A significant proportion of hospitalized patients with influenza develop complications of acute respiratory distress syndrome, driven by virus-induced cytopathic effects as well as exaggerated host immune response. Reporting in The American Journal of Pathology, published by Elsevier, investigators have found that treatment with an immune receptor blocker in combination with an antiviral agent markedly improves survival of mice infected with lethal influenza and reduces lung pathology in swine-influenza-infected piglets. Their research also provides insights into the optimal timing of treatment to prevent acute lung injury.
Previously, the investigators found that an excessive influx of neutrophils, infection fighting immune cells, and the networks they create to kill pathogens, known as neutrophil extracellular traps (NETs), contribute to acute lung injury in influenza infection. Formation of NETs by activated neutrophils occurs via a cell death mechanism called NETosis and the released NETs contain chromatin fibers that harbor toxic components.
A mouse model, commonly used in exploring influenza pathophysiology and drug therapies, was used in the current study. Because mice are not natural hosts for influenza, further validation in larger animals is necessary before testing in humans. Therefore, researchers also tested piglets infected with swine influenza virus. The animals were treated with a combination of a CXCR2 antagonist, SCH527123, together with an antiviral agent, oseltamivir.
The combination of SCH527123 and oseltamivir significantly improved survival in mice compared to either of the drugs administered alone. The combination therapy also reduced pulmonary pathology in piglets.
“Combination therapy reduces lung inflammation, alveolitis, and vascular pathology, indicating that aberrant neutrophil activation and release in NETs exacerbate pulmonary pathology in severe influenza,” explains lead investigator Narasaraju Teluguakula, PhD, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA. “These findings support the evidence that antagonizing CXCR2 may alleviate lung pathology and may have significant synergistic effects with antiviral treatment to reduce influenza-associated morbidity and mortality.”
It can be challenging to balance the suppression of excessive neutrophil influx without compromising the beneficial host immunity conferred by neutrophils. Therefore, the researchers examined the temporal dynamics of NETs release in correlation with pathological changes during the course of infection in mice. During the early inflammatory phase, three to five days post infection, significant neutrophil activation and NETs release with relatively few hemorrhagic lesions was observed. In the late hemorrhagic exudative phase, significant vascular injury with declining neutrophil activity was seen.
Dr. Teluguakula also emphasizes that these findings provide the first evidence to support the strategy of testing combination therapy in a large animal influenza model. “In view of the close similarities in pulmonary pathology and immune responses between swine and humans, pig-influenza pneumonia models can serve as a common platform in understanding pathophysiology and host-directed drug therapies in human influenza infections and may be useful in advancing the translational impact of drug treatment studies in human influenza infections.”
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A UCLA-led research team has identified a chemical cocktail that enables the production of large numbers of muscle stem cells, which can self-renew and give rise to all types of skeletal muscle cells.
The advance could lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or disease. The research was published in Nature Biomedical Engineering.
Muscle stem cells are responsible for muscle growth, repair and regeneration following injury throughout a person’s life. In fully grown adults, muscle stem cells are quiescent — they remain inactive until they are called to respond to injury by self-replicating and creating all of the cell types necessary to repair damaged tissue.
But that regenerative capacity decreases as people age; it also can be compromised by traumatic injuries and by genetic diseases such as Duchenne muscular dystrophy.
“Muscle stem cell-based therapies show a lot of promise for improving muscle regeneration, but current methods for generating patient-specific muscle stem cells can take months,” said Song Li, the study’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
Li and his colleagues identified a chemical cocktail — a combination of the root extract forskolin and the small molecule RepSox — that can efficiently create large numbers of muscle stem cells within 10 days. In mouse studies, the researchers demonstrated two potential avenues by which the cocktail could be used as a therapy.

In new findings published online March 18, 2021 in the journal Cancer Cell, an international team of researchers, led by scientists at University of California San Diego School of Medicine and Moores Cancer Center, describe how pancreatic cancer cells use an alternative method to find necessary nutrients, defying current therapies, to help them grow and spread.
Pancreatic cancer accounts for roughly 3 percent of all cancers in the United States, but it is among the most aggressive and deadly, resulting in 7 percent of all cancer deaths annually. Pancreatic cancer is especially deadly once it metastasizes, with the number of people who are alive five years later declining from 37 percent to just 3 percent.
All cancer cells require a constant supply of nutrients. Some types of cancer achieve this by creating their own vascular networks to pull in nutrients from the host’s blood supply. But other cancers, notably pancreatic ductal adenocarcinoma, are surrounded by a thick layer of connective tissue and extracellular molecules (the so-called tumor stroma) that act not just as a sort of a dividing line between malignant cells and normal host tissues, but also as a hindrance to cancer cells obtaining sufficient resources, including blood supply.
As a result, pancreatic and other nutritionally stressed cancers employ a number of adaptive mechanisms to avoid death by starvation, a risk particularly high in rapidly growing tumors. One such mechanism is autophagy or self-eating. Autophagy allows nutritionally stressed cancers to digest intracellular proteins, especially denatured or damaged proteins, and use the liberated amino acid building blocks as an energy source to fuel their metabolism.
Past research indicating autophagy is elevated in pancreatic cancer gave rise to the idea that inhibiting self-eating might be used to starve tumors. Yet, multiple clinical trials using compounds that inhibit autophagic protein degradation combined with traditional chemotherapy, did not produce any added therapeutic benefit compared to chemotherapy alone, said Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.
In the new study, Hua Su, PhD, a postdoctoral fellow in Karin’s lab and first author of the study, and collaborators investigated why pancreatic cancers survive autophagy and, in fact, appear to thrive. They found that inhibition of autophagy resulted in rapid upregulation or increased activity of a different nutrient procurement pathway called macropinocytosis, derived from the Greek for “large drinking or gulping.”
Macropinocytosis enables autophagy-compromised and nutritionally stressed cancer cells to take up exogenous proteins (found outside the cell), digest them and use their amino acids for energy generation. “This explains why autophagy inhibitors fail to starve pancreatic cancer and cannot induce its regression,” said Su. “Once autophagy is inhibited, cancer cells simply resort to a different mechanism to feed themselves.”
In experiments using mouse cancer models and human pancreatic cancers grown in mice, Su and colleagues found that a combination of autophagy and macropinocytosis inhibitors resulted in rapid and nearly complete tumor regression.
“These results provide another example of the plastic nature of pancreatic cancer metabolism,” said senior author Karin. “It also shows that combined inhibition of the two major nutrient procurement pathways can result in a successful blockade of energy supply resulting in tumor starvation and consequent shrinkage.”
Study co-author Andrew Lowy, MD, chief of the Division of Surgical Oncology at Moores Cancer Center at UC San Diego Health and a professor of surgery at UC San Diego School of Medicine, said the new data demonstrate the promise of targeting tumor metabolism as a treatment strategy and that success will likely require combining multiple agents for multiple targets.
“I believe that these findings are exciting and support the idea that we will make significant impact against this very difficult disease in the near-future,” Lowy said.
Co-authors include: Fei Yang, Rao Fu, Xiaohong Pu and Beicheng Sun, Nanjing University Medical School; Xin Li and Yinling Hu, National Cancer Institute; Randall French, Evangeline Mose, Brittney Trinh, Junlai Liu, Laura Antonucci, Yuan Liu, Avi Kumar and Christian M. Metallo, UC San Diego; Jelena Todoric, UC San Diego and Medical University of Vienna; Maria Diaz-Meco and Jorge Moscat, Weill Cornell Medicine.

Have you forgotten where you laid your keys? Ever wondered where you had parked your car? Or having trouble remembering the name of the new neighbor? Unfortunately, these things seem to get worse as one gets older. A big question for researchers is where does benign forgetfulness end and true disease begin?
One of the keys to having a healthy brain at any age is having a healthy blood-brain barrier, a complex interface of blood vessels that run through the brain. Researchers reviewed more than 150 articles to look at what happens to the blood-brain barrier as we age. Their findings were published March 15 in Nature Aging.
Whether the changes to the blood-brain barrier alters brain function, however, is still up for debate.
“It turns out very little is known how the blood-brain barrier ages,” said lead author William Banks, a gerontology researcher at the University of Washington School of Medicine, and a researcher with the Geriatrics Research Education and Clinical Center at the Veterans Affairs Puget Sound Health Care System. “It’s often hard to tell normal aging from early disease.”
The blood-brain barrier, discovered in the late 1800s, prevents the unregulated leakage of substances from blood into the brain. The brain is an especially sensitive organ and cannot tolerate direct exposure to many of the substances in the blood. Increasingly, scientists have realized that the blood-brain barrier also allows many substances into the brain in a regulated way to serve the nutritional needs of the brain. It also transports informational molecules from the blood to the brain and pumps toxins out of the brain. A malfunctioning blood-brain barrier can contribute to diseases such as multiple sclerosis, diabetes, and even Alzheimer’s disease.
Before scientists can understand how such malfunctioning can contribute to the diseases of aging, they need to understand how a healthy blood-brain barrier normally ages.

Anyone who has watched an infant’s eyes follow a dangling trinket dancing in front of them knows that babies are capable of paying attention with laser focus.
But with large areas of their young brains still underdeveloped, how do they manage to do so?
Using an approach pioneered at Yale that uses fMRI (or functional magnetic resonance imaging) to scan the brains of awake babies, a team of university psychologists show that when focusing their attention infants under a year of age recruit areas of their frontal cortex, a section of the brain involved in more advanced functions that was previously thought to be immature in babies. The findings were published March 16 in the Proceedings of the National Academy of Sciences.
“Attention is the gateway to what infants perceive and learn,” said Nick Turk-Browne, professor of psychology at Yale and senior author of the paper. “Attention is the bouncer at the door, determining what information gets into the brain, which eventually creates memories, language, and thought.”
Most previous research related to attention in babies has depended upon tracking their gaze while they are presented with visual stimuli, a process that theoretically offers insights into what is going on in their minds. Left unanswered are questions about which sections of the brain are involved in these responses, and how and why they allocate attention in these ways.
Attention in babies could depend upon on sensory areas of the brain, which process stimuli such as touch and visual stimuli and helps them react to the external world. These brain regions develop earlier in infancy than regions of the frontal cortex, which are usually associated with internal functions such as control, planning, and reasoning.

Researchers have developed a new statistical model that predicts which cities are more likely to become infectious disease hotspots, based both on interconnectivity between cities and the idea that some cities are more suitable environments for infection than others. Brandon Lieberthal and Allison Gardner of the University of Maine present these findings in the open-access journal PLOS Computational Biology.
In an epidemic, different cities have varying risks of triggering superspreader events, which spread unusually large numbers of infected people to other cities. Previous research has explored how to identify potential “superspreader cities” based on how well each city is connected to others or on each city’s distinct suitability as an environment for infection. However, few studies have incorporated both factors at once.
Now, Lieberthal and Gardner have developed a mathematical model that identifies potential superspreaders by incorporating both connectivity between cities and their varying suitability for infection. A city’s infection suitability depends on the specific disease being considered, but could incorporate characteristics such as climate, population density, and sanitation.
The researchers validated their model with a simulation of epidemic spread across randomly generated networks. They found that the risk of a city becoming a superspreader increases with infection suitability only up to a certain extent, but risk increases indefinitely with increased connectivity to other cities.
“Most importantly, our research produces a formula in which a disease management expert can input the properties of an infectious disease and the human mobility network and output a list of cities that are most likely to become superspreader locations,” Lieberthal says. “This could improve efforts to prevent or mitigate spread.”
The new model can be applied to both directly transmitted diseases, such as COVID-19, or to vector-borne illnesses, such as the mosquito-borne Zika virus. It could provide more in-depth guidance than traditional metrics of risk, but is also much less computationally intensive than advanced simulations.
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Aedes aegypti are the primary vector for mosquito-borne diseases such as dengue fever. However, the effects of climate change-related weather anomalies on mosquito populations is not well understood. A study published in PLOS Neglected Tropical Diseases by Cameron Nosrat at Stanford University, United States and colleagues suggests that early interventions may prevent disease transmission even as extreme climate events may increase the abundance of Ae. aegypti populations.
Temperature and rainfall have significant impacts on Ae. aegypti abundance, and climate change will likely intensify the frequency of extreme climate events such as floods, droughts, heat waves and cold waves. To better understand the specific effects of weather anomalies on the dynamics of vector-borne disease transmission, researchers conducted a retrospective cohort study to determine the impact of extreme rainfall and temperature on mosquito abundance and the risk of dengue infections in Kenya. Using satellite-derived climate data, the authors classified extreme climate events rainfall and temperatures as in the upper or lower 10% of historical averages. The researchers then monitored Aedes aegypti abundance using trapping methods and new dengue fever cases via blood samples collected from a cohort of 7,653 children.
Flood seasons contributed to significantly higher Ae. aegypti egg and adult abundance. However, extreme climate events and greater Ae. aegypti abundance did not correlate to an increased number of confirmed dengue fever cases. Human behaviors can modify the relationship between mosquito abundance and disease transmission, and influence infection risk. Preventative measures in the study sites may have contributed to reductions in dengue transmission. A major limitation of the study was the lack of long-term Kenya climate data; however, the authors believe their study effectively examines the influence of weather anomalies on various life stages of Ae. aegypti abundance.
According to the authors, “Dengue is the fastest-growing mosquito-borne disease in the world, and as climate change accelerates, many vulnerable populations will continue to be disproportionately impacted by this virus. Having shown floods to result in significantly increased dengue vector abundance, we hope to encourage actionable interventions to limit infection risk in light of these extreme climate events.”
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Dogs infected with the Leishmania parasite smell more attractive to female sand flies than males, say researchers.
The study published in PLOS Pathogens is led by Professor Gordon Hamilton of Lancaster University.
In Brazil, the parasite Leishmania infantum is transmitted by the bite of infected female Lutzomyia longipalpis sand flies.
Globally over 350 million people are at risk of leishmaniasis, with up to 300,000 new cases annually. In Brazil alone there are approximately 4,500 deaths each year from the visceral form of the disease and children under 15 years old are more likely to be affected.
Leishmania parasites are transmitted from infected dogs to people by sand flies when they bite. Visceral leishmaniasis affects the internal organs and is fatal if not treated.
As only female sand flies transmit the parasite, researchers wanted to understand if infection made dogs more attractive to the insect.
Professor Gordon Hamilton of Lancaster University said: “In this study we showed that infected dog odour is much more attractive than uninfected dog odour to the female sand flies. Only the females can transmit the pathogen and male sand flies, which do not transmit the parasite, are not affected by the changed odour.
“This clear-cut difference in attraction of female and male sand flies suggests that the females are preferentially attracted by parasite infected hosts and this could lead to enhanced infection and transmission opportunities for the parasite.”
The researchers had previously found that dogs infected with Leishmania parasites smelled different compared to uninfected dogs.
Professor Hamilton said: “Domestic dogs are the reservoir of infection, therefore understanding how the infection affects the attractiveness of dogs to the insect vector is important in understanding the epidemiology of the disease and offers opportunities for new control and diagnostic methodologies.”
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Even as vaccines are becoming more readily available in the U.S., protecting against the asymptomatic and pre-symptomatic spread of the virus (SARS-CoV-2) that causes COVID-19 is key to ending the pandemic, say two Georgetown infectious disease experts.
In their Perspective, “SARS-CoV-2 Transmission Without Symptoms” published March 18 in the journal Science, Angela L. Rasmussen, PhD, and Saskia V. Popescu, PhD, MA, faculty affiliates of the Center for Global Health Science and Security at Georgetown University Medical Center, make the case that symptomless transmission silently drives viral spread and is key to ending the pandemic.
“Determining the true transmission capability of asymptomatic and pre-symptomatic cases is inherently complex, but knowledge gaps should not detract from acknowledging their role in the spread of SARS-CoV-2,” the authors write.
“We can’t rely on vaccination alone to control the pandemic,” says Rasmussen. “Vaccines are great for protecting people against disease, but we don’t yet know how well they work to protect against transmission.”
Rasmussen says that from a biological perspective, it would be unlikely that a vaccine that protects well against disease would not protect against infection. “But just like the vaccines don’t offer a hundred percent protection against getting sick, they also aren’t a hundred percent likely to protect against transmission.”
In addition, while vaccines reportedly will become widely available in the U.S. by summer, that is not the case in the rest of the world where the pandemic continues unabated.
“Asymptomatic and pre-symptomatic transmission poses a unique challenge for public health and infection prevention mitigation efforts,” says Popescu. “Ultimately this is something we will need to continuously keep our eye on as we move into the next phase of the COVID-19 pandemic and a reduction of disease due to vaccinations.”
Rasmussen and Popescu conclude, “Until there is widespread implementation of robust surveillance and epidemiological measures that allow us to put out these smokeless fires, the COVID-19 pandemic cannot be fully extinguished.”
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