geissler and Evans analyzed 2002-2013 data from the National Survey of Substance Abuse Treatment Services for all SUD treatment facilities, combined with state-level characteristics. They limited their analysis to the period before 2014, when the Affordable Care Act (ACA) took effect, because the ACA also included provisions to expand Medicaid coverage of SUD.

The researchers found that the Medicaid acceptance rate increased by more than 10 percentage points over the study period, and the adjusted increase due to parity was about 5 percentage points. The change attributed to parity represented an 8.4% increase from 2009, when 54.6% of SUD facilities across the nation accepted Medicaid.

"We were able to isolate the impacts, and we found a measurable positive effect of parity," Geissler says.

Across the study period, Medicaid acceptance rates by SUD facilities were 55.5%, which was lower than private insurance acceptance rates (65.9%) and higher than Medicare acceptance (33.8%). Large geographic variation was found, with higher Medicaid acceptance rates in the Northeast and lower rates in the South and Southeast.

"The details of policies really matter," Geissler says.

The opioid epidemic has focused unprecedented attention on substance use disorders as a public health crisis and the critical need for treatment of this chronic condition, the researchers say. Following the parity law, ACA made SUD treatment an "essential health benefit," requiring coverage under certain insurance plans.

"A lot of what we're seeing is the changing landscape around substance use disorder treatment - bringing it into the mainstream and changing how people think about it," Geissler says.

The parity law was a crucial piece of that evolving process. "Our findings underscore how parity laws are critical policy tools for creating contexts that enable historically vulnerable and underserved populations with SUD to access needed health care," Geissler and Evans conclude in their paper.

EAST LANSING, Mich. - The U.S. opioid epidemic is still raging - it's particularly pronounced in low-income areas and in those where people lack access to health care services, which includes cities in Michigan and across the Rust Belt. But the effectiveness of efforts to provide treatment and recovery options to those who need it most - that is, in locations with the greatest number of deaths from opioid overdose - has been unclear.

Richard Sadler, an assistant professor in the College of Human Medicine's Division of Public Health, set out to determine whether opioid overdose deaths occurred in patterns in Flint, a city that's dealt with significant tensions and public health crises in recent years, including the Flint water crisis and a high rate of opioid overdose deaths.

Sadler mapped the distribution of opioid overdose deaths, pulling data from the Genesee County 911 Consortium, from 2013 to 2015. He also looked at whether neighborhood-level conditions - like race and socioeconomics - were related to the overdose locations. Finally, he analyzed the distribution of 47 opioid treatment sites to determine whether it corresponded to the highest-density of deaths.

The data revealed three geographic clusters with the highest concentration of opioid overdose deaths in Flint. The three neighborhoods tended to be poorer, have more white rather than black residents and had experienced economic downturn over the years.

"These three neighborhoods were distinctive from other neighborhoods in the county, but similar to each other," Sadler said. "The key characteristics were that they were the poorest, predominantly white neighborhoods and they experienced a major decline in the last 20 to 30 years. This is seen in the rate of increased vacant housing, declining median income and declining population density."

Sadler adds that he himself grew up in one of the three clusters, an area that in his childhood was a nice, regular Flint neighborhood.

"I have memories of it being a pretty cool neighborhood," he said. "Now it's quite different - many vacant lots and public health challenges."

Another key finding in the study was that the treatment centers did not, by and large, correspond to areas of the greatest density of deaths. Of the 47 centers included, only one fell within a "high threshold" cluster (that is, the center of an area of the highest concentration of opioid overdose deaths), and seven fell within a moderate intensity cluster (a ring of slightly lower concentration just outside the center). These eight centers together accounted for only 17% of the total.

For Sadler, an urban geographer by training, one of the most interesting elements of the study is the mapping method. He points out that any city interested in seeing how its opioid overdose deaths are distributed, especially relative to existing treatment centers, can do so with this type of mapping.

The policy implications that can come from this deeper insight into opioid overdose vs. treatment availability is really where the potential lies. Knowing the exact locations where the greatest need for resources exists could strongly inform how treatment and prevention options are developed and disseminated.

"These data can help determine naloxone distribution, peer recovery coaching services, outreach, marketing - all these things," Sadler said. "Cities across the nation can really keep a pulse on what's happening. In Flint, the map shows that most of the clinics are downtown. The logic for this is clear, but these may not actually be the most effective locations. The map certainly gives reason to consider other strategies, like satellite sites and mobile treatment centers."

MADISON -- A new report analyzing decades of public opinion surveys reveals that the public's trust in scientists has remained stable and high over decades.

By various measures, Americans reported that they trusted scientists more than they trusted many other institutions and professions, including journalists, judges and Congress. That trust can affect how people interpret scientific information related to human health or government policies.

In the 2018 General Social Survey (GSS), about 40 percent of respondents reported a great deal of confidence in the leaders of scientific institutions, a number that has changed little since surveying began in 1973. A majority expressed either a "great deal" or "some" confidence in the scientific community throughout the survey period.

"We can say without a doubt that the vast majority of Americans have confidence in the scientific community," says Dominque Brossard, a University of Wisconsin-Madison professor of life sciences communication and the senior author of the report. "Over and over again, scientists are at the top of trustworthy professions."

This is further supported by Harris Polls showing that, over the last two decades, roughly three-quarters of Americans surveyed said they would trust scientists to tell them the truth. This was more than they trusted most other professionals aside from doctors and teachers.

Brossard says increasing concerns among scientists over science becoming partisan are not reflected in recent GSS polls, which show fairly modest differences between Democrats' and Republicans' confidence in the scientific community. While Democrats reported higher confidence in scientists than Republicans did in 2018, members of both parties have reported similar, high levels of confidence over the past 45 years.

Yet the research team did uncover a persistent, large gap in the confidence in science expressed by rural and suburban residents. About 30 percent of rural residents expressed confidence in scientists over the last 30 years, well below the 40 percent average among all Americans. In contrast, nearly half of suburban residents reported a great deal of confidence in scientists. Trust among urban residents fluctuated more widely over time.

Brossard and her team, including graduate student and lead author Nicole Krause, published their study Sept. 24, 2019 in Public Opinion Quarterly. They analyzed long-term polls that measured some aspect of trust or confidence in institutions. Their findings suggest that recent political events have done little to erode Americans' overall high trust in science and scientists.

Brossard's team began its investigation following the 2017 March for Science. The protest sprang out of concerns that the Trump administration would discount or suppress scientific information, and it appeared to mark an increase in the politicization of science.

Yet, Brossard's team found little evidence of major differences between Democrats and Republicans in their confidence in scientific leaders. In the 2018 GSS, the proportion of Republicans reporting confidence in scientists -- about 40 percent -- was comparable to the proportion among all Americans.

The same poll revealed an uptick in confidence among Democrats in 2018, to about half of the population surveyed, which created a modest partisan gap. But partisan-specific confidence is less stable than overall confidence and has fluctuated between 35 percent and 50 percent of Democrats, Republicans and independents over the past 45 years.

Similarly, about 40 percent of Christians expressed a great deal of confidence in scientists, in line with the general population. Members of other religions or no religion expressed higher rates of confidence, between 50 percent and 60 percent.

"Our study focused on aggregate trends, but among the few subgroups we assessed, we didn't see sharp declines in confidence in scientists," says Krause. "Instead, we saw long-standing gaps or new gaps emerging because one group's confidence has been increasing relative to others."

The researchers also found high levels of trust in scientists on specific issues, like the environment, and in other countries, including the United Kingdom and Germany.

The results suggest that there is stable trust in the institution at many levels, in contrast to some media narratives that highlight partisanship in science. Brossard is concerned that these narratives obscure other factors affecting trust in the institution.

"Trust in science is about more than politics," she says. "There's no war on science among the American public."

Bacteria associated with Crohn's disease rely on multiple stress responses to survive, multiply, and tolerate antibiotics within white blood cells called macrophages, according to a study published November 14 in the open-access journal PLOS Pathogens by Olivier Espéli of the College de France and PSL Research University in Paris, France, and colleagues.

Crohn's disease is a chronic disease that causes inflammation and irritation in the digestive tract. The disease is characterized by an imbalance in the intestinal microbiome. In particular, adherent-invasive Escherichia coli (AIEC) strains have been implicated in the disease. AIEC colonize intestinal cells and survive and replicate within macrophages. In the new study, the researchers demonstrated that the AIEC LF82 strain can switch between replicating and non-growing states within macrophages. This switch can result from a stress response called the stringent response immediately after uptake by macrophages, or at later stages, from DNA damage and a stress response called SOS during replication within macrophages.

First, a stress response called the stringent response halts the replicative cell cycle of AIEC LF82 for a few hours, during which a large number of AIEC LF82 acquire the ability to tolerate antibiotic treatments. Later, when AIEC multiplication restarts, it requires DNA repair, suggesting that AIEC have accumulated DNA damage during the first hours after infection. In this second phase, non-growing bacteria appeared frequently from the population of growing AIEC LF82, raising the proportion of antibiotic-tolerant AIEC LF82 by up to 10% of the population. The results suggest that a reservoir of antibiotic-tolerant, non-growing bacteria could be responsible for long-term survival in the host as well as relapsing infections.

Espéli adds, "Within their macrophage's niche, Crohn's disease associated bacteria become tolerant to antibiotics."

New research from Dr. Luis M. Schang and his group at the Baker Institute for Animal Health has identified a new mechanism that plays a role in controlling how the herpes virus alternates between dormant and active stages of infection.

The herpes virus causes cold sores and genital sores, as well as life-threatening infections in newborns, encephalitis and corneal blindness.

Treatment of the virus is difficult, because it hides out in nerve cells and emerges months or years later to reactivate the infection.

In Schang's group, Mi Yao Hu and Esteban Flores Cortes discovered that the virus switches between the "latent" stage and the "lytic" stage, in which it is actively replicating, depending on how tightly its DNA is packaged into bundles called chromatin.

Their findings are in a paper, "Chromatin Dynamics and the Transcriptional Competence of HSV-1 Genomes During Lytic Infections," which published Nov. 14 in PLOS Pathogens. Schang's group collaborated with scientists from the University of Alberta, Canada, and University College London (UCL).

"Any problem that herpes causes is because of reactivation from latency," Schang said. "That's the reason why antivirals cannot cure the infection and why so far it's been impossible to develop a vaccine. Latency and reactivation are a major focus for herpes virus research."

When the herpes virus enters a cell, the cell tries to protect itself by wrapping the viral DNA tightly around spool-like proteins called histones and condensing it into chromatin, which causes the virus to go dormant. But if the cells are unsuccessful, the chromatin is only loosely bundled, leaving the viral DNA accessible. The virus particles can then turn on their genes and replicate using the cell's machinery to start a lytic infection, causing disease.

Most researchers have focused on when and how individual genes on the herpes virus genome are turned on and off during infection to figure out how the virus switches between latent and lytic stages. In the new study, however, the group showed that the dynamics of the chromatin regulate whether the entire herpes virus genome is turned on, which must occur before any individual genes can be expressed. This new mechanism represents a previously overlooked way to regulate gene expression at the level of the entire viral chromosome.

With this new knowledge, researchers can further explore the interplay between the virus and host cells that determines whether viral DNA is expressed. Antiviral drugs to treat herpes have existed since the 1960s, but thus far a cure or an effective vaccine has been out of reach.

"Latency and gene regulation is a big problem because we do not know nearly enough about it," said Schang. "It's big black box in herpes biology."

The discovery opens up new directions for exploring how the virus reactivates after lying dormant. Herpes' ability to lay low has thwarted efforts to create effective vaccines or antiviral drugs that fully prevent or cure the infection.