Culture

New studies from the Center for Advanced Bioenergy and Bioproducts Innovation (CABBI) shed more light on the economic and environmental costs of mandates in the Renewable Fuels Standard (RFS), a federal program to expand the nation's biofuels sector.

Researchers said the studies indicate the need to adopt more targeted policies that value the environmental and ecosystem benefits of perennial bioenergy crops over cheaper options -- and provide financial incentives for farmers to grow them.

The RFS was issued in 2005 and updated through the Energy Independence and Security Act of 2007 to enhance U.S. energy security, reduce greenhouse gas (GHG) emissions, and promote rural development. The 2007 standards mandated blending 36 billion gallons of first-generation biofuels (made from food crops like corn, such as ethanol) and second-generation biofuels (made from the biomass of miscanthus or other energy feedstocks) with fossil fuels by 2022, to replace petroleum-based heating oil and fuel. The corn ethanol mandate has been met, with 15 billion gallons produced annually, but production of cellulosic biofuels has been negligible. Targets beyond 2022 are yet to be determined.

The biofuel mandates impact the environment in multiple ways -- affecting land use, GHG emissions, nitrogen (N) application, and leakage of harmful nitrogen compounds into the soil, air, and water. Those impacts vary by feedstock, as do the economic costs and benefits for consumers buying food and fuel and for producers, depending on cultivation costs and the competition for cropland for alternative uses.

The first study calculated the net economic and environmental costs of the RFS mandates and found that maintaining the corn ethanol mandate would lead to a cumulative net cost to society of nearly $200 billion from 2016 to 2030 compared to having no RFS. The social cost of nitrogen damage from corn ethanol production substantially offsets the social benefits from GHG savings.

On the other hand, implementation of the additional cellulosic mandate could provide substantial economic and environmental benefits with technological innovations that lower the costs of converting biomass to cellulosic ethanol and policies that place a high monetized value for GHG mitigation benefits. That study, published in Environmental Research Letters, was led by CABBI Sustainability Theme Leader Madhu Khanna and Ph.D. student Luoye Chen from the University of Illinois Urbana-Champaign.

The second study examined how full implementation of the RFS mandates will affect water quality in the Mississippi/Atchafalaya River Basin (MARB) and Gulf of Mexico, which are plagued by nitrogen runoff from corn and soybean fields. Rising N levels have depleted oxygen and created a hypoxic dead zone in the gulf. Specifically, this study looked at whether diversifying cropland with perennial energy crops -- such as CABBI grows -- could reduce N loss associated with corn production and thus improve water quality while meeting RFS goals.

It found that the most economical place to grow perennial bioenergy crops, which typically require less nitrogen fertilizer and lower N runoff, was on idle cropland. This limited their potential to reduce N runoff, which would be highest if they replaced N-intensive row crops on cropland. The N reduction benefits of bioenergy crops would also be more than offset by the increase in runoff generated by the harvesting of low-cost crop residues such as corn stover -- leaves and stalks of corn left after the grain is harvested -- for cellulosic biomass. The findings suggest that targeted incentives for reducing N loss are needed to persuade growers to replace N-intensive row crops as well as biomass from corn stover with bioenergy crops. Published in Environmental Science and Technology, the study was led by Associate Professor of Agronomy Andy VanLoocke and Ph.D. student Kelsie Ferin of Iowa State University.

Together, the studies showed that maintaining the corn ethanol mandate pushes more land into corn production, which increases the market price of other agricultural commodities. While producers might benefit from higher market prices, consumers who buy fuel or agricultural products pay the cost. And although the corn ethanol mandate can help mitigate GHG by displacing fossil fuels with biofuels, it increases nitrogen leaching because of increased fertilizer use with expanded corn production. That worsens water quality in the MARB and Gulf of Mexico and leads to a huge environmental and social cost.

In contrast, the cellulosic ethanol mandate could provide an overall benefit with the right policies. Supporting research and development to lower the cost of converting biomass to cellulosic ethanol would substantially reduce production costs and increase social benefits, and a high monetized value for GHG mitigation could offset all other costs.

These findings should lead policymakers to question the effectiveness of technology mandates like the RFS that treat all cellulosic feedstocks as identical. It incentivizes cheaper options like corn stover and limits incentives to grow high-yielding perennial energy crops that have lower carbon intensity and N-leakage but are more costly under current technology.

CABBI researchers hope performance-based policies -- including the low carbon fuel standard, carbon and nitrogen leakage taxes, or limits on crop-residue harvest and N application -- can be implemented to supplement the RFS mandates after 2022.

The complexity of biofuel policies requires expertise from both agronomists and economists, as in these studies. Both research teams developed integrated economic and biophysical models incorporating a broad range of factors into their analyses.

"CABBI provides a great opportunity for this kind of research, inspiring collaborations from different disciplines," Khanna said.

MEMPHIS, Tenn. - For the first time in published literature, Le Bonheur Children's Hospital and University of Tennessee Health Science Center (UTHSC) researchers showed that a variety of white blood cells known as eosinophils modify the respiratory barrier during influenza A (IAV) infection, according to a recent paper in the journal Cells. This research could have implications in understanding SARS-CoV-2 (COVID-19) infection in asthmatic patients.

The Le Bonheur/UTHSC study found that eosinophils immunomodulate airway epithelial cells during IAV infection, helping to neutralize the virus and protect the airway. The study was led by University of Tennessee Health Science Center Postdoctoral Fellow Meenakshi Tiwary, PhD, from the lab of Director of the Pediatric Asthma Research Program and Plough Foundation Chair of Excellence in Pediatrics, Amali Samarasinghe, PhD, in collaboration with Robert Rooney, PhD, assistant professor of pediatrics at the University of Tennessee Health Science Center and director of the Biorepository and Integrative Genomics Initiative at Le Bonheur, and Swantje Liedmann, PhD, a postdoctoral fellow at St. Jude Children's Research Hospital.

"We examined eosinophil responses to influenza A virus during the early phase of infection and found that eosinophils exhibit multiple functions as active mediators of antiviral host defense," said Samarasinghe. "These include virus neutralization, trafficking to draining lymphoid organs and, most importantly, protecting the airway barrier from virus-induced cytopathology."

The study used both mouse models and cell culture models to observe eosinophil responses during the early phases of IAV infection. Investigators found that eosinophils altered the respiratory epithelial transcriptome to enhance epithelial cell defense against virus-induced damage. As eosinophil-deficient allergic mice had heightened virus-induced damage to the epithelial barrier, eosinophil and epithelial cell interactions are necessary for host protection during influenza.

Further results included the following:

Eosinophils are activated within 20 minutes of virus infection. As a result of IAV infection, eosinophil movement into and out of the lungs increased, and activated eosinophils expressed markers necessary to migrate into lymphoid organs from the site of infection

Crosstalk between airway epithelial cells and eosinophils promotes activation in both cell types. The presence of eosinophils reduced expression of specific surface markers in epithelial cells when placed in close proximity during IAV infection. This is especially important given that this study provides direct evidence that eosinophils are not toxic to host tissue.

This study builds on research from Samarasinghe's lab investigating why asthmatics were less likely to suffer from severe disease than non-asthmatics during the swine flu pandemic of 2009. Previous research has shown that eosinophils have a higher prevalence in asthmatic lungs and aided patients during infection.

"Reports from the COVID-19 pandemic have early indicators that patients with allergic asthma are not at increased risk of severe COVID-19," said Samarasinghe. "It is tempting to speculate that eosinophils may play an antiviral role against SARS-CoV-2, similar to their function against influenza A and other virus infections."

An Academic Analytics Research Center (AARC) study published in the journal Scientometrics found that senior faculty (scholars who earned their terminal degree 30 or more years ago) research publication activity exceeded expectations based on age cohort population for book chapters and book publications, and senior scholars largely kept pace in terms of journal article publications. "Across all disciplines, senior faculty may be uniquely positioned to invest their time in a longer-term publication effort, shifting their research focus to the review and synthesis of ideas through the publication of books and chapters," said AARC Senior Researcher and Co-Author of the study, Bill Savage, Ph.D.

The study explored the publishing activity of 167,299 unique faculty members at American Ph.D. granting universities in six broad fields over a five-year period (2014-2018). Comparing the publication activity of early career, mid-career, and senior faculty, the study describes a generalized career research trajectory as a gradual change of focus away from journal article publications and toward book and book chapter publication.

Peter Lange, former Provost and current Thomas A. Langford University Professor of Political Science and Public Policy at Duke University and Senior Advisor to AARC, commented "This article shows convincingly that a widespread belief - that as scholars age, especially in fields driven by grants and journal publication, their scholarly productivity declines - is incorrect. It changes but does not necessarily decline, and it changes in ways that enrich the scholarly literature."

AARC Director and Co-Author of the study, Anthony Olejniczak, Ph.D., commented "Synthesizing years of knowledge production to explore new topics or re-examine old ones is an important service to one's field, one that senior scholars are especially able to perform." The study uncovered important implications for voluntary separation programs, departmental and program review processes, and retirement planning strategies.

Irvine, Calif., April 27, 2021 -- University of California, Irvine biologists have developed a new genetically engineered mouse model that, unlike its predecessors, is based on the most common form of Alzheimer's disease. The advance holds promise for making new strides against the neurodegenerative disease as cases continue to soar. Their study appears in the journal, Nature Communications.

Link to study: https://www.nature.com/articles/s41467-021-22624-z

While over 170 Alzheimer's mouse models have been in use since the 1990s, those models mimic early-onset AD, also known as "familial AD," which accounts for less than 5 percent of total AD cases. Until recently, scientists introduced mutations found in familial risk human genes, such as the amyloid precursor protein and presenilin 1, into the mouse genome to generate the mouse models. The UCI team decided to take a new approach by developing a mouse model better positioned to analyze causes of late-onset AD. Also called "sporadic AD," this new model encompasses the remaining 95 percent of cases.

"We believed models developed on the rare familial type might be a reason therapies have worked in the lab but haven't translated into clinical trial success," said Frank LaFerla, professor of neurobiology & behavior and the study's co-senior author; he is also dean of the UCI School of Biological Sciences and director of the UCI Alzheimer's Disease Research Center. "We decided it was time to begin developing a model that embodies the far more common late-onset form of AD."

"The existing AD models have been invaluable to the field by helping provide a better understanding of the pathogenesis of the disease." said David Baglietto-Vargas, assistant research professor of neurobiology & behavior and the study's first author. "Unfortunately, many of those same models have unique physiological alterations that have led scientists to misinterpret some experimental findings."

Rather than introduce mutations from familial-AD risk genes into the mouse, the UCI team generated the new model by using genetic engineering to switch three amino acids in the mouse amyloid precursor protein to make it more closely mirror its human counterpart. The result is what the researchers are calling a "platform model" for late-onset AD.

While the mice don't display the more advanced brain plaque and tangle pathology linked with the disease, the model manifests AD-associated conditions that precede and likely underline more advanced pathology. These AD-related conditions include age-related alterations in cognition, inflammation, brain volume and others consistent with human changes.

"This model can be used to understand very early events in the brain that may be relevant," said Kim Green, professor and vice-chair of neurobiology & behavior and co-senior author of the study. "We can use environmental and genetic factors to examine which aspects of aging are important in developing late-onset AD."

"This mouse is a foundational step toward modeling late-onset AD with its hallmark features of plaques and tangles," said Grant MacGregor, professor of developmental & cell biology and study co-author. "It will take a lot more time and inclusion of additional subtle AD-associated genetic changes to achieve it, but the result of this study suggests we are on the right path and that our approach may bear fruit."

Unless there are medical breakthroughs, the number of Americans 65 and older with Alzheimer's could rise from 6.2 million currently to 12.7 million by 2050, according to the Alzheimer's Association.

Just as humans receive the first members of their microbiomes from their mothers, seeds may harbor some of the first microorganisms plants encounter. While these initial microbes could become influential players in the plants' microbiomes, the microbial communities that colonize seeds have not received as much attention as root, shoot, or soil microbiomes. To understand how seed microbiomes are assembled, a group of researchers at the University of Saskatchewan (Canada) examined the relative effects of growth environment and plant genotype on the seed microbiome of canola, a globally important crop grown in diverse environments.

In their recently published paper in Phytobiomes Journal, Zayda Morales Moreira, Bobbi Helgason, and James Germida characterized the seed microbiomes of eight canola lines harvested in different years and from different sites in Saskatchewan that are representative of local canola growing regions. They found that seed microbiomes differed not only by harvest year and location, but also by the variety of canola, indicating that both genetic and environmental factors play important roles in seed microbiome assembly. These findings suggest that both plant breeding and seed production conditions could be used to shape beneficial seed microbiomes. Lead author Zayda Morales Moreira believes "increasing our knowledge of how microbial communities carried by seeds are assembled, transmitted, and preserved offers a promising way for breeding programs to consider microbial communities when selecting for more resilient and productive cultivars."

This paper lays the groundwork for future research into the seed microbiome, such as examining how these differently assembled communities of microbes affect plant growth and resilience. Their results also suggest the presence of a core microbiome in all seed samples that includes potentially beneficial microbes such as Pseudomonas spp., which are known to promote plant growth. If seed-derived microbes improve seedling survival or become key components of the microbiome throughout the plants' life cycles, optimizing seed microbiomes--through breeding or seed inoculants--could be an important tool for managing plant microbiomes in agriculture. The authors hope that understanding the seed microbiome will advance current sustainable agricultural practices and breeding techniques.

Researchers have spent more than three decades developing and studying miniature biosensors that can identify single molecules. In five to 10 years, when such devices may become a staple in doctors' offices, they could detect molecular markers for cancer and other diseases and assess the effectiveness of drug treatment to fight those illnesses.

To help make that happen and to boost the accuracy and speed of these measurements, scientists must find ways to better understand how molecules interact with these sensors. Researchers from the National Institute of Standards and Technology (NIST) and Virginia Commonwealth University (VCU) have now developed a new approach. They reported their findings in the current issue of Science Advances.

The team built its biosensor by making an artificial version of the biological material that forms a cell membrane. Known as a lipid bilayer, it contains a tiny pore, about 2 nanometers (billionths of a meter) wide in diameter, surrounded by fluid. Ions that are dissolved in the fluid pass through the nanopore, generating a small electric current. However, when a molecule of interest is driven into the membrane, it partially blocks the flow of current. The duration and magnitude of this blockade serve as a fingerprint, identifying the size and properties of a specific molecule.

To make accurate measurements for a large number of individual molecules, the molecules of interest must stay in the nanopore for an interval that is neither too long nor too short (the "Goldilocks" time), ranging from 100 millionths to 10 thousandths of a second. The problem is that most molecules only stay in the small volume of a nanopore for this time interval if the nanopore somehow holds them in place. This means that the nanopore environment must provide a certain barrier -- for instance, the addition of an electrostatic force or a change in the nanopore's shape -- that makes it more difficult for the molecules to escape.

The minimum energy required to breach the barrier differs for each type of molecule and is critical for the biosensor to work efficiently and accurately. Calculating this quantity involves measuring several properties related to the energy of the molecule as it moves into and out of the pore.

Critically, the goal is to measure whether the interaction between the molecule and its environment arises primarily from a chemical bond or from the ability of the molecule to wiggle and move freely throughout the capture and release process.

Until now, reliable measurements to extract these energetic components have been missing for a number of technical reasons. In the new study, a team co-led by Joseph Robertson of NIST and Joseph Reiner of VCU demonstrated the ability to measure these energies with a rapid, laser-based heating method.

The measurements must be conducted at different temperatures, and the laser heating system ensures that these temperature changes occur rapidly and reproducibly. That enables researchers to complete measurements in less than 2 minutes, compared to the 30 minutes or more it would otherwise require.

"Without this new laser-based heating tool, our experience suggests that the measurements simply won't be done; they would be too time consuming and costly," said Robertson. "Essentially, we have developed a tool that may change the development pipeline for nanopore sensors to rapidly reduce the guesswork involved in sensor discovery," he added.

Once the energy measurements are performed, they can help reveal how a molecule interacts with the nanopore. Scientists can then use this information to determine the best strategies for detecting molecules.

For example, consider a molecule that interacts with the nanopore primarily through chemical -- essentially electrostatic -- interactions. To achieve the Goldilocks capture time, the researchers experimented with modifying the nanopore so that its electrostatic attraction to the target molecule was neither too strong nor too weak.

With this goal in mind, the researchers demonstrated the method with two small peptides, short chains of compounds that form the building blocks of proteins. One of the peptides, angiotensin, stabilizes blood pressure. The other peptide, neurotensin, helps regulate dopamine, a neurotransmitter that influences mood and may also play a role in colorectal cancer. These molecules interact with nanopores primarily through electrostatic forces. The researchers inserted into the nanopore gold nanoparticles capped with a charged material that boosted the electrostatic interactions with the molecules.

The team also examined another molecule, polyethylene glycol, whose ability to move determines how much time it spends in the nanopore. Ordinarily, this molecule can wiggle, rotate and stretch freely, unencumbered by its environment. To increase the molecule's residence time in the nanopore, the researchers altered the nanopore's shape, making it more difficult for the molecule to squeeze through the tiny cavity and exit.

"We can exploit these changes to build a nanopore biosensor tailored to detecting specific molecules," says Robertson. Ultimately, a research laboratory could employ such a biosensor to identify biological molecules of interest or a doctor's office could use the device to identify markers for disease.

"Our measurements provide a blueprint for how we can modify the interactions of the pore, whether it be through geometry or chemistry, or some combination of both, to tailor a nanopore sensor for detecting specific molecules, counting small numbers of molecules, or both," said Robertson.

Skoltech researchers used Google Trends' Big Data ensuing from human interactions with the Internet to develop a new methodology - a tool and a data source - for analyzing and researching the growth of startups. A paper reporting these important findings was published in technology management journal, Technological Forecasting and Social Change.

Startups and high-growth technology-based ventures they transform into are regarded as the key drivers of economic development, innovation, and job creation on the national and global level. However, despite their crucial importance for the economy and high interest from researchers and policy-makers, startups display growth patterns that are difficult to analyze. These fragile, early-stage private businesses, which may quickly scale up, do not have time, interest, or obligation to share much data about what they achieved, when, or how. Thus, to outside observers, startups look like "black boxes" whose progress can hardly be assessed due to a lack of objective information.

Maksim Malyy, a PhD student from the Skoltech Center for Entrepreneurship and Innovation (CEI), has been intrigued by this problem since he worked in a startup accelerator in St. Petersburg before joining Skoltech. Looking into theoretical and practical aspects of the problem for the last three years, Maksim, his supervisor, professor Zeljko Tekic, and Skoltech assistant professor Tatiana Podladchikova came up with valuable insights on how to deal with the data scarcity problem in studying startups. Some of their findings were published in the paper.

Maksim explains why this research is so important: We demonstrate that web-search traffic information, in particular Google Trends data, can serve as a valuable source of high-quality data for analyzing the advancement of startups and growth-oriented technology-based new ventures they evolve into. We analyzed a large and transparently selected set of US based companies and showed the existence of a strong correlation between the curves based on Google searches by company name and those depicting valuations achieved through a series of investment rounds.

According to the authors, this correlation enables using Google Trends data as a proxy measure of growth instead of non-public and rarely available measures like sales, employee and market share growth. Google Trends data, which are public, easy to collect and available for almost any company since its inception, can help in building more accurate and even real-time data-driven growth paths for startups. With these evolution curves, one could revisit some old answers, ask new questions, and come up with more solid concepts, theories, and predictions.

Maksim believes that this study has strong implications for start-up research: Our findings suggest that for startups, especially thriving unicorns or B2C digital platforms, the proposed approach may become an equivalent of an X-ray scan, offering a cheap, easy, and non-invasive way to understand the workings of a technology-based new venture.

By way of comment, professor Tekic and professor Podladchikova cite a report by one of the reviewers: "I think this paper will stand the test of time and be useful for many years to come. It truly is a fascinating study."

SAN FRANCISCO, CA--April 27, 2021--In the 40-some years since the beginning of the HIV/AIDS epidemic, scientists have learned a lot about the virus, the disease, and ways to treat it. But one thing they still don't completely understand is which exact cells are most susceptible to HIV infection.

Without this knowledge, it is difficult to envision targeting these cells to protect the millions of people who encounter the virus for the first time every year, or the infected people in which infection will likely rebound if they go off therapy.

Scientists have known for a long time that the virus homes in on so-called memory CD4+ T cells, a type of cell that helps the human body build lasting immunity against pathogens. But that is still too broad a category to target for therapy.

"CD4+ T cells orchestrate the immune response against all kinds of pathogens, so you can't just eliminate them to prevent HIV infections," says Gladstone Associate Investigator Nadia Roan, PhD. "But if you can find the more specific subsets of CD4+ T cells that are highly susceptible to HIV infection, you may be able to specifically target those cells without detrimental side effects."

Much knowledge about HIV infection comes from in vitro experiments (in a petri dish), where scientists expose CD4+ T cells cultured in the lab to the virus. These cell cultures are not a perfect model for the human body's complex ecosystems in which infection normally takes place. Might in vitro infection yield a skewed view of the virus's preference?

To answer this question, Roan and her team compared CD4+ T cells infected in vitro to the CD4+ T cells circulating in the blood of 11 individuals at various stages of infection. Some blood samples were taken before the donors had started treatment with antiretroviral therapy, some after. Yet others came from individuals who had stopped their treatment and were experiencing new rounds of infection.

Using technology they have honed over the years, the researchers established a detailed atlas of the CD4+ T cells in individuals not on antiretroviral treatment, which they have now published in the scientific journal Cell Reports.

"Our work affords novel insight into the basics of how HIV behaves in the human body, rather than just in a lab dish," says Roan, who is also an associate professor of urology at UC San Francisco. "It informs our understanding of what really happens during an active infection, which is interesting in its own right. Moreover, we know that some infected cells become reservoirs of latent virus, so our work could help us better understand how the reservoir forms during an infection."

The technology Roan and her team deployed, called CyTOF/PP-SLIDE, distinguishes cells with exquisite precision based on the proteins they contain or carry on their surface. With this information, the scientists can classify CD4+ T cells into myriad subsets, and then determine whether some subsets are more susceptible to infection than others.

A crucial perk of this technology is that it can trace infected cells back to their original state prior to infection.

"That's important," says Guorui Xie, PhD, a postdoctoral researcher in Roan's lab and the first author of the study. "We know that when HIV infects cells, it remodels the cells such that they no longer contain the exact same levels of proteins as they did before infection. With CyTOF/PP-SLIDE, we can identify the uninfected cells that most closely match the infected ones in the same patient. These uninfected cells can give us important information about what the cells targeted by HIV resembled before the virus remodeled them."

Roan's team found that remodeling was indeed extensive in blood CD4+ T cells infected in vivo (in people) as well as in vitro. In the process, they made a surprising finding about one of HIV's preferred targets. Prior studies have suggested that HIV prefers to infect a subtype of CD4+ T cells, called Tfh, and Roan's team confirmed these cells to be susceptible to HIV. However, they also discovered that the virus can infect non-Tfh cells and remodel them such that they adopt features of Tfh cells.

"This result strikes a cautionary note in our field," says Roan. "You really can't tell which cells HIV prefers to target simply by looking at infected cells. You need to know what the cells looked like before remodeling."

The scientists also found that remodeling causes infected blood cells to alter their surface in ways that may change how they move through the body. Roan prudently speculates that this might help the virus steer infected cells toward sites where it can infect even more cells.

"Whatever its exact purpose, remodeling is probably not just a chance event," adds Roan. "A virus as small as HIV depends crucially on the resources provided by its host to grow and spread. It's likely that nothing the virus does to its host cell is an accident."

The profile of HIV's favorite cells differed somewhat between in vitro and in vivo infections. Nevertheless, the researchers found one subset of cells that was preferentially infected in both cases, and could become a useful model for further lab studies.

The team also confirmed that not all CD4+ T cells are equally susceptible to HIV infection in vivo, which gives them hope that the most susceptible cells could eventually become targets of preventive interventions.

Xie and Roan are now planning to obtain blood samples from more donors to see whether HIV's targets differ between a first infection and the return of the virus after a lapse in therapy, or between men and women. Ultimately, they would also like to look at in vivo-infected cells from mucosal tissues such as the gut and genital tract, where most HIV infections begin. But these samples are much harder to procure.

In the meantime, the researchers are making public the atlas of all the cells they have analyzed, along with the dozens of proteins they found to be affected in these cells after HIV infection, which they hope will be a valuable resource for the HIV research community.

"There is still much to discover in this atlas that may help uncover new insights into HIV infection and how it develops, and perhaps lead to the identification of new approaches for HIV/AIDS prevention," says Roan.

DALLAS - April 27, 2021 - Researchers with the Peter O'Donnell Jr. Brain Institute at UT Southwestern have identified a new protein implicated in cell death that provides a potential therapeutic target that could prevent or delay the progress of neurodegenerative diseases following a stroke.

Scientists from the departments of pathology, neurology, biochemistry, and pharmacology at UTSW have identified and named AIF3, an alternate form of the apoptosis-inducing factor (AIF), a protein that is critical for maintaining normal mitochondrial function. Once released from mitochondria, AIF triggers processes that induce a type of programmed cell death.

In a study published in the journal Molecular Neurodegeneration, the UT Southwestern team collaborated with researchers at The Johns Hopkins University School of Medicine and found that, following a stroke, the brain switches from producing AIF to producing AIF3. They also reported that stroke triggers a process known as alternative splicing, in which a portion of the instructions encoding AIF is removed, resulting in the production of AIF3. Defective splicing can cause disease, but modifying the splicing process may offer potential for new therapies.

In both human brain tissue and mouse models developed by researchers, AIF3 levels were elevated after a stroke. In mice, the stroke-induced production of AIF3 led to severe progressive neurodegeneration, hinting at a potential mechanism for a severe side effect of stroke observed in some patients. Stroke has been recognized as the second most common cause of dementia, and it is estimated that 10 percent of stroke patients develop post-stroke neurodegeneration within one year.

The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves the combined effect of losing the original form of AIF in addition to gaining the altered AIF3, leading to both mitochondrial dysfunction and cell death.

"AIF3 splicing causes mitochondrial dysfunction and neurodegeneration," says senior author Yingfei Wang, Ph.D., assistant professor of pathology and neurology and a member of the O'Donnell Brain Institute. "Our study provides a valuable tool to understand the role of AIF3 splicing in the brain and a potential therapeutic target to prevent or delay the progress of neurodegenerative diseases."

The findings are important for understanding the aftereffects of stroke, which strikes nearly 800,000 U.S. residents annually. Stroke kills one person every four minutes, according to the Centers for Disease Control and Prevention (CDC), and about one in every six deaths from cardiovascular disease is attributed to stroke - with ischemic strokes accounting for about 87 percent of all cases. Leading causes of stroke include high blood pressure, high cholesterol, smoking, obesity, and diabetes. Stroke also disproportionately affects certain populations and occurs more often in men, though more women than men die from stroke. CDC figures show Black people have twice the risk of first-time stroke than white people and a higher risk of death. Hispanic populations have seen an increase in death rates since 2013, while other populations have not.

Des Plaines, IL - In a randomized, double-blind trial of patients with acute undifferentiated agitation in the emergency department, droperidol was more effective for sedation and was associated with fewer episodes of respiratory depression than lorazepam or either dose of ziprasidone. This is the conclusion of Randomized Double-blind Trial of Intramuscular Droperidol, Ziprasidone, and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department, to be published in the April 2021 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

Agitation is a common presentation in emergency medicine, ranging from a state of restlessness to overtly violent behavior and can result in injury to both patients and their caregivers. The purpose of this study was to compare intramuscular droperidol, ziprasidone, and lorazepam in patients with acute agitation in the emergency department, using the proportion of patients adequately sedated at 15 minutes as the primary outcome measure. Secondary outcomes included rates of rescue medication, respiratory depression, adverse medication effects, and emergency department length of stay. The authors suggest that larger studies are needed to confirm these findings, particularly to address safety outcomes.

The lead author of the study is Marc L. Martel, MD, of the Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota.

The findings of the study are discussed with Dr. Martel in a recent AEM podcast titled, I Can't Fight This Med Any Longer - Droperidol for Acute Agitation.

COLUMBIA, Mo. -- Having grown up poor in a rural village in Zimbabwe, Wilson Majee saw firsthand as a child the lack of educational opportunities that were easily accessible and how that impacted the youth in his village.

Now an associate professor in the University of Missouri School of Health Professions, Majee researches the challenges facing disadvantaged, rural youth. He found in a recent study that young people who are disengaged from their communities are much more likely to participate in risky behaviors such as substance abuse, particularly in rural areas that lack educational opportunities.

For the study, Majee spoke with youth in rural South Africa about the factors contributing to drug abuse for the NEET population, which stands for young people around the world "Not in Employment, Education or Training." He found that a lack of educational opportunities, combined with other factors - such as a lack of motivation, absent adult role models and few recreational activities - compound to create feelings of hopelessness and despair in young people. These feelings can influence drug use and other risky behaviors.

"All of these factors the young people mentioned, in addition to poverty, unemployment and a lack of basic resources such as health facilities, libraries, available drinking water and internet access, compound together to limit opportunities for rural youth," Majee said. "Toward the end of Apartheid in South Africa, there was a mass migration of young people to urban cities, and since then, the necessary infrastructure has not been put in place in rural areas to help struggling youth successfully advance in life."

The number of young people around the world in the NEET population, currently an estimated 273 million worldwide and 10 million in the United States, has been steadily increasing since 2017, according to the International Labor Organization. Majee explained that, as it was for him almost 35 years ago, access to higher education has remained a major challenge for rural youth, particularly those who have never traveled to larger cities where more resources and universities are typically located.

"At the time I was pursuing higher education, there was only one university in all of Zimbabwe, and it was very far from my village, so I was overwhelmed at first when I attended because I had never been to a big city before," Majee said. "I also knew I had to be among the best students in the nation to earn a spot at the university."

According to Majee, in rural South Africa, as in rural Zimbabwe, primary and secondary schools often lack the infrastructure and resources necessary to prepare students for diverse fields.

"Rural schools not only lack qualified teachers, but they also often lack a variety of subject choices for students to take, as many rural schools do not offer classes in science, information technology, engineering or math," Majee said. "Yet we live in a technology-driven world that is fueled by these STEM subjects; so rural youth see no value in going to school if they can't learn the subjects that will help them get a job."

When Majee asked the rural South African youth who participated in the study for possible solutions to their challenges, the most common suggestion was creating smaller, community college-style satellite campuses for major universities that would be located in rural areas to increase access to those resources. Others emphasized the need for agriculture training programs, educating parents and community members on the power of role models and mentors, and the establishment of internet cafés to provide youth with a safe environment to explore topics that interest them.

"These complex solutions will require collaboration from community members, families, youth, private organizations, universities, researchers and government," Majee said. "These are multi-level issues the youth are facing, which calls for diverse stakeholders to come together to address them."

The goal of Majee's research is to empower youth by exploring strategies that help them become engaged members of their communities so they are less likely to participate in risky behaviors like drug abuse and crime.

"Young people today are the future community leaders of tomorrow," Majee said. "We need to invest in them to make sure they have the skills and knowledge they need to save their communities in the future, which will ultimately benefit society at large."

Neurons result from a highly complex and unique series of cell divisions. For example, in fruit flies, the process starts with stem cells that divide into mother cells (progenitor cells), that then divide into precursor cells that eventually become neurons.

A team of the University of Michigan (U-M), spearheaded by Nigel Michki, a graduate student, and Assistant Professor Dawen Cai in the departments of Biophysics (LS&A) and Cell and Developmental Biology at the Medical School, identified many genes that are important in fruit flies' neuron development, and that had never been described before in that context.

Since many genes are conserved across species such as between fruit flies (Drosophila), mice, and humans, what is learnt in flies can also serve as a model to better understand other species, including humans. "Now that we know which genes are involved in this form of neurogenesis in flies, we can look for them in other species and test for them. We work on a multitude of organisms at U-M and we've the potential to interrogate across organisms," explains Michki. "In my opinion, the work we did is one of the many pieces that will inform other work that will inform disease," adds Michki. "This is why we do foundational research like this one."

Flies are also commonly used in many different types of research that might benefit from having a more comprehensive list of the fly genes with their associated roles in neuron cell development.

The discovery

Neurons are made from stem cells that massively multiply before becoming neurons. In the human brain, the process is extremely complex, involving billions of cells. In the fly brain, the process is much simpler, with around 200 stem cells for the entire brain. The smaller scale allows for a fine analysis of the neuronal cell division process from start to finish.

In flies, when the stem cell divides, it yields another stem cell and a progenitor cell. When this last one divides, it makes a so-called precursor cell that divides only once and gives rise to two neurons. Genes control this production process by telling the cells either to divide --and which particular type of cell to produce-- or to stop dividing.

To this day, only a few of the genes that control this neuron development process have been identified and in this publication in Cell Reports, the scientists have characterized many more genes involved. Along the timeline of the neuron development process, the U-M team could precisely record which genes were involved and for how long.

In particular, at the progenitors' stage, the scientists identified three genes that are important at this stage for defining what 'kind' of neuron each progenitor will make; these particular genes had never been described before in this context. They also validated previously known marker genes that are known to regulate the cell reproduction process.

When they applied their analysis technique to the other phases of the neuron development process, they also recorded the expression of additional genes. However, it is still unknown why these genes go up in expression at different steps of the neuron development process and what role they actually play in these different steps. "Now that many candidate genes are identified, we are investigating the roles they play in the neuron maturation and fate determination process," says Cai. "We are also excited to explore other developmental timepoints to illustrate the dynamic changes of the molecular landscape in the fly brain."

"This work provides rich information on how to program stem cell progeny into distinct neuron types as well as how to trans-differentiate non-neuronal cell types into neurons. These findings will have significant impact on the understanding of the normal brain development as well as on neuron regeneration medicine," adds Cheng-Yu Lee, a Professor from the U-M Life Sciences Institute who collaborated with the Cai Lab.

The techniques

This study is mostly based on high-throughput single-cell RNA-sequencing techniques. The scientists took single cells from fruit flies' brains and sequenced the RNA, generating hundreds of gigabytes of data in only one day. From the RNA sequences, they could determine the developmental stage of each neuron. "We now have a very good understanding of how this process goes at the RNA level," says Michki.

The team also used traditional microscope observations to localize where these different RNAs are being expressed in the brain. "Combining in silico analysis and in situ exploration not only validates the quality of our sequencing results, but also restores the spatial and temporal relationship of the candidate genes, which is lost in the single cell dissociation process," says Cai.

At the beginning of their study, the scientists analyzed the large data set with open-source software. Later, they developed a portal (MiCV) that eases the use of existing computer services and allows to test for repeatability. This portal can be utilized for cell and gene data analysis from a variety of organs and does not require computer programming experience. "Tools like MiCV can be very powerful for researchers who are doing this type of research for the first time and who want to quickly generate new hypotheses from their data," says Michki. "It saves a lot of time for data analysis, as well as expenses on consultant fees. The ultimate goal is to allow scientists to focus more on their research rather than on sometimes daunting data analysis tools." The MiCV tool is currently being commercialized.

Rockville, Md. (April 27, 2021)--Researchers from Wake Forest School of Medicine in North Carolina have demonstrated that a common diabetes drug inhibits the spread of Clostridioides difficile, or C. diff--a potentially life-threatening infection commonly acquired during hospital stays. The team will present their work virtually at the American Physiological Society's (APS) annual meeting at Experimental Biology 2021.

C. diff is the most common hospital-acquired infection in the U.S. It starts in the intestines, often after a course of antibiotics. The Centers for Disease Control and Prevention categorizes the bacteria C. diff as a public health threat that "require[s] urgent and aggressive action." In 2017, nearly 223,900 people required hospitalization for its treatment, and at least 12,800 died from it. Of those who recover, 1 in 6 people experience reinfection within eight weeks. Antibiotic-resistant strains are also a growing concern.

Metformin, approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes, is the fourth most prescribed drug in the U.S. Earlier studies have shown that metformin beneficially alters the microbiomes of people with diabetes and of the elderly. Inspired by these findings, Shaohua Wang, PhD, a researcher in the lab of Hariom Yadav, PhD, evaluated the effect of metformin on C. diff infection in three different models. She tested the treatment in cell cultures, mice and an ex vivo model of the human microbiota developed by the lab.

In all three systems, metformin had the desired effect. It reduced C. diff proliferation in the cell culture. In the ex vivo model, it both reduced the population of the pathogen and increased the growth of closely related nonpathogenic bacteria. Lastly, in the mouse model, it reduced C. diff in the colon a hundredfold and limited the pathogen's spread to organs outside the intestine.

Yadav, who now heads the University of South Florida Center for Microbiome Research, plans to move forward with future studies that "determine the mechanisms by which metformin inhibits C. difficile infections and clinical efficacy in patients with [C. difficile infection]."

Rockville, Md. (April 27, 2021)--Fatty acid supplements may protect children with high cholesterol from heart disease later in life by increasing their blood levels of healthy omega-3 fatty acids, according to a new study. Researchers from the Uniformed Services University of the Health Sciences in Bethesda, Maryland, will present their work virtually this week at the American Physiological Society's (APS) annual meeting at Experimental Biology 2021.

Previous research has shown that high blood levels of beneficial fatty acids, including omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) found in seafood, are associated with a lower risk of coronary artery disease and a higher likelihood of healthy aging. "Since coronary artery disease develops early in life in children with high cholesterol, there needs to be lifelong treatment started in childhood," said Marguerite M. Engler, PhD, first author of the new study. This is especially important as global obesity rates in young people are rising and the long-term safety of cholesterol-lowering statin drugs in children is not known.

The researchers of the current study examined children ages nine to 16 who had a history of high blood cholesterol levels. The children followed a Mediterranean diet--known for being rich in lean proteins, vegetables, whole grains and "healthy" fats such as olive oil and fish--for six weeks, followed by the continuation of the diet plus an EPA supplement for another six weeks. The research team measured the children's fatty acid levels before beginning and after the Mediterranean diet for six weeks, and again after the combination of the diet and EPA supplement for six weeks. Taking the EPA supplement for six weeks raised the blood levels of both EPA and DPA. DPA is anti-inflammatory in nature and keeps platelets from sticking together, which gives the fatty acid cardioprotective properties.

"The good news is that our findings show that we can change the lipid profile in the blood of children at high risk for heart disease with an omega-3 fatty acid supplement to a more favorable anti-inflammatory [lipid profile] that has been associated with decreased risk of heart disease and [with] healthy aging," Engler said.

Rockville, Md. (April 27, 2021)--Exposure to extreme heat (95 degrees Fahrenheit and above) and humidity for eight hours raises the core body temperature and causes dehydration, resulting in an increased risk of acute kidney injury, according to a new study. The researchers, from the Indiana University School of Public Health-Bloomington and University at Buffalo Center for Research and Education in Special Environments in New York, will present their findings virtually at the American Physiological Society's (APS) annual meeting at Experimental Biology 2021.

Acute kidney injury, which is defined as a sudden decline in kidney function, is a major cause of hospitalization during heat waves, especially in vulnerable populations such as older adults and obese individuals. This disorder is expected to worsen as the frequency, intensity and duration of heat waves expand in the U.S. due to climate change, according to study co-author Hayden Hess, PhD. As a result, there is concern the public health burden during these extreme hot weather events will be exacerbated.

The study was conducted in a group of adult men who were subjected to a heat- and humidity-controlled environmental chamber. The findings also indicate the risk of acute kidney injury was only evident when environmental conditions outpaced the ability of study participants to maintain core body temperature when cooling and hydrating were not permitted.

Researchers say this information will help lay a foundation for additional studies that improve understanding of the causal mechanisms that lead to a higher risk of acute kidney injury induced by extreme heat exposure. The findings will also be used to develop treatment and prevention measures-- such as cooling strategies and hydration recommendations--to reduce the risk of acute kidney injury in vulnerable populations.