Culture

New Rochelle, NY, August 11, 2020--A single intravenous dose of MRG-110, an anti-microRNA drug, significantly reduced miR-92a levels in the blood of healthy humans. Inhibition of miR-92a has shown beneficial effects in animal models, including improved vascularization after myocardial infarction, and accelerated wound healing, according to the peer-reviewed journal Nucleic Acid Therapeutics. Click here http://doi.org/10.1089/nat.2020.0871) to read the article for free through September 12, 2020.

"Based on documented, promising therapeutic potential, locked nucleic acid (LNA)-based anti-miR-92a was further developed and tested in a first in human study," said Stefanie Dimmeler, PhD, Goethe University, Frankfurt, Germany and coauthors. "MRG-110 caused de-repression of gene targets in human peripheral blood cells."

"This is an important randomized, double-blind, placebo-controlled, dose-escalating study translating previous work on systemically delivered LNA-modified anti-miR oligonucleotide compounds to efficiently lower miR-92a levels in human peripheral blood," 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.

ITHACA, N.Y. - In flood-prone areas of the Hudson River valley in New York state, census areas with more white and affluent home owners tend to file a higher percentage of flood insurance claims than lower-income, minority residents, raising the issue of developing more nuanced, need-based federal flood insurance subsidies in these floodplains, according to a new study.

"Are we taxing America so that people with second homes on the water don't have to pay as much?" asked Brian Rahm, director of the New York State Water Resources Institute at Cornell University.

Rahm is a co-author of the paper "Predicting Flood Insurance Claims with Hydrologic and Socioeconomic Demographics via Machine Learning: Exploring the Roles of Topography, Minority Populations, and Political Dissimilarity," which published in the Journal of Environmental Management. James Knighton, an assistant professor at the University of Connecticut, is lead author of the study.

Flood insurance rate maps determine areas where people with federally backed mortgages are required to buy flood insurance, which is then subsidized by the Federal Emergency Management Agency (FEMA), lowering the insurance cost and the reducing the risk of living in a floodplain. At the same time, current flood insurance rates do not adequately account for how social demographics affect risk and vulnerability, but FEMA is taking steps to better understand the issues, Rahm said.

"In a lot of areas of society right now, issues of diversity, equity and environmental justice matter," Rahm said. "The study suggests that flooding risk, vulnerability and recovery are influenced by the same types of factors of diversity and equity and access to government."

New York state river and coastal flooding leads to average annual residential insurance claims totaling $110 million, according to FEMA claims datasets.

The researchers combined social demographic data with hydrologic and topographic data to map flood-prone areas. When this data was run through a computer model, the researchers found that while topographic details did predict rates of flood insurance claims, predictions improved when social demographic variables - the percentage of minority residents, the value and age of houses, and political leanings in relation to state politics - were also factored in.

The study showed that places where residents take advantage of the flood insurance claims system tend to be more white, more affluent and, in New York, more Republican leaning, though these areas also have a mix of property values, and lower-income and minority residents, Rahm said.

The study raises implications that flood risk is not the same as flood vulnerability: Two houses may be side by side with the same risk, but only one homeowner may have the resources to raise their house, thereby reducing the house's vulnerability to damage.

Also, by examining political leanings, the researchers tried to tease out how a person's political identity may influence their willingness to engage with the government and file a claim.

"Some people might file claims while others don't, simply because of how they view government and their relationship with government," Rahm said. "At times, folks who have more resources are better able to utilize the system" and file claims, he said.

Traditional models of flood risk often depend purely on hydrologic and topographic factors. "We found that by bringing in some of these social demographic variables, we could actually better predict where the flood claims were coming from," Rahm said.

Humans are not the only social animal struggling with new infectious diseases. When Hamilton College Associate Professor of Biology Andrea Townsend began studying the social behavior of American crows, her work was complicated by West Nile virus, an emerging disease with devastating effects on crow populations. Her research pivoted to investigating the effects of disease on crow social behavior. "It made me wonder how social animals should, in general, respond to novel diseases," Townsend said. "Do other animals 'socially distance' during disease outbreaks, like humans during the COVID-19 pandemic?"

Joined by evolutionary psychologist Keelah Williams (Hamilton College) and disease ecologists Dana Hawley (Virginia Tech) and Jessica Stephenson (University of Pittsburgh), Townsend reviewed studies of species ranging from frogs and wolves to lobsters and bats to examine responses to emerging diseases across the animal kingdom. The review, "Emerging infectious disease and the challenges of social distancing in human and non-human animals" is published in the Proceedings of the Royal Society B and accessible at https://royalsocietypublishing.org/doi/10.1098/rspb.2020.1039#d1e1096.

They found that some social species appear to become less social after the emergence of new diseases, but others do not, with responses depending on the importance of these social interactions for each species and the ways in which the diseases are transmitted.

Emerging infectious diseases present a particular challenge for social species because their specific symptoms can be unfamiliar. However, as this review shows, many animals use general cues that might be typical for any disease, like lethargy or unusual appearance, allowing them to respond rapidly to novel pathogens. This overgeneralization of "infection cues" has a downside: it can lead to hypervigilance, particularly when an individual perceives itself to be vulnerable to disease. Across species, infectious disease pressure can increase differentiation among social groups (i.e., ingroup-outgroup awareness); in humans, it can lead to xenophobia and aversion to "foreign others."

In all species, reducing sociality has costs. Social isolation in humans might reduce the risk of COVID-19, for example, but human loneliness has been linked to an elevated risk of non-infectious disease. Solitary gorillas may be less likely to contract Ebola, but might experience higher risk of predation and infanticide. Less aggressive Tasmanian devils may be less likely to contract transmissible cancer from other devils, but may miss out on mating opportunities. Therefore, changing social interactions might not be a sustainable long-term response to infectious disease in all species.

Does technology help when it comes to dealing with social distancing? The evidence is mixed. Social media, for example, can increase loneliness by making observers feel "less happy" by comparison, exacerbating perceived social isolation. In contrast, however, synchronous virtual communication platforms could maintain or even enhance some of the benefits of sociality for humans, buffering us, to some extent, from the negative health effects of perceived isolation and giving us a unique advantage over other animals during periods of social distancing.

Some physicians are ordering thyroid tests for unsupported reasons
While most thyroid ultrasound orders are warranted, researchers say guidelines could be clearer to help reduce overdiagnosis of thyroid cancer

ANN ARBOR, Michigan -- Up to one-third of physicians reported sending patients for a thyroid ultrasound for reasons not supported by clinical care guidelines, a new study led by University of Michigan Rogel Cancer Center researchers finds.

Routine use of ultrasounds to detect cancerous thyroid nodules have led to a significant increase in thyroid cancer cases in recent years, although many are low-risk and unlikely to cause serious harm.

Researchers surveyed 610 surgeons, endocrinologists and primary care physicians who were involved in thyroid cancer care. Physicians were given different patient scenarios and asked when they would schedule a thyroid or neck ultrasound.

An overwhelming majority of physicians said they used ultrasound for reasons that are supported by clinical care guidelines, such as a large nodule that can be felt or one seen on another imaging test. But 33% said they ordered an ultrasound because the patient wanted it and 28% said abnormal thyroid function tests drove their decision - a factor the Choosing Wisely Campaign specifically advises against.

Results are published in JAMA Surgery.

"This study is the first to look at why physicians are using thyroid ultrasound for patients. While often it's for clinically relevant reasons, a substantial number of physicians are not ordering them for reasons that are clinically supported," says senior study author Megan R. Haymart, M.D., Nancy Wigginton Endocrinology Research Professor of Thyroid Cancer and professor of internal medicine at Michigan Medicine.

When asked what most influenced their decisions for patients with thyroid nodules, 69% cited recent clinical guidelines. Haymart says this shows the situation is malleable.

"We can change behavior and help physicians use thyroid ultrasound more appropriately, which will reduce the incidence of low-risk thyroid cancer," she says.

Organizations such as the National Comprehensive Cancer Network and the American Thyroid Association offer care guidelines based on data and outcomes from published studies. In addition, the Choosing Wisely campaign, which launched in 2012, identifies tests and procedures that should be discussed between patients and physicians to ensure appropriate and necessary treatment.

"There is not specifically a guideline for when to order a thyroid ultrasound. The guidelines start once you find a nodule," says study first author Debbie W. Chen, M.D., an endocrinology fellow at Michigan Medicine. "Our study suggests there is an opportunity when working on the next set of guidelines to look a little upstream, before a clinical diagnosis, and offer better guidance for when thyroid ultrasound is necessary."

The key, researchers say, is to identify those thyroid cancers that will require treatment but to avoid overdiagnosis by finding nodules that are slow-growing and may never need treatment.

The finding that physicians were ordering thyroid ultrasounds because patients asked for them suggests a need for more education and discussion, Haymart says.

"There's so much emphasis in medicine on patient satisfaction. You do want patients to be satisfied, but physicians also have to do what's medically appropriate," she says. "Developing decision aids could help patients understand and decide when thyroid ultrasound is appropriate and when it's not."

New research using the most comprehensive study of feathered dinosaurs and early birds has revised the evolutionary relationships of dinosaurs at the origin of birds. An international team of researchers, led by Professors Michael Pittman and Rui Pei, at Hong Kong University, from five different countries, including McGill University Professor Hans Larsson published their findings in the journal Current Biology. The team pored over fossils, developed a novel analytical pipeline to search for evolutionary trees, and estimated how each species may have crossed the stringent thresholds for powered flight.

"Our revised evolutionary tree supports the traditional relationship of dromaeosaurid ('raptors') and troodontid theropods as the closest relatives of birds. It also supports the status of the controversial anchiornithine theropods as the earliest birds", said Pei. With this improved evolutionary tree, the team reconstructed the potential of bird-like theropods for powered flight, using proxies borrowed from the study flight in living birds.

The team found that the potential for powered flight evolved at least three times in theropods: once in birds and twice in dromaeosaurids. "The capability for gliding flight in some dromaeosaurids is well established so us finding at least two origins of powered flight potential among dromaeosaurids is really exciting," said Pittman.

"This was a fun collaboration over several years", commented Larsson. "For the first time, we have a well resolved evolutionary tree of these small, feathered dinosaurs to ask questions about how birds originated. We were able to map biomechanical limits to all these species and propose a picture of experimentation within a spectrum of near-flight to fully-flighted capabilities in these wonderful little carnivores. This goes against the simple, linear stepping forward through evolution model of bird origins and instead presents one were an explosive radiation of feathered dinosaurs were experimenting with many kinds of wing-assisted locomotion. I think this is the most realistic view of bird origins to date."

TORONTO, ON - A new study by a team of researchers from the University of Toronto (U of T) has identified the region of the brain's hippocampus that links low income with decreased memory and language ability in children.

Previous research has shown that children from lower income families on average score lower in memory and language abilities than their higher income peers.

It is also known that a brain region that supports these abilities -- called the hippocampus -- is sensitive to the chronic stress that can be associated with lower socioeconomic status and that it is smaller in volume in children from lower income families.

Surprisingly, previous research had failed to show that the hippocampus underlies income-related gaps in cognition.

"What we found -- and what makes this result novel -- is that it's the anterior hippocampus that is associated with differences in cognition related to income," says Alexandra Decker, lead author of a study published today in Nature Communications.

Decker is a PhD candidate in the Department of Psychology in the Faculty of Arts & Science at U of T. Her co-authors are professors from the department and include co-senior-author Amy Finn, Katherine Duncan and Donald J. Mabbott who is also with The Hospital for Sick Children (SickKids) in Toronto.

Decker and her colleagues arrived at their result by analyzing data previously gathered from a diverse sample of over 700 children, adolescents and young adults that included assessments of memory and vocabulary, as well as annual family income. They also studied MRI scans of participants.

[subhead] Stresses and availability of resources associated with low socioeconomic status

The hippocampus is located in the brain's temporal lobe. As part of the limbic system, it plays a vital role in learning and memory.

Previous research linked socioeconomic status and decreased levels of cognition but did not identify the hippocampus as the underlying cause, in part because the hippocampus was viewed as a single, homogeneous structure.

The result produced by Decker and her colleagues was based on growing evidence that the hippocampus comprises two distinct regions -- the posterior and anterior. According to Decker, "These regions develop differently and play different roles in cognition -- and they have different sensitivities to stress."

The researchers found that lower socioeconomic status was associated with reduced size of the anterior hippocampus but not the posterior or whole hippocampus.

Although the data used in the study was limited to family income, Decker and her colleagues describe factors associated with socioeconomic status that could play a role in the effect -- including stress and the availability of material and non-material resources.

"Parents from families with higher incomes are more able to take time off work and are less likely to be working multiple jobs," says Decker. "They're also generally able to consistently afford enrolment in enriching programs and nutritious meals."

What's more, she says, children from lower socioeconomic backgrounds can experience a range of stressors. "For example, the stress borne by their parents about being able to make rent, pay bills and afford groceries."

[subhead] Insight for researchers, educators and policy makers

In addition, the researchers found that increases in income benefited brain development only up to a certain threshold.

"The relationship between income and the anterior hippocampus seems to be significant up to about an annual family income of about $75,000," says Decker. "There appear to be diminishing benefits at higher levels -- which raises the question, why?

"More research needs to be done to answer this," she says. "But it could be that at around $75,000, particular needs have been met."

The researchers say the finding may be helpful to researchers, educators, and policy makers interested in promoting brain and cognitive health in children from families with lower incomes. It may also provide insight into the types of cognitive processes that require more support in these children.

According to Finn, who is head of the Learning and Neural Development Lab at U of T, "These findings can help us understand how children from lower income backgrounds are uniquely disadvantaged compared to their peers from higher-income families on measures of cognitive ability.

"Understanding how these factors interact," she says, "is central to designing means to boost cognitive performance in children from lower income backgrounds, with implications for social mobility, reducing achievement gaps and much more."

"It raises the possibility," adds Decker, "that we may eventually be able to prevent -- at least to some extent -- these negative effects on the brain. It suggests how we might be able to make a difference."

HOUSTON - (Aug. 12, 2020) - Rice University chemist Han Xiao and his team have successfully expanded the genetic code of Escherichia coli bacteria to produce a synthetic building block, a "noncanonical amino acid." The result is a living indicator for oxidative stress.

The work, they say, is a step toward technologies that will allow the generation of novel proteins and organisms with a variety of useful functions.

Their study appears in the Cell Press journal Chem.

Amino acids are the building blocks of DNA. In general, organisms need only 20 of them to program the entire set of proteins necessary for life. But Xiao, with the help of a $1.8 million National Institutes of Health grant, set out to see how a 21st amino acid would enable the design of "unnatural organisms" that serve specific purposes.

The new study does just that by engineering bacteria to produce the extra amino acid, called 5-hydroxyl-tryptophan (5HTP), which appears naturally in humans as a precursor to the neurotransmitter serotonin, but not in E. coli. The novel production of 5HTP prompts the bacteria to produce a protein that fluoresces when the organism is under metabolic stress.

"The process requires a lot of interdisciplinary techniques," Xiao said. "In this study, we combined synthetic chemistry, synthetic biology and metabolic engineering to create a strain that synthesizes and encodes a 21st noncanonical amino acid, and then uses it to produce the desired protein."

Xiao said programming the autonomous unnatural bacteria was a three-step process: First, the researchers led by graduate student Yuda Chen created bioorthogonal translational machinery for the amino acid, 5HTP. Second, they found and targeted a blank codon -- a sequence in DNA or RNA that doesn't produce a protein -- and genetically edited it to encode 5HTP. Third, by grafting enzyme clusters from other species into E. coli, they gave the bacteria the ability to produce 5HTP.

"These 5HTP-containing proteins, isolated from the programmed bacteria, can be further labeled with drugs or other molecules," Xiao said. "Here, we show the strain itself can serve as a living indicator for reactive oxygen species, and the detection limit is really low."

While researchers have reported the creation of more than 200 noncanonical amino acids to date, most of them cannot be synthesized by their host organisms. "This has been an ongoing field for decades, but previously people focused on the chemical part," Xiao said. "Our vision is to engineer whole cells with the 21st amino acid that will let us investigate biological or medical problems in living organisms, rather than just dealing with cells in the lab.

"Moving this technology to the host species eliminates the need to inject artificial building blocks into an organism, because they can synthesize and use it on their own," he said. "That allows us to study noncanonical amino acids at a higher, whole organism level."

Ultimately, the researchers hope customized building blocks will allow targeted cells, like those in tumors, to make their own therapeutic drugs. "That's an important future direction for my lab," Xiao said. "We want cells to detect disease, make better medicines and release them in real time. We don't think that's too far away."

Co-authors of the paper are Rice postdoctoral fellows Juan Tang, Lushun Wang and Zeru Tian, undergraduate student Adam Cardenas and visiting scholar Xinlei Fang, and Abhishek Chatterjee, an assistant professor of chemistry at Boston College. Xiao is the Norman Hackerman-Welch Young Investigator and an assistant professor of chemistry.

The Cancer Prevention and Research Institute of Texas, the Robert A. Welch Foundation, a John S. Dunn Foundation Collaborative Research Award and a Hamill Innovation Award supported the research.

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Read the abstract at https://doi.org/10.1016/j.chempr.2020.07.013

This news release can be found online at https://news.rice.edu/2020/08/12/programmed-bacteria-have-something-extra/

Follow Rice News and Media Relations via Twitter @RiceUNews

Related materials:

Extra amino acid could work wonders: http://news.rice.edu/2019/09/27/extra-amino-acid-could-work-wonders-2/

Antibodies get easy upgrade with pClick: http://news.rice.edu/2018/11/05/antibodies-get-easy-upgrade-with-pclick-2/

Xiao Lab: https://xiao.rice.edu/index.html

Rice Department of Chemistry: https://chemistry.rice.edu

Wiess School of Natural Sciences: https://naturalsciences.rice.edu

Images for download:

https://news-network.rice.edu/news/files/2020/08/0817_STRESS-1-WEB.jpg
Rice University researchers introduced noncanonical amino acid building blocks into proteins in living cells, pioneering a powerful tool for investigating and manipulating the structure and function of proteins. The resulting unnatural organism, a strain of Escherichia coli bacteria, is able to monitor low levels of oxidative stress. (Credit: Xiao Lab/Rice University)

https://news-network.rice.edu/news/files/2020/08/0817_STRESS-2-WEB.jpg
CAPTION: Han Xiao. (Credit: Jeff Fitlow/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice's undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 4 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance.

HOUSTON - A combination regimen of venetoclax and azacitidine was safe and improved overall survival (OS) over azacitidine alone in certain patients with acute myeloid leukemia (AML), according to the Phase III VIALE-A trial led by The University of Texas MD Anderson Cancer Center.

The results were presented in the virtual 25th European Hematology Association (EHA) Annual Congress and were published today in the New England Journal of Medicine.

The addition of venetoclax, an inhibitor of the BCL-2, to azacitidine resulted in a median OS of 14.7 months compared to 9.6 months in patients receiving azacitidine alone. Additionally, 66.4% of patients receiving the combination therapy achieved complete remission, while azacitidine alone achieved a 28.3% complete remission rate.

The responses to treatment were both rapid and durable: 43% of patients in the combination therapy group exhibited a response to treatment during the first cycle, and the observed median duration of remission was 17.5 months.

Treating a subgroup of AML patients without effective therapeutic options
Although there is not yet a reliable standard treatment regimen for AML, many patients receive chemotherapy and/or a stem cell transplant. However, not all patients are eligible for these therapies.

"A large portion of patients with AML, including those older than 75 or those who have medical comorbidities, cannot tolerate existing treatment strategies, and the patients with AML who are ineligible for intensive chemotherapy often experience poor prognoses," said Courtney D. DiNardo, M.D., lead investigator and associate professor of Leukemia. "We launched the VIALE-A trial to evaluate whether we could safely use a combination therapy to treat this critical patient population."

In this multi-institution trial, 431 patients were randomized in a 2:1 ratio to receive either the combination of venetoclax and azacitidine or azacitidine plus placebo. The primary objective was to evaluate whether the combination improved OS compared to azacitidine, with additional goals to examine the safety of the combination therapy.

Combination treatment shows positive safety results
These results demonstrate that the combination of venetoclax and azacitidine has a safety profile similar to that of both drugs separately. The most common adverse events in both the experimental and placebo treatment groups were hematologic and gastrointestinal. In general, rates of adverse events were consistent between the two treatment groups, although a higher frequency of neutropenia (42% vs. 29%) and febrile neutropenia (42% vs.19%) was observed with the combination therapy comparted to azacitidine and placebo.

"The primary adverse events seen with azacitidine and venetoclax are related to increased cytopenias, including neutropenia and neutropenia-related infections," said DiNardo. "Key management guidelines include dosing interruptions between cycles to allow for count recovery in the setting of a leukemia-free marrow, and the use of granulocyte colony-stimulating factor as an adjunct to improve neutrophil count once a patient is in remission."

New research provides options for patients
This research is likely to be practice-changing for the treatment of some groups of patients with AML. Additional research is needed to evaluate how new therapies, including this combination therapy, can improve outcomes for all patients with AML.

"While this combination represents a key advance in AML therapy, improving both remission and survival rates in newly diagnosed patients with AML, many unfortunately will still relapse," said DiNardo. "Our next steps include an evaluation of azacitidine and venetoclax as a backbone to which additional novel therapeutics are being evaluated in particularly high risk populations."

This trial (NCT02993523) was supported by Abbvie and Genentech. A full list of co-authors and their disclosures is included in the paper.

RIVERSIDE, Calif -- A research team led by scientists at the University of California, Riverside, has outlined how the Zika virus, which constituted an epidemic threat in 2016, suppresses the immune system of its host.

The Zika virus, or ZIKV, spreads through mosquito bites and sexual intercourse. Currently, no approved vaccine or antivirals against ZIKV exist.

"Suppressing host immunity is a common strategy employed by viruses to achieve successful infection," said Jikui Song, a professor of biochemistry at UCR, who co-led the study. "Our work provides valuable structural and functional information on the interaction between ZIKV and its host and offers a framework for the development of vaccines and antivirals."

The study appears in Nature Structural & Molecular Biology.

Song explained the steps involved in suppressing the host immune response. ZIKV encounters the first line of defense by way of a type I interferon, or IFN, response in the host. Secreted by infected cells, IFNs are natural substances that help the host's immune system fight infection. Once ZIKV infects the cell, it presents a nonstructural protein, NS5, which interacts with a key player in the type I IFN pathway: the STAT2 protein. The interaction between ZIKV NS5 and STAT2 degrades STAT2, which inhibits the type I IFN response.

The research involved first solving the crystal structure of a complex between a large fragment of ZIKV NS5 and STAT2. This crystal structure guided the researchers in solving the cryo-EM structure of ZIKV NS5 and STAT2, which then led them to come up with a model for how ZIKV NS5 suppresses human STAT2.

"Understanding the interaction, at the molecular level, between ZIKV NS5 and the host immune factor STAT2, opens up a new window for the rational design of live attenuated vaccines and antivirals" said study co-leader Rong Hai, an assistant professor of virology at UCR. "Targeting the virus-host interaction may also provide an important approach for drug development against SARS-CoV-2, the virus that causes COVID-19."

The researchers also generated a panel of mutant ZIKV viruses.

"To our knowledge, these are the first NS5-based ZIKV mutants, which have the potential to be used as live attenuated ZIKV vaccines," Hai said.

Next, the researchers will work on the structure and function of SARS-CoV-2 proteins to identify new targets against COVID-19.

At the start of her 2008 field season at El Parque El Piñalito in the Misiones province in northeastern Argentina, Ilaria Agostini knew something was terribly wrong. Agostini has studied Misiones' two howler monkey species since 2005--brown (Alouatta guariba clamitans) and black and gold (A. caraya) howlers. Both lived at relatively low densities in the park, but still existed in one of the most continuous, well-preserved remnants of habitat known as the Atlantic Forest. She knows them better than anyone in the world.

But the treetops were silent, void of the booming chorus for which the howler monkeys are named.

"At the beginning, I found one dead monkey. Then in two hours, another one. In all my team and I found 14 dead howlers," said Agostini, a biologist at the Instituto de Biología Subtropical of Argentina. "That first day, we started to suspect it was yellow fever."

From 2007 to 2009, a devastating yellow fever virus outbreak nearly decimated El Piñalito's howler monkey populations. The brown and black and gold howlers are extremely susceptible to the disease that enslavers introduced to the Americas. In the last few years, logging activity has progressively affected the howlers' habitat and brought humans closer to wildlife, increasing the risk of virus transmission from the loggers to the howlers. When laboratory analyses confirmed that the monkey's died from yellow fever, health authorities vaccinated human populations to prevent further transmission. By then, the damage was done.

"Our howler groups just disappeared from the park. We found almost no signs of a presence until 2014--six years after the outbreak," Agostini said.

A recent United Nations report predicts that more diseases that spread from animals to humans, such as COVID-19, will emerge due to habitat destruction. The flip-side--human disease spreading to animals--is also true. How will increased virus transmission affect wild animal populations? The yellow virus outbreak in El Parque El Piñalito provided a natural laboratory to investigate.

In a study led by the University of Utah, an international research team tested whether howler monkeys who survived the yellow virus outbreak had any genetic variations that may have kept them alive. The article was published online on June 25, 2020 in the American Journal of Physical Anthropology.

In 2017, Nicole Torosi, postdoctoral researcher at Rutgers University and then a doctoral student at the University of Utah, joined Agostini in El Piñalito to search for any living brown or black and gold howlers. They eventually counted nine brown howlers and two black and gold howlers. Torosin sequenced the genomes of liver samples that Agostini's team had collected from monkeys who died before the outbreak, right after the outbreak, and she extracted DNA from the poop of those who had survived.

"We saw many more dead black and gold howler monkeys than brown howlers after the outbreak," said Torosin, postdoctoral researcher at Rutgers University. "We wondered if there were genetic differences that may have helped the brown howlers survive somehow."

The scientists focused on two immune genes that detect the type of single-stranded RNA viruses to which yellow fever virus belongs. The genes, toll-like receptor (TLR) 7 and TLR 8, recognize and destroy the invading viruses in both humans and non-human primates.

The team found no genetic variants present at higher rates in the surviving monkeys than in the deceased ones. However, in comparing the two species, they found three mutations in the DNA sequence of the brown howler individuals. Two of these mutations result in amino acid changes in the part of the protein that detects the disease. In a companion study published in Molecular Phylogenetics and Evolution, Torosin found that the changes were positively selected in the brown howler population.

"If the amino acid sequence is different, then the protein is different, and that could affect the entire downstream response to dealing with the virus," said Torosin. "Maybe that's why more brown howlers survived."

The researchers hypothesize that the brown howlers were exposed to a different virus in the past that selected for the mutations and may have helped them deal with yellow fever virus. Torosin's next steps are to do an immune test for the two species by exposing cells to the virus to see what the responses are in a controlled environment

"With COVID-19, we've seen how a virus that originated in China can spread across the world. Here, humans brought a virus to primates that have evolved without exposure to it for tens of millions of years and it nearly wiped them out," said co-author Timothy Webster, anthropologist at the U. "We're interacting with species in new ways that are creating new immune challenges, both for humans and for other species."

Rebuilding the chorus

There are still howler monkeys in the park, but they need time to recover and reorganize into groups--if they're not wiped by another outbreak, which is a real possibility, Agostini said. In order to document their progress, Agostini and her team of Proyecto Carayá Rojo, together with the NGO Asociación Civil Centro de Investigaciones del Bosque Atlántico (CeIBA), came up with a new way of tracking--by recording their calls using wildlife acoustic recorders.

"Just looking for them in the forest isn't efficient. They're so elusive, and live at such low densities, you can go days without finding them," she said. "Recording their vocalizations could be very useful for howlers. They give these very loud calls."

AMES, Iowa - Scientists searching the most ancient corners of the genome of a reptile native to New Zealand found patterns that help explain how the genomes of all vertebrates took shape, according to a recently published study.

The study, completed by a global team of collaborators and published in the journal Nature, details for the first time the assembled genome of the tuatara, a rare reptile species of great cultural significance to indigenous populations in New Zealand. The tuatara, whose ancestors once roamed the Earth with dinosaurs, is the last living species of the order Rhynchocephalia, a key link between ancient reptilian species and modern reptiles, birds and mammals, said Nicole Valenzuela, a professor of ecology, evolution and organismal biology at Iowa State University and co-author of the study. Valenzuela said a deep dive into the tuatara genome sheds light on the genomic structure of a huge range of species, including humans.

"Part of this research was the genealogy of the tuatara to help us figure out which branch of the tree of life it belongs to," Valenzuela said. "We found it diverged from snakes and lizards around 250 million years ago."

Lead author Neil Gemmell, a geneticist at New Zealand's University of Otago, said the sequencing of the tuatara genome, which is 67% bigger than humans, has revealed a genomic architecture unlike anything previously reported. Gemmell said the genome helps confirm the evolutionary position and unique life history of this ancient reptile.

"If we consider a tree of life, with species diverging over time and splitting off into groups such as reptiles, birds and mammals, we can finally see with some certainty where the tuatara sits," Gemmell said.

Valenzuela's lab contributed an analysis of the distribution of cytosine and guanine, two of the four building blocks of the genetic alphabet, when they come together in the tuatara's DNA (called CpG nucleotides). The study found patterns resembling those of painted turtles that are normally associated with the epigenetic regulation of gene expression. The researchers initially thought these patterns may have a connection with temperature-dependent sex determination, a trait shared by tuataras and painted turtles whereby temperatures influence the sex of young specimens as they develop in the egg. However, Valenzuela said further investigation found this characteristic of the tuatara's genome is similar to most other vertebrates, including humans. That means this highly conserved genomic feature reaches back over 300 million years of evolution, she said.

This kind of research required the scientists to sift through the genome for clues.

"It's like forensic science in the genome," she said. "By reading the genome and picking out these footprints left by epigenetic processes, we see how that affects the sequence of the genome over hundreds of millions of years."

The tuatara is of special significance to the Maori people of New Zealand, and the study authors worked in partnership with Maori representatives from the beginning of the research on all decision-making. Valenzuela said that kind of engagement with indigenous communities is rare in genomic projects published to date and could increase awareness of the conservation of the tuatara.

"It's a template for future genomic efforts all over the world that can be adopted and improved upon," Valenzuela said.

Electric fish generate electric pulses to communicate with other fish and sense their surroundings. Some species broadcast shorter electric pulses, while others send out long ones. But all that zip-zapping in the water can get confusing. The fish need to filter out their own pulses so they can identify external messages and only respond to those signals.

A solution to this problem is a brain function called a corollary discharge. It's sort of like a negative copy of the original message -- something that tells the fish: Ignore this.

But an animal's brain doesn't have to block sensory inputs during the entire message to effectively ignore its own signal, according to new research from biologists at Washington University in St. Louis.

Instead, the inhibitory signal -- that call to ignore -- is delayed in fish that communicate using longer electric pulses, versus those using shorter pulses.

"In fish that communicate with longer pulses, sensory responses to their own pulse are delayed," said Bruce Carlson, professor of biology in Arts & Sciences. "Thus, a delayed corollary discharge optimally blocks electrosensory responses to the fish's own signal."

Carlson and Matasaburo Fukutomi, a postdoctoral fellow in his laboratory, published their new research on African mormyrid weakly electric fish in the Journal of Neuroscience.

A brief, well-defined period of inhibition keeps electric fish from missing out on other important external signals, Carlson said.

Time-shifted tune-out

Scientists have known about corollary discharges since the 1950s. In the decades since, corollary discharges have been found in many different species and sensory systems, but it remained unknown how corollary discharges were modified as communication signals evolved.

Previous work on corollary discharge in electric fish had been done with species that communicate using short-duration electric pulses, those lasting less than 1 millisecond.

For their new study, Carlson and Fukutomi included these fish and five additional species that communicate using electrical pulses ranging in duration from 0.1 to 10 milliseconds.

"We found the sensory neurons respond with spikes in a narrow time window regardless of pulse duration," Fukutomi said. "These spikes occurred in a specific part of the self-generated pulse, the first peak of the pulse. In addition, we compared the time courses between the corollary discharge inhibition and the pulse and found that the time-shifted inhibition overlapped the first peak of the electric pulse.

"Time-shifted inhibition is a reasonable change because longer-lasting inhibition would result in an unnecessarily long insensitive period," he said. "I am impressed that there is a solution that makes more sense in real organisms than we might have expected."

The new findings have broader implications for understanding the evolution of brains.

"Despite the complexity of sensory and motor systems working together to deal with the problem of separating self-generated from external signals, it seems like the principle is very simple," Carlson said. "The systems talk to each other. Somehow, they adjust to even widespread, dramatic changes in signals over short periods of evolutionary time."

As part of continuing research, Carlson and Fukutomi are working to pinpoint the place in the brain circuit where the delay is adjusted, and how that adjustment is made. They are also investigating how the inhibition delay changes over the individual lifetime of a fish.

The researchers also recently co-authored a new review paper on the contributions of electric fish to the study of corollary discharge in Frontiers in Integrative Neuroscience.

Even though humans aren't able to generate electric fields, research on corollary discharge in electric fish has provided insights that are important in medical science as well as basic science. Dysfunction of corollary discharge may be related to psychiatric diseases such as schizophrenia in humans, for example.

"I love strange creatures, including electric fish," Fukutomi said. "We can only feel electricity as pain, but we never sense electricity as the fish does.

"Surprisingly, electrosensory systems share a lot of general features with other sensory systems," he said. "I am very excited to be studying these fish."

Women are more likely than men to suffer adverse side effects of medications because drug dosages have historically been based on clinical trials conducted on men, suggests new research from the University of California, Berkeley, and the University of Chicago.

Researchers analyzed data from several thousand medical journal articles and found clear evidence of a drug dose gender gap for 86 different medications approved by the Federal Drug Administration (FDA), including antidepressants, cardiovascular and anti-seizure drugs and analgesics, among others.

"When it comes to prescribing drugs, a one-size-fits-all approach, based on male-dominated clinical trials, is not working, and women are getting the short end of the stick," said study lead author Irving Zucker, a professor emeritus of psychology and of integrative biology at UC Berkeley.

The findings, published in the journal Biology of Sex Differences, confirm the persistence of a drug dose gender gap stemming from a historic disregard of the fundamental biological differences between male and female bodies, Zucker said.

Women in the studies analyzed by Zucker and University of Chicago psychologist Brian Prendergast were given the same drug dose as the men, yet had higher concentrations of the drug in their blood, and it took longer for the drug to be eliminated from their bodies.

And, in more than 90% of cases, women experienced worse side effects, such as nausea, headache, depression, cognitive deficits, seizures, hallucinations, agitation and cardiac anomalies. Overall, they were found to experience adverse drug reactions nearly twice as often as men.

For decades, women were excluded from clinical drug trials based, in part, on unfounded concerns that female hormone fluctuations render women difficult to study, Zucker said.

Moreover, until the early 1990s, women of childbearing age were kept out of drug trial studies due to medical and liability concerns about exposing pregnant women to drugs and risking damage to their fetuses -- as was the case in the 1950s and '60s with thalidomide, which caused limb birth defects in thousands of children worldwide.

"Neglect of females is widespread, even in cell and animal studies where the subjects have been predominantly male," Zucker said.

Zolpidem, the popular sleep medication marketed as Ambien, lingers longer in the blood of women than of men, causing next-morning drowsiness, substantial cognitive impairment and increased traffic accidents, Zucker said. For these reasons, the FDA in 2013 halved the recommended dosage prescribed to women.

In acknowledging the widespread male bias in both human and animal studies, the National Institutes of Health mandated in 2016 that grant applicants would be required to recruit male and female participants in their protocols.

While the inclusion of females in drug trials has increased in recent years, many of these newer studies still fail to analyze the data for sex differences, Zucker said.

Going forward, Zucker and Prendergast make the case for a broader awareness -- in medical research, the medical profession and the pharmaceutical industry -- of the biological sex and gender differences that put women at a disadvantage when taking prescription drugs. They recommend dosage reductions for women for a wide range of drugs.

Eric Ross and Sean Cascarina, biochemistry and molecular biology researchers at Colorado State University, have released a research paper identifying a protein encoded by SARS-CoV-2, the virus that causes COVID-19, that may be associated with the quick spread of the virus through cells in the human body.

Through powerful application of the foundational sciences and bioinformatic analysis their research highlights key characteristics of the virus that could one day be important in the development of a treatment for COVID-19.

Before COVID-19, Ross and Cascarina had been studying prions - misfolded proteins that can transmit their abnormal shape onto normal variants of the same protein. Prions cause several fatal and transmissible neurodegenerative diseases, including Mad Cow Disease in cattle and Creutzfeldt-Jakob disease in humans. Cascarina's sub-focus has been on low-complexity domains - regions in a protein's sequence that differ from typical regions in their amino acid composition and chemical behavior.

What makes these low-complexity protein domains interesting is their tendency toward liquid-liquid phase separation, similar to oil separating from water. Some of these proteins form "biomolecular condensates" in a cell, which are small areas in a cell where the protein is highly-concentrated, analogous to the oil droplets that form when oil separates from water.

Creating new virus packages

When Ross and Cascarina pivoted to study COVID-19 earlier this year, they found that the nucleocapsid, or N, protein in the SARS-CoV-2 virus has a low-complexity domain that may utilize liquid-liquid phase separation to facilitate the packaging of viral RNA into new virus particles that can infect neighboring cells.

The N protein may also be associated with reducing an infected cell's anti-viral stress response. Cells often form something called stress granules, a type of biomolecular condensate, to respond to a change in their environment, and these granules may have an anti-viral effect.

"The cell can react to a stress event by making changes in the cellular environment," said Ross, "including making these modifications to some proteins."

"But viruses obviously want to avoid a cell's defenses," Cascarina added. "They want to be infectious, so sometimes they are able to regulate these stress granules." By hijacking the normal stress response, the virus may be able to reduce the cell's anti-viral response capabilities.

Since the acceptance of their paper on May 31, four other labs across the country have confirmed parts of Cascarina's hypothesis about the N protein.

The application of this research could be for the development of treatments once a person has already contracted the virus, rather than preventing infection like a vaccine. Both of these areas of research are essential to slowing and ending the COVID-19 pandemic.

"Medically, if you could counteract the virus' ability to interfere with a cell's immune response, then you could help the cells to fight off the virus," said Ross. "I think this falls into the category of very basic science: if we understand the viral process, then conceivably we can try to design a drug that reverses that process."

When injured, the spinal cord swells, restricting blood flow, resulting in further, often critical and permanent motor, sensory, and autonomic function damage. Rapid prevention of spinal cord swelling immediately after injury is key to preventing more serious damage. The only treatment to date has been steroid therapy with methylprednisolone, which is minimally effective.

Now, in an open-access paper published in Frontiers in Bioengineering and Biotechnology, a group led by Marlan and Rosemary Bourns College of Engineering Jacques S. Yeager, Sr. Professor of Bioengineering Victor G. J. Rodgers and UCR School of Medicine biomedical sciences professor Devin Binder describes an osmotic therapy device that gently removes fluid from the spinal cord to reduce swelling in injured rats with good results. The device can eventually be scaled up for testing in humans.

The device consists of a tangential flow module supporting a semipermeable membrane connected to a hydrogel that rests on the exposed spinal cord. Artificial cerebrospinal fluid containing the protein albumin to initiate osmosis passes across the device side of the membrane, transporting water molecules from the spinal cord. Both fluids drain into a small chamber and cycle again through the device to remove more water. The amount of water removed is small compared to the amount of osmolyte, allowing for recirculation.

The authors have found in previous studies that relatively small increases in the percent of water content can cause significant swelling in the brain. These experiments showed that the osmotic therapy device removed enough water to prevent brain swelling and was capable of removing even more. They also found that removing the excess water quickly enough in brain swelling improved neurological outcomes. This is a key hope for the spinal cord device as well.

The team plans to continue improving the device through longer experiments on rats before eventually moving on to human trials.

Together with biomedical sciences professor Byron Ford, Rodgers is developing a similar device that drains fluid directly from the brain and introduces neuregulin-1, a molecule produced naturally by the body to regulate communication between cells in the brain and heart and promote their growth, to improve treatment and reduce damage of severe strokes.