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A new look inside Ebola’s “viral factories”

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Credit: Image courtesy Saphire Lab, La Jolla Institute for Immunology
Two views of Ebola’s “viral factories” inside host cells. The image on the left was captured via confocal immunofluorescence microscopy and shows Ebola’s viral factories in pink. The image on the right was captured using electron tomography and shows viral factories in orange.

Newswise — LA JOLLA, CA—New research in the journal Nature Communications gives scientists an important window into how Ebola virus replicates inside host cells. The study, led by scientists at La Jolla Institute for Immunology (LJI), reveals the inner workings of “viral factories,” clusters of viral proteins and genomes that form in host cells.

The research team, which included experts from Scripps Research and UC San Diego School of Medicine, found that Ebola virus’s replication machinery forms fascinating microscopic structures that become viral factories. By understanding the architecture and function of these microscopic manufacturing hubs, researchers may be closer to developing new therapies that interrupt the Ebola virus life cycle and prevent severe disease.

“We are imaging these fluid and dynamic assembly centers for the first time. Understanding how they work and what they require gives us the information needed to defeat them,” says LJI President and CEO Erica Ollmann Saphire, Ph.D., senior author of the new study.

What is a viral factory?

Scientists first spotted what would turn out to be “virus factories” in virus-infected animal cells back in the 1960s, but they didn’t know what they were seeing. Within a sea of normal cellular proteins, these areas looked like fuzzy splotches.

“People had already seen that Ebola-infected cells had these ‘inclusions,’” says LJI Postdoctoral Researcher Jingru Fang, Ph.D., first author of the new study. For a long time, scientists thought of these “inclusions” as helpful visual indicators of infection, without understanding their true purpose. “But in fact, these ‘inclusion bodies’ actively gather an enormous quantity of viral proteins and viral RNAs.”

Many viral pathogens, including rabies virus and RSV (respiratory syncytial virus) form inclusions in host cells, Fang explains. “Recent studies suggest that these cellular inclusions are the site where viruses make their RNA genomes. They are ‘viral factories’ with actual functional purpose: to offer a secured space for viral RNA synthesis,” says Fang. “The process of viral RNA synthesis involves flux of viral building blocks. This means molecules gathered inside viral factories should be able to move freely rather than being static.”

For the new study, Saphire, Fang and their colleagues wondered: Can we observe the movement of viral building blocks directly in living cells?

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Fang began by tagging a viral protein called VP35 with a fluorescent marker that makes the protein glow in the dark. VP35 is a critical component of the viral factory and is important for viral RNA synthesis (and the making of new copies of Ebola virus). Working with imaging experts in the LJI Microscopy and Histology Core, Fang followed the glowing proteins in live cells, which express a simplified and non-infectious version of Ebola viral factories.

Under the microscope, Fang and colleagues could indeed see and even measure how molecules move inside the viral factories formed in host cells. This finding added evidence that viral proteins are clumping together like droplets so they can churn out the proteins needed to help the virus replicate. Those mysterious inclusions really are viral factories. The researcher dubbed these “droplet-like” viral factories.

Then the scientists saw something odd. Some of the glowing proteins didn’t gather into clumps. Instead, they joined up with a smattering of other viral proteins, creating a fluorescent swirl that evoked van Gogh’s “Starry Night.” These trails of viral proteins still had the right ingredients to replicate Ebola virus, so the scientists dubbed them “network-like” viral factories.

“These are two different flavors of the viral factory,” says Fang. “People have mostly focused on the droplet-like form, which is the majority, and not paid too much attention to this other form.”

Besides their shapes, there was a key difference between the two factories. It appeared the network-like factories had the right ingredients for the incoming Ebola virus to express its genes, but they didn’t actually produce virus progenies.

A multi-tasking machine

Next, the researchers looked at a key player in infection: a protein called virus polymerase. Polymerase is a multifunctional nanomachine that comes with the virus. This machine not only copies the Ebola virus genomic material, it also transcribes the viral genome into messenger RNAs, which instruct infected cells to produce loads of viral proteins. The researchers wanted to understand how this viral machine functions inside viral factories.

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Ebola virus polymerase is already known as a hard-working protein—all Ebola viral proteins have to be. Ebola virus is a highly efficient pathogen because it gets by with just seven genes (humans have more than 20,000 genes). Saphire has led research showing that Ebola virus survives by making proteins that can transform and take on different jobs during the course of infection.

Just last year, Saphire, Fang, and collaborators published a related discovery that viral polymerase actually harnesses a druggable human protein to help the virus replicate its genome. The team reported that while polymerase is essential for viral replication, the polymerase doesn’t actually jump into action until infection is well underway.

This work was important for understanding how polymerase stepped into action, but scientists also needed to know where polymerase was active. Fang knew it would be important to look at what polymerase might be up to in viral factories.

The researchers discovered that polymerase actually builds its own special structures inside viral factories. Many copies of polymerase gather in small bundles, called foci. The researchers found that these bundles spread out when a droplet-like viral factory starts replicating viral material.

Scientists aren’t sure exactly why polymerase needs to form bundles before it can do its job, but the spatial arrangement of the bundles must be important. As Fang points out, the idea of many small components coming together to build a structure isn’t a new concept in nature. “You can use a beehive or coral reef as the analogy to help understand why a specific spatial arrangement is important for a biological system to function,” she says.

With this finding, scientists now know how to find different kinds of viral factories and how polymerase organizes itself down on the factory floor.

Fighting back

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More than 30 human pathogens are known to assemble viral factories inside host cells, including respiratory syncytial virus (RSV) and even rabies virus. With this new view of Ebola’s viral factories, the scientists are curious whether other viruses construct similar forms of viral factories—and whether other viruses use their own versions of polymerase in the same way.

“If that’s true, maybe we can target the feature of viral factory formation that has been shared by multiple different viruses,” says Fang.

Going forward, Fang would also like to study how Ebola virus forms viral factories in different kinds of host cells. Do these viral factories look different in cells from animals (such as the virus’s natural hosts, the fruit bats) that can carry the virus around without getting sick? “Can we find some explanation for host-specific viral pathogenesis?” she asks.

The new study also demonstrates the importance of collaboration across San Diego’s Torrey Pines Mesa. The LJI team worked closely with Scripps Research Professor Ashok Deniz, Ph.D., and UC San Diego Professor Mark H. Ellisman, Ph.D., Director of the National Center for Microscopy and Imaging Research.

“The combination of state-of-the-art tools available on the Torrey Pines Mesa allowed us to combine the biophysical characterization with the human health insight,” says Saphire

Additional authors of the study, “Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories,” include Guillaume Castillon, Sebastien Phan, Sara McArdle, Chitra Hariharan, and Aiyana Adams.

This study was supported by the National Institute of Health (grants NIH S10OD021831, R24GM137200, and S10OD021784), an Imaging Scientist grant (2019‐198153) from the Chan Zuckerberg Initiative, LJI institutional funds, and the Donald E. and Delia B. Baxter Foundation Fellowship.

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DOI: 10.1038/s41467-023-39821-7

Source: La Jolla Institute for Immunology

About La Jolla Institute

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. Visit lji.org for more information.

Journal Link: Nature Communication, July-2023

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Biden helped bring science out of the lab and into the community − emphasizing research focused on solutions

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Biden began his presidency in the throes of the COVID-19 pandemic. Evan Vucci/AP Photo

Arthur Daemmrich, Arizona State University

President Joe Biden was inaugurated in January 2021 amid a devastating pandemic, with over 24 million COVID-19 cases and more than 400,000 deaths in the U.S. recorded at that point.

Operation Warp Speed, initiated by the Trump administration in May 2020, meant an effective vaccine was becoming available. Biden quickly announced a plan to immunize 100 million Americans over the next three months. By the end of April 2021, 145 million Americans – nearly half the population – had received one vaccine dose, and 103 million were considered fully vaccinated. Science and technology policymakers celebrated this coordination across science, industry and government to address a real-world crisis as a 21st-century Manhattan Project.

From my perspective as a scholar of science and technology policy, Biden’s legacy includes structural, institutional and practical changes to how science is conducted. Building on approaches developed over the course of many years, the administration elevated the status of science in the government and fostered community participation in research.

Raising science’s profile in government

The U.S. has no single ministry of science and technology. Instead, agencies and offices across the executive branch carry out scientific research at several national labs and fund research by other institutions. By elevating the White House Office of Science and Technology Policy to a Cabinet-level organization for the first time in its history, Biden gave the agency greater influence in federal decision-making and coordination.

Formally established in 1976, the agency provides the president and senior staff with scientific and technical advice, bringing science to bear on executive policies. Biden’s inclusion of the agency’s director in his Cabinet was a strong signal about the elevated role science and technology would play in the administration’s solutions to major societal challenges.

Under Biden, the Office of Science and Technology Policy established guidelines that agencies across the government would follow as they implemented major legislation. This included developing technologies that remove carbon dioxide from the atmosphere to address climate change, rebuilding America’s chip industry, and managing the rollout of AI technologies.

Close-up of gloved hand holding square semiconductor chip
The CHIPS and Science Act of 2022 boosted research and manufacture of semiconductor chips in the U.S. Narumon Bowonkitwanchai/Moment via Getty Images

Instead of treating the ethical and societal dimensions of scientific and technological change as separate from research and development, the agency advocated for a more integrated approach. This was reflected in the appointment of social scientist Alondra Nelson as the agency’s first deputy director for science and society, and science policy expert Kei Koizumi as principal deputy director for policy. Ethical and societal considerations were added as evaluation criteria for grants. And initiatives such as the AI bill of rights and frameworks for research integrity and open science further encouraged all federal agencies to consider the social effects of their research.

The Office of Science and Technology Policy also introduced new ways for agencies to consult with communities, including Native Nations, rural Americans and people of color, in order to avoid known biases in science and technology research. For example, the agency issued government-wide guidance to recognize and include Indigenous knowledge in federal programs. Agencies such as the Department of Energy have incorporated public perspectives while rolling out atmospheric carbon dioxide removal technologies and building new hydrogen hubs.

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Use-inspired research

A long-standing criticism of U.S. science funding is that it often fails to answer questions of societal importance. Members of Congress and policy analysts have argued that funded projects instead overly emphasize basic research in areas that advance the careers of researchers.

In response, the Biden administration established the technology, innovation and partnerships directorate at the National Science Foundation in March 2022.

The directorate uses social science approaches to help focus scientific research and technology on their potential uses and effects on society. For example, engineers developing future energy technologies could start by consulting with the community about local needs and opportunities, rather than pitching their preferred solution after years of laboratory work. Genetic researchers could share both knowledge and financial benefits with the communities that provided the researchers with data.

Fundamentally, “use-inspired” research aims to reconnect scientists and engineers with the people and communities their work ultimately affects, going beyond publication in a journal accessible only to academics.

The technology, innovation and partnerships directorate established initiatives to support regional projects and multidisciplinary partnerships bringing together researchers, entrepreneurs and community organizations. These programs, such as the regional innovation engines and convergence accelerator, seek to balance the traditional process of grant proposals written and evaluated by academics with broader societal demand for affordable health and environmental solutions. This work is particularly key to parts of the country that have not yet seen visible gains from decades of federally sponsored research, such as regions encompassing western North Carolina, northern South Carolina, eastern Tennessee and southwest Virginia.

Community-based scientific research

The Biden administration also worked to involve communities in science not just as research consultants but also as active participants.

Scientific research and technology-based innovation are often considered the exclusive domain of experts from elite universities or national labs. Yet, many communities are eager to conduct research, and they have insights to contribute. There is a decades-long history of citizen science initiatives, such as birdwatchers contributing data to national environmental surveys and community groups collecting industrial emissions data that officials can use to make regulations more cost effective.

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Going further, the Biden administration carried out experiments to create research projects in a way that involved community members, local colleges and federal agencies as more equal partners.

Hand-drawn signs displayed on a fence against a green field, with messages about climate change around a sign that reads 'It's our future'
Collaboration between the community, academia, industry and government can lead to more effective solutions. Deb Cohn-Orbach/UCG/Universal Images Group via Getty Images

For example, the Justice40 initiative asked people from across the country, including rural and small-town Americans, to identify local environmental justice issues and potential solutions.

The National Institutes of Health’s ComPASS program funded community organizations to test and scale successful health interventions, such as identifying pregnant women with complex medical needs and connecting them to specialized care.

And the National Science Foundation’s Civic Innovation Challenge required academic researchers to work with local organizations to address local concerns, improving the community’s technical skills and knowledge.

Frontiers of science and technology policy

Researchers often cite the 1945 report Science: The Endless Frontier, written by former Office of Scientific Research and Development head Vannevar Bush, to describe the core rationales for using American taxpayer money to fund basic science. Under this model, funding science would lead to three key outcomes: a secure national defense, improved health, and economic prosperity. The report, however, says little about how to go from basic science to desired societal outcomes. It also makes no mention of scientists sharing responsibility for the direction and impact of their work.

The 80th anniversary of Bush’s report in 2025 offers an opportunity to move science out into society. At present, major government initiatives are following a technology push model that focuses efforts on only one or a few products and involves little consideration of consumer and market demand. Research has repeatedly demonstrated that consumer or societal pull, which attracts development of products that enhance quality of life, is key to successful uptake of new technologies and their longevity.

Future administrations can further advance science and address major societal challenges by considering how ready society is to take up new technologies and increasing collaboration between government and civil society.

Arthur Daemmrich, Professor of Practice in the School for the Future of Innovation in Society, Arizona State University

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This article is republished from The Conversation under a Creative Commons license. Read the original article.

The science section of our news blog STM Daily News provides readers with captivating and up-to-date information on the latest scientific discoveries, breakthroughs, and innovations across various fields. We offer engaging and accessible content, ensuring that readers with different levels of scientific knowledge can stay informed. Whether it’s exploring advancements in medicine, astronomy, technology, or environmental sciences, our science section strives to shed light on the intriguing world of scientific exploration and its profound impact on our daily lives. From thought-provoking articles to informative interviews with experts in the field, STM Daily News Science offers a harmonious blend of factual reporting, analysis, and exploration, making it a go-to source for science enthusiasts and curious minds alike. https://stmdailynews.com/category/science/


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Know These 4 Core Factors to Avoid a Heart Health Syndrome

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(Family Features) In the U.S., 1 in 3 adults is at risk for a newly recognized syndrome that comes from a combination of heart disease, kidney disease, type 2 diabetes and excess body weight. This cluster of conditions, called cardiovascular-kidney-metabolic (CKM) syndrome, is an example of how problems in one part of your body can affect other parts.

To avoid CKM syndrome, health experts suggest paying close attention to four of the American Heart Association’s Life’s Essential 8 – blood pressure, lipids, body weight and blood sugar level – which are core health factors that impact your metabolic health.

Good metabolic health means your body uses energy well and keeps these factors in a normal range. However, when numbers are off in one area, it can affect others, raising your risk for heart disease, stroke, kidney disease and diabetes.

Consider these tips from the American Heart Association to help keep your core health factors under control.

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Blood Pressure
High blood pressure, also known as hypertension, happens when the force of your blood pushing against the walls of your blood vessels is too high. High blood pressure is a leading cause of heart disease, stroke and kidney disease.

Because high blood pressure doesn’t have symptoms, the only way to know you have it is to get your blood pressure checked. Healthy blood pressure is below 120/80. If your blood pressure is 130/80 or higher, talk to your doctor about checking your other core health factors.

Lifestyle changes can help reduce high blood pressure. One example is a Dietary Approaches to Stop Hypertension (DASH) eating pattern that’s low in fat and rich in fruits, vegetables, whole grains and low-fat dairy products. Losing 10 pounds and reducing alcohol consumption can also reduce blood pressure.

Cholesterol
Cholesterol is a waxy substance your liver makes then circulates in the blood where your body uses it to build cells and make vitamins and hormones. You may also get cholesterol from eating animal products. If there’s too much cholesterol circulating, your risk of type 2 diabetes, heart disease and stroke may increase.

For optimal CKM health, your LDL cholesterol should be below 100 and triglycerides below 150. Triglycerides are the most common type of fat in the body. If your triglyceride level is 135 or higher, talk to your doctor about decreasing your risk.

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Losing body weight and increasing physical activity decrease triglyceride levels. In addition, DASH and Mediterranean (plant-based, high-fiber, low-fat) eating patterns support healthy LDL and triglyceride levels.

Body Weight
Healthy weight may be determined by body mass index (BMI), a number that represents your weight in relation to your height. Extra body fat can mean a higher risk for many health problems, including heart disease, stroke, high blood pressure, high cholesterol and diabetes.

CKM syndrome starts when BMI is 25 or higher and waist circumference is 88 centimeters or higher for women and 102 centimeters or higher for men. Aim for a BMI between 18.5-25.

To lose weight and keep it off, start by setting realistic goals. Understand how much and why you eat, manage portion sizes, make smart snack substitutions and be physically active.

Blood Sugar
High blood sugar can slowly damage the kidneys. In fact, diabetes is the leading cause of kidney disease, and it increases the risk of heart attack and stroke.

Blood sugar is measured in two ways: a fasting blood glucose test (short term blood sugar) and an A1C test (long term blood sugar control). A normal fasting blood glucose level is 70-99 and a normal A1C level is below 5.7%. Fasting blood glucose above 125 and A1C of 6.5% or higher means you have diabetes.

Habits that help you avoid high blood pressure, weight gain and high cholesterol also keep your blood sugar in check. These are especially important if you have a family history of diabetes.

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Learn more about CKM syndrome and how to manage your risk at heart.org/CKMhealth.

Photos courtesy of Shutterstock

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SOURCE:
American Heart Association


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Expert Pregnancy Tips for Staying Healthy This Winter

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(Family Features) Staying up to date on recommended vaccines is important during pregnancy. This is especially true during the winter months when more people tend to get sick from flu, COVID-19 and RSV. These viruses can be especially dangerous for pregnant people and babies.

Vaccines are an important part of routine pregnancy care, both for you and your baby. Getting vaccinated against flu and COVID-19 can cut your risk of hospitalization by about half.

Now is the time to get vaccinated if you haven’t already. Flu vaccines help protect you from getting the flu and getting seriously ill, so it’s a good idea to schedule an appointment now. The latest COVID-19 vaccines are important too because they lower your risk of serious illness. An RSV vaccine may also be recommended for when you are 32-36 weeks pregnant. Be sure to talk to your doctor.

“Right now, we are seeing a concerning increase in cases of respiratory diseases, such as the flu, COVID-19 and RSV,” said Adm. Rachel Levin, MD, assistant secretary for health at the U.S. Department of Health and Human Services. “I encourage all pregnant people to take preventive action to protect their health and the health of their baby. The best and safest way to do this is to get vaccinated. Getting vaccinated is easy and is usually covered by insurance.”

Help Protect Your Baby 
When you get flu, COVID-19 and RSV vaccines, you’re helping protect your baby by passing your immunity on to them. Getting vaccinated against flu, COVID-19 and RSV during pregnancy can protect your baby during the first 6 months of life. These viruses can be very harmful to newborns. In fact, RSV is the leading cause of hospitalization in infants

Talk to Your Doctor About Timing
Millions of people in the U.S. have already gotten vaccinated against flu, COVID-19 and RSV this season. If you haven’t gotten your vaccines yet, be sure to talk with your doctor. They can help you choose the right vaccines and determine the best timing to help protect you and your baby.

Get the Facts
Getting vaccinated can give you peace of mind, ensuring you have done everything you can to protect yourself and your baby from serious respiratory illness. Information can give you power and comfort, especially when you’re pregnant.

Go to cdc.gov/RiskLessDoMore to learn more about flu, COVID-19 and RSV vaccines, or go to vaccines.gov to get started today.

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Photo courtesy of Shutterstock

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SOURCE:
U.S. Department of Health and Human Services


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