Culture

PHILADELPHIA - Multiple sclerosis (MS), characterized by increasing muscle weakness and paralysis, has a number of treatments that help stall progression of the disease when used early on in the disease. But the current treatments can hardly reverse damage that has already occurred in brain cells called neurons. New research suggests that a compound found in the peels of fruits such as apples and prunes, and some herbs, can reduce further damage to neurons, and also help rebuild the protective sheaths covering neurons, reversing the damage.

"Although the evidence is preliminary - our data is from animal models of disease - it's encouraging to see a compound that both halts and repairs damage in MS, in the lab," says Guang-Xian Zhang, PhD, co-senior author and Professor of Neuroscience at the Sidney Kimmel Medical College at Thomas Jefferson University. The study was published in the Proceedings of the National Academy of Sciences (PNAS) on Monday April 6th.

"There is additional work we must do to test the safety of this compound, ursolic acid" says co-senior author A.M. Rostami, MD, PhD, chair of the department of Neurology at the Vickie and Jack Farber Institute for Neuroscience - Jefferson Health. "But this is a great new lead for disease treatment."

The researchers used a lab-grade purified form of ursolic acid in mice that had established MS disease. "Many experiments have looked at mice in the acute phase, when disease is just starting or at the peak," says Dr. Zhang. "Instead, we tested whether this compound was effective in chronic disease, once there has already been chronic damage to tissues of central nervous system."

Drs. Zhang, Rostami, together with first author Yuan Zhang and colleagues used an established mouse model of multiple sclerosis that develops the disease slowly over the course of its life, mimicking human disease. At about day 12, the mouse begins the acute phase of the disease, when signs of MS, partial paralysis, appear, and when currently-available medications are most effective. The researchers, however, started treating mice at day 60, - a far more advanced stage of the disease when chronic tissue damage has been formed in brain and spinal cords, which needs to be repaired and regenerated.

Researchers treated the mice for 60 days, and began to see an improvement at day 20 of treatment. The mice which were paralyzed at the start of the experiment, regained the ability to walk around again, although with weakness, after treatment.

"It's not a cure, but if we see a similar response in people, it would represent a significant change in quality of life. And most significantly, it's a reversal, which we really haven't seen before with other agents at such a late stage of disease," says Dr. Zhang.

The researchers also investigated just how ursolic acid acted on cells. They observed that it suppressed Th17 cells - a type of immune cell that is one of the main drivers of the pathological autoimmune response in MS. Many currently active therapies appear to suppress Th17. But the Jefferson researchers showed that the compound could activate precursor cells to mature into much needed myelin-sheath-making cells, called oligodendrocytes.

"This maturation effect is the most crucial," says Dr. Zhang. "Myelin-sheath-making oligodendrocytes are depleted in MS. And the stem cells that produce new oligodentrocytes are dormant and unable to mature. This compound helps activate those stem cells into making new oligodendrocytes, and is likely responsible for the reversal of symptoms we saw."

The next steps for the investigators include testing the compound for safety. Although ursolic acid is available as a dietary supplement, it could be toxic at high doses. "There are still a number of tests to complete before the first clinical trials," says Dr. Rostami. "However, we are moving quickly with this promising approach."

Today, the Arabian Peninsula is one of the most arid regions in the world. But its climate has not always been the same, and the past has seen both greater aridity and more humidity at different points in time. As a region at risk of water stress in a heating world, Arabia is of significant interest to scientists studying climate change.

In the current study, archaeologists from the Max Planck Institute for the Science of Human History in Jena, Germany, conduct the first detailed comparison of human-environment interactions across Arabia, examining southeastern Arabia and the emerging record from northern Arabia. They find that ancient peoples responded to climate changes in a variety of ways, based on the region in which they lived and the environmental, social and technological resources available to them.

High mobility, water management, and economic transformation in northern Arabia

Approximately 10,000 years ago, Arabia saw a significant increase in rainfall and an expansion of lakes and vegetation which supported human settlements across the peninsula. In the millennia that followed, however, a series of extreme droughts led to drastic ecosystem changes.

In northern Arabia, the presence of large, shallow aquifers and seasonal playas facilitated survival through highly variable climatic conditions, including several centuries-long droughts. In particular, desert oases - including one in what is now the city of Jubbah - sustained human occupation, and the archaeological record indicates human presence in the surrounding Nefud Desert at multiple times during a 9000-year period. The discovery of the Jebel Oraf rockshelter on the fringes of the Jubbah oasis and a lakeside site with more than 170 hearths and remains of cattle show long-term habitation of the region. As Dr. Maria Guagnin explains, "pastoralist populations occupied the region repeatedly across millennia, relying on mobility and an extensive knowledge of the landscape and its resources to survive climatic changes and droughts."

During the 'Dark Millennium,' an arid period lasting from approximately 5,900 to 5,300 years ago during which much of Arabia is thought to have been uninhabitable, the researchers again find evidence of occupation at the Jubbah oasis. In other areas of northern Arabia, people constructed walls around oases, built landscape features to capture water runoff and began excavating wells. "Taken together," Dr. Huw Groucutt notes, "these finds indicate that the presence of extensive shallow aquifers, in combination with high population mobility, water management strategies and economic transformation, provided opportunities for the long-term survival of north Arabian populations."

Southeastern populations sought out the resource-rich coast in the face of droughts

Southeastern Arabia, in contrast with the north, seemingly enjoyed fewer sources of groundwater and saw a more direct correlation between the succession of ancient droughts and dramatic social change. After the Holocene Humid Phase, a subsequent climatic downturn lasting from 8,200 to 8,000 years ago brought effects so extreme that it is thought to have been linked to a shift from hunting and gathering to domesticated animal herding, according to previous research. Subsequent droughts (7,500 to 7,200 years ago and 6,500 to 6,300 years ago) correspond with declines in interior desert occupation, the development of herder and fisher communities on the coast, and the establishment of a maritime trade network between Arabian pastoralists and agricultural communities in Mesopotamia.

The extreme aridity of the 'Dark Millennium' brought about the abandonment of the southeast Arabian desert interior and the migration of populations to the Gulf coast. Previous research findings suggest, however, that even coastal populations felt the effects of strained resources. Earlier excavations at the seaside site of Ras al-Hamra reveal that Omani coastal populations from this period were in poor overall health. Specially arranged dugong (marine mammal) bone mounds excavated on the island of Akab in the United Arab Emirates suggest ritualized acts of consumption, perhaps a response to food scarcity.

Past responses highlight the need for sustainable solutions to confront climate change

Understanding the relationship between regional manifestations of climate change and adaptations that allow for societal resilience can provide valuable lessons for modern societies the world over. "For millennia, moving away from hard-hit regions was the main human response to severe climate downturns," says lead author Professor Michael Petraglia, "but with growing population sizes and an increasing investment in place, options for human mobility have decreased over time. In the same way, the rapid depletion of aquifers in recent years highlights the need for sustainable solutions to meet environmental challenges."

The researchers stress that taking action now to address the climate emergency is in the world's best interest. "Sometimes people dismiss climate change as something we don't need to worry too much about, because we've faced it before," notes Professor Nicole Boivin, director of the Institute's Department of Archaeology and a coauthor of the study. "But the scenarios we face now are unprecedented. Not only is human-caused climate change more unpredictable, but the options available to societies today are much more limited than those that allowed our ancestors to weather past changes."

Research led by scientists at the University of Southampton has found settlers arrived in East Polynesia around 200 years earlier than previously thought.

Colonisation of the vast eastern Pacific with its few and far-flung island archipelagos was a remarkable achievement in human history. Yet the timing, character, and drivers of this accomplishment remain poorly understood.

However, this new study has found a major change in the climate of the region, which resulted in a dry period, coinciding with the arrival of people on the tiny island of Atiu, in the southern group of the Cook Islands, around 900AD.

Findings are published in the paper, 'Human settlement of East Polynesia earlier, incremental and coincident with prolonged South Pacific drought' in the journal PNAS.

"The ancestors of the Polynesians, the Lapita people, migrated east into the Pacific Ocean as far as Fiji, Tonga and Samoa, reaching them around 2800 years ago. But for almost 1500 years humans failed to migrate any further into the pacific," explains lead researcher, Professor David Sear of the University of Southampton. "Our research gives us a much more accurate timescale of when people first arrived in the region and helps answer some key questions about why they made their hazardous journey east."

A team of geographers, archaeologists and geochemists from the UK, New Zealand and the US, worked with the people of Atiu, to collect core samples of lake mud, charting over 6000 years of history. Back in the labs in UK and US, the mud samples were subjected to a range of analyses including new techniques for reconstructing precipitation, and detecting the presence of mammalian faeces.

Apart from fruit bats, the Southern Cook Islands never had mammal populations before humans settled there, so when the researchers found evidence of mammal faeces alongside other evidence for landscape disturbance and burning, it was a clear sign of the arrival of people. Within 100 years the first settlers, most likely from Tonga or Samoa, changed the landscape by burning native forest to make way for crops.

The team, including undergraduate and postgraduate students from the universities of Southampton and Washington, as well as scientists from Newcastle, Liverpool and Auckland universities, also examined lake sediments from Samoa and Vanuata. Using this data, they found evidence for a major climate change which coincided with the newly established arrival time of the settlers.

The data revealed a major change in the climate of the South Pacific region with the main rainbands that bring water to the archipelagos of Vanuatu, Samoa, Tonga and Fiji migrating north. The result was the driest period in the last 2000 years.

This led the researchers to conclude that, alongside growing populations, water stress drove decisions to make dangerous voyages, aided by changes in winds that enabled easterly sailing. Soon after the arrival of people to Atiu, the climate changed again. Rain returned to the eastern Pacific - supporting a rapid (c. 200 years) settlement of the remaining islands of Polynesia.

Professor Sear adds: "Today, changing climate is again putting pressures on Pacific island communities, only this time the option to migrate is not so simple. Within two centuries of first arrival those first settlers changed the landscape and the ecology, but were able to make a home. Pacific islanders now live with modified ecologies, permanent national boundaries and islands already occupied by people. The ability to migrate in response to changing climate is no longer the option it once was."

Almost half of apparently healthy people between the ages of 40 and 50 could be accumulating fatty plaques--atheromas--in their arteries at a much faster rate than was previously thought. The Journal of American College of Cardiology (JACC) has today published new data from the PESA-CNIC-Santander study demonstrating that atheroma plaques extend rapidly through the arteries of 40% of asymptomatic individuals aged between 40 and 50 years.

Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), led by Dr Valentín Fuster, Director of the CNIC and lead investigator on the PESA-CNIC-Santander study, have also found that the progression of atherosclerosis is directly related to classical cardiovascular risk factors: age, sex, hypertension, cholesterol, smoking, and diabetes.

PESA ('Progression of early subclinical atherosclerosis') is a partnership between the CNIC and Santander Bank. The study has been monitoring 4200 healthy middle-aged men and women with noninvasive imaging technology and omics biomarkers for more than 10 years. The use of noninvasive imaging technologies, says Dr Fuster, "allows us to identify the progression of the disease earlier than is possible with classical markers, such as the presence of coronary calcium detected by computed tomography (CT), thus allowing us to identify individuals at higher risk who could benefit from early intervention."

The simpler imaging techniques like 2D and 3D ultrasound are accessible and do not involve exposure to radiation. With these techniques, explains CNIC Clinical Research Director Dr Borja Ibañez, "we can detect and quantify the burden and volume of atherosclerotic disease and precisely monitor its progression, thus identifying individuals who stand to benefit from earlier and more intensive prevention."

The 2019 European Prevention Guidelines recognize the utility of imaging techniques to evaluate cardiovascular risk in individuals beyond the conventional risk factors of age, sex, hypertension, cholesterol, smoking, and diabetes. "The recommended technique is low dose radiation CT, which evaluates the presence of calcium in the coronary arteries as an indirect measure of the presence of atherosclerotic plaques. But the guidelines also highlight the value of ultrasound to evaluate the burden of atherosclerosis in the carotid and femoral arteries."

The JACC article presents a 3-year follow-up study of the PESA cohort that makes the first direct comparison between these two imaging-based risk markers: coronary calcium by CT and atherosclerosis burden in the carotid and femoral arteries by 2D and 3D ultrasound. "The results show that ultrasound of the peripheral arteries is a more efficient method for detecting atherosclerosis progression than the study of coronary calcium by CT," said lead author Dr Beatriz López-Melgar.

Atherosclerosis is characterized by the accumulation of fatty deposits in the artery walls. The disease is normally detected at an advanced stage, when it has already caused clinical events such as a heart attack or stroke. Treatment of the disease at this symptomatic stage is of limited effectiveness, and most patients experience a decline in quality of life. The treatment of these patients, moreover, places a significant burden on health care resources.

"This study is the first to analyze the progression of atherosclerosis at frequent intervals. The previous view was that the disease progressed very slowly throughout life. However, the new results show that the disease progressed very rapidly in 40% of the individuals analyzed," said Dr Ibañez. "Future data from the PESA study will show whether this progression is associated with subsequent cardiovascular events. Until now, the speed of atherosclerosis progression has not been a factor in assessing individual risk."

A previous PESA analysis had already shown that atherosclerosis is generally present in young middle-aged individuals. "With the new study, we have shown how atherosclerosis progresses in its initial phases, before the development of symptoms," emphasized Dr Fuster.

"The key finding of the study is that over a short follow-up of just 3 years, 40% of individuals aged between 40 and 50 years showed major progression of atherosclerosis in distinct locations, including the carotid, femoral, and coronary arteries," emphasized Dr López-Melgar. "This rapid disease progression could make these individuals more vulnerable to developing symptoms or having clinical events such as a heart attack or stroke."
The researchers conclude that the findings, while they await validation from the occurrence of events in the PESA cohort in the future, will be of great value for the identification of strategies to stall the epidemic of cardiovascular disease.

Scientists are hopeful that a new drug -- called EIDD-2801 -- could change the way doctors treat COVID-19. The drug shows promise in reducing lung damage, has finished testing in mice and will soon move to human clinical trials.

As of April 3, the novel coronavirus SARS-CoV-2 had infected more than 1 million people with COVID-19 and caused more than 58,000 deaths in a worldwide pandemic. Currently, no antiviral drugs have been approved to treat SARS-CoV-2 or any of the other coronaviruses that cause human disease.

Researchers at the UNC-Chapel Hill Gillings School of Global Public Health are playing a key role in the development and testing of EIDD-2801. Virologists in the lab of William R. Kenan Jr. Distinguished Professor of epidemiology Ralph Baric, are working with colleagues in the lab of Mark Denison, Edward Claiborne Stahlman Professor of pediatrics at Vanderbilt University Medical Center (VUMC), and with George Painter, chief executive officer of the nonprofit DRIVE (Drug Innovation Ventures at Emory) and director of the Emory Institute for Drug Development (EIDD), where EIDD-2801 was discovered.

The results of the team's most recent study were published online April 6 by the journal Science Translational Medicine. The paper includes data from cultured human lung cells infected with SARS-CoV-2, as well as mice infected with the related coronaviruses SARS-CoV and MERS-CoV.

The study found that, when used as a prophylactic, EIDD-2801 can prevent severe lung injury in infected mice. EIDD-2801 is an orally available form of the antiviral compound EIDD-1931; it can be taken as a pill and can be properly absorbed to travel to the lungs.

When given as a treatment 12 or 24 hours after infection has begun, EIDD-2801 can reduce the degree of lung damage and weight loss in mice. This window of opportunity is expected to be longer in humans, because the period between coronavirus disease onset and death is generally extended in humans compared to mice.

"This new drug not only has high potential for treating COVID-19 patients, but also appears effective for the treatment of other serious coronavirus infections," said senior author Baric.

Compared with other potential COVID-19 treatments that must be administered intravenously, EIDD-2801 can be delivered by mouth as a pill. In addition to ease of treatment, this offers a potential advantage for treating less-ill patients or for prophylaxis -- for example, in a nursing home where many people have been exposed but are not yet sick.

"We are amazed at the ability of EIDD-1931 and -2801 to inhibit all tested coronaviruses and the potential for oral treatment of COVID-19. This work shows the importance of ongoing National Institutes of Health (NIH) support for collaborative research to develop antivirals for all pandemic viruses, not just coronaviruses" said Andrea Pruijssers, the lead antiviral scientist in the Denison Lab at VUMC.

Denison was senior author of a December 2019 study that first reported that EIDD-1931 blocked the replication of a broad spectrum of coronaviruses.

These interinstitutional collaborators, supported by an NIH grant through the University of Alabama at Birmingham, also performed the preclinical development of remdesivir, another antiviral drug currently in clinical trials of patients with COVID-19. In the new Science Translational Medicine paper, Maria Agostini, a postdoctoral fellow in the Denison lab, demonstrated that viruses that show resistance to remdesivir experience higher inhibition from EIDD-1931.

"Viruses that carry remdesivir resistance mutations are actually more susceptible to EIDD-1931 and vice versa, suggesting that the two drugs could be combined for greater efficacy and to prevent the emergence of resistance," said Painter.

Clinical studies of EIDD-2801 in humans are expected to begin later this spring. If they are successful, the drug could not only be used to limit the spread of SARS-CoV-2, but also could control future outbreaks of other emerging coronaviruses.

"With three novel human coronaviruses emerging in the past 20 years, it is likely that we will continue to see more," said first author Timothy Sheahan, a Gillings assistant professor of epidemiology and a collaborator in the Baric Lab. "EIDD-2801 holds promise to not only treat COVID-19 patients today, but to treat new coronaviruses that may emerge in the future."

Apes in U.S. zoos host bacterial communities in their intestinal tracts that are more similar to those of people who eat a non-Western diet than to the gut makeup of their wild ape cousins, according to a new study from Washington University in St. Louis. Further, even wild apes that have never encountered antibiotics harbor microbes with antibiotic resistance genes.

The findings suggest that contact with people shapes the gut microbial communities, or microbiomes, of gorillas and chimpanzees, and that the gut microbiomes of wild apes provide clues to human-ape interactions that could inform efforts to protect the endangered species. The study also highlights a way to identify new antibiotic resistance genes before they become widely established in bacteria in people, giving researchers time to develop tools to counter such genes before they threaten human health.

The study is available online in The ISME Journal.

The gut microbiome supplies us with vitamins, helps digest food, regulates inflammation and keeps disease-causing microbes in check. Antibiotics can change the makeup of the gut microbiome in lasting ways.

"It's difficult to figure out exactly how antibiotics affect the human gut microbiome when almost everyone is born with bugs that already have antibiotic resistance genes," said senior author Gautam Dantas, PhD, a professor of pathology and immunology, of molecular microbiology, and of biomedical engineering at Washington University School of Medicine. "Wild apes are the closest thing we have to pre-antibiotics humans. Luckily, we got the opportunity to work with two highly respected primatologists."

Co-authors Crickette Sanz, PhD, an associate professor of biological anthropology in Arts & Sciences at Washington University, and David Morgan, PhD, a research fellow at the Lester E. Fisher Center for the Study and Conservation of Apes at Lincoln Park Zoo in Chicago and an honorary research scientist at Washington University, study wild chimpanzees and gorillas in a remote area of Nouabalé-Ndoki National Park in the Republic of Congo. The park is managed by the Wildlife Conservation Society and the Congolese government. To learn about the apes' gut microbiomes, Sanz, Morgan and their field teams followed apes in known groups and discreetly collected fecal samples from 18 wild chimpanzees and 28 wild gorillas. The noninvasive sampling method allowed the researchers to collect data on the apes without disturbing them.

The samples were stored in liquid nitrogen, carried to the park headquarters, and transported by dugout canoe down the Sangha River and then by truck to Brazzaville, the capital of the Republic of Congo, where they were held in a freezer until they could be shipped to Dantas' lab. The researchers also collected and shipped fecal samples from 81 people who lived on the outskirts of the park.

Meanwhile, Dantas and first author Tayte Campbell, PhD - then a graduate student in Dantas' lab - arranged to obtain fecal samples from 18 chimpanzees and 15 gorillas living at either the Saint Louis Zoo or the Lincoln Park Zoo. The researchers identified the kinds of bacteria and the antibiotic genes present in the gorilla, chimpanzee and human samples, and compared the results to publicly available data on people who live in the U.S., Peru, El Salvador, Malawi, Tanzania, or Venezuela and follow hunter-gatherer, rural agriculturalist, or urban lifestyles.

The gut microbiomes of people whose data was included in the study fell into two groups. In one were hunter-gatherers and rural agriculturalists who typically eat a diet heavy in vegetables and light in meat and fat; this group included the people from the outskirts of the national park in the Republic of Congo. In the second group were urban people who eat a meat-rich Western diet. Wild gorillas and chimpanzees formed a third group distinct from both human groups. But captive apes fell into the first group; they were most similar to people who ate non-Western diets.

"Chimpanzees are endangered, and Western lowland gorillas are critically endangered; their main threats are habitat destruction, poaching and disease," Sanz said. "Measuring the gut microbiome could be a way to monitor apes' exposure to anthropogenic threats so we can identify areas of concern and develop effective, evidence-based mitigation strategies."

The researchers also identified several previously unknown antibiotic resistance genes in the wild apes and people from the Republic of Congo, including one that confers resistance to colistin, an antibiotic of last resort. For now, the genes reside in bacteria harmless to humans. But bacteria have the ability to share genes, so any antibiotic resistance gene could find its way into a more dangerous species of bacteria.

"Rare sampling opportunities of wild apes like in this study gives us a look into the future," Campbell said. "When we find these novel antibiotic resistance genes in the environment, we can study them and possibly find ways to inhibit them before they show up in human pathogens and make infections very difficult to treat."

"It would be very interesting to expand this research across a broader range of conservation contexts, such as commercial logging zones and tourist operations," Morgan added. "With the arrival of human activities and associated anthropogenic disturbances, wild apes may be exposed to antibiotic resistance genes. We don't know much about how antibiotic resistance spreads through natural environments, so that could have implications for human public health that we don't yet understand. That's something we'd like to investigate."

A targeted therapy, currently being studied for treatment of certain cancers including glioblastoma, may also be beneficial in treating other neurologic diseases, a study at the University of Cincinnati shows.

The study, being published online April 6 in the journal EBioMedicine, revealed that the effects of a therapy delivery system using microscopic components of a cell (nanovesicles) called SapC-DOPS may be able to provide targeted treatment without harming healthy cells. This method could even prove to be successful in treating other neurologic conditions, like Parkinson's disease.

This study is led by Xiaoyang Qi, professor in the Division of Hematology Oncology, UC Department of Internal Medicine, and Ying Sun, research professor in the UC Department of Pediatrics and a member of the Division of Human Genetics at Cincinnati Children's Hospital Medical Center.

One neurological challenge that may benefit from the therapy, Gaucher disease, is "a serious and rare genetic condition in which a type of lipid accumulates in cells and certain organs. The disorder can cause bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, as well as poor coordination, seizures and cognitive problems in some patients; it is caused by a hereditary deficiency of a certain enzyme," says Qi, who is a corresponding author on the study. "Patients need enzyme replacement therapy to treat this condition, but a major limitation of FDA-approved enzyme replacement therapy is failure to cross the blood-brain barrier in the body. Therefore, the treatments available are only effective for patients who have Gaucher's affecting their internal organs, like their livers and spleens, but not their brain or nervous system.

"[Certain] nanovesicles have the ability to cross the blood-brain barrier and selectively target brain tissue, providing a biological vehicle for delivering the enzyme replacement therapy."

In the early 2000s, Qi developed SapC-DOPS, a combination of a cell protein, SapC, and a phospholipid, DOPS, that assembled into tiny cavities can selectively target cells and deliver therapies while sparing all other unaffected cells and tissues. In the past, he has studied that nanovesicle in cancer animal models looking at brain, lung, skin, prostate, blood, breast and pancreatic cancers. Results were promising, and now the human version of this nanovesicle is now being studied in clinical trials for treatment of glioblastoma.

This study shows its penetration into the brain is through a specific receptor and the lymphatic circulation system, which helps rid the body of toxins and waste.

"In this study, we showed that the nanovesicle was able to deliver the enzyme to the necessary tissues in animal models, especially the brain," Sun says. "This novel therapeutic approach corrects the deficiency of the enzyme in central nervous system cells and tissues and is efficient in reducing inflammation and neurological issues in animal models with [some types of] Gaucher disease."

"Our study presents a new targeted use for our nanovesicle and provides a new strategy for treating this type of Gaucher disease," Qi adds. "This is the tip of the iceberg when thinking about applications and it could mean promising treatments for other neurologic conditions.

"Although this study was focused on a rare disease, there may be implications for similar but vastly more common conditions such as Parkinson's disease where decreased activity of the same enzyme have been documented in the patients' brains. Without improvements in treatment, this type of Gaucher disease will remain lethal. This has the potential to improve patient care."

What The Study Did: What combination of healthy lifestyle factors were associated with the most years lived without chronic diseases was the focus of this analysis that included data from more than 100,000 adults who were participants in 12 European studies. Participants' levels of smoking, weight, physical activity and alcohol consumption were compared with the number of years from age 40 to 75 that they were without chronic disease, including type 2 diabetes, coronary heart disease, stroke, cancer, asthma and chronic obstructive pulmonary disease.

Authors: Solja T. Nyberg, Ph.D., of the University of Helsinki, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.0618)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: About 2,400 students in the 12th grade were surveyed about the frequency and mode of use (smoking, vaping and edibles) of marijuana from 2015 to 2018.

Authors: Megan E. Patrick, Ph.D., of the University of Minnesota in Minneapolis, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2020.0175)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

DURHAM, N.C. - Using a bedroom air filter that traps fine particles of pollution with diameters smaller than 2.5 micrometers can significantly improve breathing in asthmatic children, a new study by American and Chinese scientists shows.

It's the first study to document that physiological improvements occur in the childrens' airways when air filters are in use, and it suggests that with consistent use, the filters may help prevent, not just alleviate, asthmatic flare-ups.

While using the filters daily for two weeks, children in the study experienced decreased airway resistance and lung inflammation and increased airway elasticity, among other benefits.

"Pharmaceutical companies have spent large amounts to develop drugs that can work on lower airways, but they are very expensive. Our results show that using an air purifier to reduce the exposure of lower airways to pollutants could help asthmatic children breathe easier without those costly drugs," said Junfeng Zhang, professor of global and environmental health at Duke University's Nicholas School of the Environment.

"This warrants a clinical trial to confirm findings," he said. Zhang and his colleagues published their paper April 6 in JAMA Pediatrics, a journal of the American Medical Association.

Fine particulate matter (PM2.5) is a ubiquitous air pollutant originating from fossil fuel emissions, wildfires and other biomass burning, industrial sources, and gasoline- and diesel-powered vehicles. Thirty times smaller in diameter than a human hair, the particles are easily inhaled and can penetrate deep into the small, or lower, airways where they can trigger or exacerbate asthma symptoms. Inhalers don't help, since they are only designed to open upper airways.

The researchers conducted the double-blind crossover study in a Shanghai suburb during a period of moderately high PM2.5 pollution in 2017. They gave 43 children with mild to moderate asthma two air filters to use in their bedrooms. One was a high-efficiency particulate air (HEPA) filter capable of removing PM2.5; the other was a sham filter. Each filter was used for two weeks in random order with a two-week interval in between. Neither the children nor their families knew which filter was which.

Results showed that PM2.5 concentrations inside the children's bedrooms were a third to two-thirds lower when the real air filters were in use than when the sham ones were being used, said Michael H. Bergin, professor of civil and environmental engineering at Duke's Pratt School of Engineering.

This drop coincided with significant improvements in how easily air flowed in and out of the children's small airways and lungs, Bergin said. These improvements included a 24% average reduction in total airway resistance, a 43.5% average reduction in small airway resistance, a 73.1% average increase in airway elasticity, and a 27.6% average reduction in exhaled nitric oxide, a biomarker of lung inflammation.

Although the benefits lasted only as long as the real air filters were in use, "it's probable that if children use the filters on an ongoing daily basis they will see continued benefits," Zhang said.

If clinical trials confirm the new study's findings, the filters could serve as a practical preventive measure for asthma management in polluted outdoor or indoor environments worldwide, he said.

They could also be lifesavers in areas near wildfires.

"Look at the high PM2.5 pollution levels that occurred in San Francisco last year as a result of smoke from the California wildfires, and at the air-quality problems happening this year from the bushfires in Australia," he said. "People should really consider using one of these devices during wildfires."

With the goal of ensuring that single-cell RNA sequencing, a current focus of intense research, makes use of the best possible methods, an international group has benchmarked 13 different methods. The group, led by Holger Heyn of the Centro Nacional de Análisis Genómico (CNAG-CRG) in Spain, found that the Quartz-seq2 method, developed by a team in the RIKEN Center for Biosystems Dynamics Research, was overall the best method developed to sequence single-cell RNA. The research was published in Nature Biotechnology.

The group began the project based on the concern that in the past, lack of benchmarking on methods used for genomic analysis has given rise to problems later in the process, as different groups were using different methods that had varying standards and came up with different results. With this in mind, a number of groups working on the analysis of single cell RNA came together to evaluate different methods to ensure that there is good reproducibility.

Single-cell DNA sequencing is seen as the next major project in genomic research. Initially, genomic research, exemplified by the Human Genome Project, sought to determine the DNA sequence that is found in all the cells in any organism. But what makes things complicated is that although the cells in an organism share the same DNA code, in fact the cells are all phenotypically different because different genes are expressed or not expressed based on epigenetic factors. There are enormous differences in the expression of genetic regions known as promoters and enhancers, which do not code proteins directly but act on other genetic regions. Understanding the genetic makeup of individual cells would make it possible to identify how individual cells differ in conditions such as cancer and how cells change during the development process. Currently, researchers participating in the Human Cell Atlas are working to develop a comprehensive atlas of gene expression in different cell types.

To make the comparison, the group used the 13 methods to analyze a set of approximately 3,000 cells selected to fulfill four conditions: it included a variety of cell types, some of the cells were very similar, with only subtle differences in gene expression, the cells had trackable markers, and they included cells from different species. The cells were mostly human peripheral blood cells and mouse colon cells, but also included a small set of dog cells.

The methods were evaluated based on how precisely they could detect cell profiles and marker expression. The group evaluated the methods using six key metrics: gene detection, overall level of expression in transcriptional signatures, cluster accuracy, classification probability, cluster accuracy after integration, and mixability. These metrics were selected to compare the methods in terms of their accuracy, applicability to various cell types, ability to distinguish between closely related cell types, ability to produce reproducible profiles, ability to detect population markers, compatibility with other methods, and have good predictive value for cell mapping.

As a result, they found that the Quartz-seq2 method, developed by researchers at RIKEN in Japan, was particularly accurate, scoring highest on the benchmark. According to Itoshi Nikaido, leader of the group that developed the method, "We were very happy that our method was selected as overall best, and plan to further improve it so that we can achieve the best results in projects such as the Human Atlas Project."

According to Dr. Heyn, "The protocols showed profound performance differences and we hope that our work contributes to developing standards and guidelines towards the production of high-quality datasets for the Human Cell Atlas and broader single-cell community."

University of Groningen scientists observed the characteristics of a single enzyme inside a nanopore. This revealed that the enzyme can exist in four different folded states, or conformers, that play an active role in the reaction mechanism. These results will have consequences for enzyme engineering and the development of inhibitors. The study was published in Nature Chemistry on 6 April.

Enzymes are folded proteins that have a specific three-dimensional structure that creates an active site that can bind a substrate and catalyse a specific reaction. In recent years, it has become clear that enzymes are not rigid structures but that the folded proteins exist as an ensemble of conformations in equilibrium around an energetically stable ground state.

Wind tunnel

Studying the transition between states requires observing single enzymes for a prolonged period of time, which is challenging. University of Groningen Associate Professor of Chemical Biology Giovanni Maglia developed funnel-shaped nanopores that can trap proteins. By measuring the ionic current across such a nanopore, embedded in an artificial lipid membrane, Maglia was able to observe conformational changes in enzymes. 'You could compare it with studying a car in a wind tunnel,' he explains. 'Opening a window or a door will change the airflow. In a similar way, a change in the folding structure of the enzyme changes the ionic current through the pore.'

Maglia used his nanopore system to study the enzyme dihydrofolate reductase (DHFR), which converts dihydrofolate into tetrahydrofolate. 'We chose this enzyme because it has been studied as a model system for enzyme dynamics for over thirty years, using all available techniques. In addition, inhibitors of this enzyme, such as methotrexate, are used as anti-cancer drugs.

Efficient release

Measurements of DHFR revealed the presence of four different conformers, with different affinities for the substrates. Maglia: 'Switching between these four states was very slow. This means that you can only see them in these kinds of long-lasting single enzyme studies.'

Adding the reaction inhibitor methotrexate, which binds to the enzyme, caused a very rapid transition between states and changed the enzymes' affinity. 'Our conclusion is that the reactions of the enzyme with different compounds provide the free energy for conformational changes,' says Maglia. Furthermore, conformational change also changed the enzymes' affinity. This makes sense, as the enzyme needs to bind two substrates and, after completing the reaction, must release both. 'The substrate and the product are very similar molecules, so the enzyme needs to change its affinity for an efficient release.'

Two states

Based on these studies, Maglia can see the enzyme switching between two states: after binding the substrate, NADPH drives the reaction which then changes the conformation of the enzyme and thereby its affinity. Subsequently, binding a new substrate brings it back to the first state. 'This explains two of the four conformers that we observed; we cannot yet make sense of the other two,' Maglia admits. It is impossible to derive structural information from the measurements.

Nevertheless, the study shows the power of nanopore technology in determining the structural changes of enzymes. 'We also now know that this enzyme has four different ground states and must switch between them to function.' This adds a challenge to enzyme design: not only should this produce a reactive centre, but it should also allow the necessary conformational changes. Maglia: 'This may explain why artificially designed enzymes often do not work as efficiently as natural enzymes.' Finally, the study will also allow scientists to identify new inhibiting drugs that bind tighter to DHFR than methotrexate.

Researchers have made a major breakthrough in developing gene-editing tools to improve our understanding of one of the most important ocean microbes on the planet.

The international project, co-led by scientists at the University of East Anglia (UEA) in the UK, unlocks the potential of the largest untapped genetic resource for the development of natural products such as novel antibacterial, antiviral, anti-parasitic and antifungal compounds.

Ocean microbes regulate global cycles of carbon and essential nutrients such as nitrogen and phosphorous. Despite their significance, government and industry funding is still largely used for research and development with non-marine organisms. This is partly due to a lack of awareness of the importance of marine microbes, limited understanding about their biology, as well as difficulties in accessing and sustainably exploiting them.

Addressing this requires genetic manipulation tools that have not been readily available for many different ecologically and biotechnologically important groups of marine microbes such as protists, which share a subcellular organisation similar to plants and animals.

Unlike plants and animals, they are unicellular and of remarkable diversity. Some represent the origins of complex life forms on land, others such as photosynthetic protists, called phytoplankton, contribute almost as much to global annual carbon fixation as land plants.

Published in the journal Nature Methods, this new study aims to improve understanding of the basic biology and evolution of marine protists, with potentially valuable outcomes for evolutionary studies, nanotechnology, biotechnology, medicine, and pharmacology.

The three-year collaborative project, supported primarily by the Gordon and Betty Moore Foundation, involved 53 international laboratories comprising more than 100 researchers. It has resulted in the development of new genetic model systems, summarised in a synthetic 'Transformation Roadmap'. This outlines DNA delivery methods, gene expression constructs and genome editing approaches, and is available as a resource for the wider research community.

Lead UK author Thomas Mock, professor of marine microbiology at UEA's School of Environmental Sciences, said the study builds on decades of research that have contributed to an increasingly coherent picture of the oceanic ecosystem.

"The oceans harbour the most significant microbial diversity on Earth in terms of maintaining habitability," said Prof Mock. "These organisms and how their genes function are therefore incredibly important to understand because of their vital role in the health of the planet. They also represent how life has evolved over the last 1.5 billion years. They are so old that it's not been possible to fully understand their cell biology and functional biodiversity.

"Our reported breakthroughs on genetic manipulation will allow the research community to dissect cellular mechanisms from a range of important protists, which will collectively provide insights into their reproduction, metabolism and signaling.

"These insights will improve our understanding about their role in the oceans, and they are invaluable for biotechnological applications such as building factories for biofuel or the production of bioactive compounds."

The study involved attempting to introduce foreign DNA into the host genomes of 39 protist species, in order to understand their gene functions and how they adapt to changes. Of these, more than 50% were genetically manipulated successfully, which will now enable researchers to carry out functional studies of thousands of new genes carried in their genomes.

CAMBRIDGE, MA -- Imagine you are meeting a friend for dinner at a new restaurant. You may try dishes you haven't had before, and your surroundings will be completely new to you. However, your brain knows that you have had similar experiences -- perusing a menu, ordering appetizers, and splurging on dessert are all things that you have probably done when dining out.

MIT neuroscientists have now identified populations of cells that encode each of these distinctive segments of an overall experience. These chunks of memory, stored in the hippocampus, are activated whenever a similar type of experience takes place, and are distinct from the neural code that stores detailed memories of a specific location.

The researchers believe that this kind of "event code," which they discovered in a study of mice, may help the brain interpret novel situations and learn new information by using the same cells to represent similar experiences.

"When you encounter something new, there are some really new and notable stimuli, but you already know quite a bit about that particular experience, because it's a similar kind of experience to what you have already had before," says Susumu Tonegawa, a professor of biology and neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at MIT's Picower Institute for Learning and Memory.

Tonegawa is the senior author of the study, which appears today in Nature Neuroscience. Chen Sun, an MIT graduate student, is the lead author of the paper. New York University graduate student Wannan Yang and Picower Institute technical associate Jared Martin are also authors of the paper.

Encoding abstraction

It is well-established that certain cells in the brain's hippocampus are specialized to store memories of specific locations. Research in mice has shown that within the hippocampus, neurons called place cells fire when the animals are in a specific location, or even if they are dreaming about that location.

In the new study, the MIT team wanted to investigate whether the hippocampus also stores representations of more abstract elements of a memory. That is, instead of firing whenever you enter a particular restaurant, such cells might encode "dessert," no matter where you're eating it.

To test this hypothesis, the researchers measured activity in neurons of the CA1 region of the mouse hippocampus as the mice repeatedly ran a four-lap maze. At the end of every fourth lap, the mice were given a reward. As expected, the researchers found place cells that lit up when the mice reached certain points along the track. However, the researchers also found sets of cells that were active during one of the four laps, but not the others. About 30 percent of the neurons in CA1 appeared to be involved in creating this "event code."

"This gave us the initial inkling that besides a code for space, cells in the hippocampus also care about this discrete chunk of experience called lap 1, or this discrete chunk of experience called lap 2, or lap 3, or lap 4," Sun says.

To further explore this idea, the researchers trained mice to run a square maze on day 1 and then a circular maze on day 2, in which they also received a reward after every fourth lap. They found that the place cells changed their activity, reflecting the new environment. However, the same sets of lap-specific cells were activated during each of the four laps, regardless of the shape of the track. The lap-encoding cells' activity also remained consistent when laps were randomly shortened or lengthened.

"Even in the new spatial locations, cells still maintain their coding for the lap number, suggesting that cells that were coding for a square lap 1 have now been transferred to code for a circular lap 1," Sun says.

The researchers also showed that if they used optogenetics to inhibit sensory input from a part of the brain called the medial entorhinal cortex (MEC), lap-encoding did not occur. They are now investigating what kind of input the MEC region provides to help the hippocampus create memories consisting of chunks of an experience.

Two distinct codes

These findings suggest that, indeed, every time you eat dinner, similar memory cells are activated, no matter where or what you're eating. The researchers theorize that the hippocampus contains "two mutually and independently manipulatable codes," Sun says. One encodes continuous changes in location, time, and sensory input, while the other organizes an overall experience into smaller chunks that fit into known categories such as appetizer and dessert.

"We believe that both types of hippocampal codes are useful, and both are important," Tonegawa says. "If we want to remember all the details of what happened in a specific experience, moment-to-moment changes that occurred, then the continuous monitoring is effective. But on the other hand, when we have a longer experience, if you put it into chunks, and remember the abstract order of the abstract chunks, that's more effective than monitoring this long process of continuous changes."

Tonegawa and Sun believe that networks of cells that encode chunks of experiences may also be useful for a type of learning called transfer learning, which allows you to apply knowledge you already have to help you interpret new experiences or learn new things. Tonegawa's lab is now working on trying to find cell populations that might encode these specific pieces of knowledge.

A Japanese research team has successfully developed a system to predict the severity of Alport syndrome, a serious hereditary kidney disease that occurs in about 1 out of 5,000 people in the US. Patients with Alport syndrome have abnormalities in the causative protein, type IV collagen, that often lead to chronic renal dysfunction requiring dialysis. Without a kidney transplant, this can eventually lead to kidney failure and death.

Estimating the severity of the disease has been difficult but researchers from Kumamoto University, in collaboration with Kobe University researchers, recently demonstrated that severity prediction can be made by analyzing a person's type IV collagen genotype. The researchers discovered this after studying the behavior of several genetic mutations using a proprietary type IV collagen trimer evaluation system that can predict the severity of nephropathy in Alport syndrome patients. They expect their development will contribute to the advancement of precision medicine for hereditary intractable diseases.

Type IV collagen forms a complex of three polypeptide chains (a trimer of fibrous proteins). Mutations in any of the chain genes cause abnormalities in the polypeptide chains, resulting in renal dysfunction. Several hundred mutations of type IV collagen have been reported so far and the severity of the disease varies depending on the mutation. Identification of these mutations is important to predict the severity of renal pathology.

This study uses a system (Split NanoLuc®) developed by Professor Hirofumi Kai of Kumamoto University that is highly sensitive to abnormalities of type IV collagen trimers. Prof. Kai's group evaluated the intracellular trimer formation and extracellular trimer secretion of nine (four severe, four mild, one non-pathogenic) type IV collagen gene mutants. Severe mutations significantly reduced the formation and secretion of collagen IV trimers. Additionally, most of the mild mutations produced only a slight reduction of the extracellular secretory trimer. This shows that nephropathy severity is mostly determined by the ability of type IV collagen trimers to form intracellularly and secrete extracellularly. Furthermore, the non-pathogenic mutant collagen did not show any changes in trimer behavior.

These results demonstrate that it is possible to distinguish between pathogenic and non-pathogenic mutations with the Split NanoLuc® evaluation system. This can provide important data for estimating the pathological severity and identification of pathogenic mutations. In particular, it allows for the construction of a system to predict the severity of nephropathy using only the gene mutation information in Alport syndrome patients.

"The remarkable progress of genome analysis technology in recent years has enabled comprehensive analysis of disease-related genes. The momentum of precision medicine based on genetic information is increasing for various diseases," said Associate Professor Tsuyoshi Shuto, who co-authored this study. "In the field of hereditary kidney disease, large-scale genetic analysis has become widespread. Accurate diagnoses and new disease classifications through identification of causative gene mutations are being diligently conducted. We expect that this research will greatly advance the field of precision medicine for various hereditary diseases as well as Alport syndrome."