Culture

There's chaos in the night sky, about 60 to 600 miles above Earth's surface. Called the ionosphere, this layer of Earth's atmosphere is blasted by solar radiation that breaks down the bonds of ions. Free electrons and heavy ions are left behind, constantly colliding.

This dance was previously measured through a method called incoherent scatter radar in the northern hemisphere, where researchers beam radio wave into the ionosphere. The electrons in the atmosphere scatter the radio wave "incoherently". The different ways they scatter tell researchers about the particles populating the layer.

Now, researchers have used radar in Antarctica to make the first measurements from the Antarctic region. They published their preliminary results on September 17, 2019 in the Journal of Atmospheric and Oceanic Technology.

"Incoherent scatter radar is currently the most powerful tool available to investigate the ionosphere because it covers a wide altitudinal range and it observes essential ionospheric parameters such as electron density, ion velocity, ion and electron temperatures, as well as ion compositions," said Taishi Hashimoto, assistant professor at the National Institute of Polar Research in Japan. While these radars are powerful, they're also rare due to their size and power demand.

Using the Program of the Antarctic Syowa Mesosphere-Stratosphere-Troposphere/Incoherent Scatter (PANSY) radar, the largest and fine-resolution atmospheric radar in the Antarctic, researchers performed the first incoherent scatter radar observations in the southern hemisphere in 2015. They also made the first 24-hour observation in 2017. While analyzing these observations, Hashimoto and the team expected to see significant differences between the southern measurements and the northern measurements, as Earth's lower atmosphere has a strong asymmetry between hemispheres.

"Clearly, observations in the southern hemisphere are crucial to revealing global features of both the atmosphere and the ionosphere," Hashimoto said.

It's not as simple as taking the measurements, however. Consider the radar as a pebble skipped across a pond's surface. The researchers want to learn how the pebble vertically displaces the water as it skips and eventually sinks. They aren't interested in the concentric ripples created at each skip, but they're so similar that it's difficult to discern which measurements are the ones needed.

These ripples are known as field-aligned irregularities, and Hashimoto's team applied a computer program that can recognize the different signals and suppresses the irregularities that could obscure the data.

"Our next step will be the simultaneous observation of ionosphere incoherent scatter and field-aligned irregularities, since the suppression and extraction are using the same principle from different aspects," Hashimoto said. "We are also planning to apply the same technique to obtain other types of plasma parameters, such as the drive velocity and ion temperature, leading to a better understanding of auroras."

A dentist's drill might not be the best way to tackle tooth decay in children's teeth, a new study has concluded.

Findings from a major dental trial suggest that preventing tooth decay from occurring in the first place is the most effective way for parents to help avoid pain and infection from decay in their children's teeth.

A three-year study comparing three different treatment options for tooth decay in children's teeth, led by dentists from the Universities of Dundee, Newcastle, Sheffield, Cardiff, Queen Mary University of London and Leeds, has found no evidence to suggest that conventional fillings are more effective than sealing decay into teeth, or using prevention techniques alone, in stopping pain and infection from tooth decay in primary teeth.

The FiCTION trial, the largest of its kind to date, also found that 450 children who took part in the study experienced tooth decay and pain, regardless of which kind of dental treatment they received.

Professor Nicola Innes, Chair of Paediatric Dentistry at the University of Dundee and lead author on the paper published today, said, "Our study shows that each way of treating decay worked to a similar level but that children who get tooth decay at a young age have a high chance of experiencing toothache and abscesses regardless of the way the dentist manages the decay.

"What is absolutely clear from our trial is that the best way to manage tooth decay is not by drilling it out or sealing it in - it's by preventing it in the first place."

During the study, more than 1,140 children between the ages of three and seven with visible tooth decay were recruited by dentists working in one of 72 dental clinics throughout the country. One of three treatment approaches was then chosen randomly for each child's dental care for the duration of the trial, which was up to three years.

The first approach avoided placing any fillings and aimed to prevent new decay by reducing sugar intake, ensuring twice-daily brushing with fluoridated toothpaste, application of fluoride varnish and placing of fissure sealants on the first permanent molar (back) teeth.

The second option involved drilling out tooth decay, which was based upon what has been considered the standard "drill and fill" practice for more than 50 years together with preventive treatments. The third treatment strategy was a minimally invasive approach where tooth decay was sealed in under a metal crown or a filling to stop it progressing together with preventive treatments.

The main trial findings, published in the Journal of Dental Research found no evidence to suggest that any of the treatment strategies were better than another in terms of making a difference in children's experience of pain or infection, quality of life or dental anxiety between groups.

All three different ways of treating decay were acceptable to children, parents and dental professionals.

Sealing-in with preventive treatment was most likely to be considered the best way of managing children's decay if society are willing to pay a minimum of £130 to avoid an episode of pain or infection.

Professor Anne Maguire, Chair of Preventive Dentistry at Newcastle University and one of the co-chief investigators said, "The FiCTION findings have focused attention again on the need to prevent dental decay before it begins but also provided some reassurance that if decay does develop in a child's mouth, there are a number of treatment options available which can be tailored to the clinical and behavioural needs of an individual child."

Professor Gail Douglas, Chair of Dental Public Health at the University of Leeds and one of the chief investigators, said, "All of the children in our study were chosen to take part because they already had tooth decay and unfortunately even with lots of care and attention from the dentist once children have decay, there's quite a chance that it will cause further problems.

"The good news however is that tooth decay can be prevented. Brushing your teeth with fluoride toothpaste, especially last thing before bedtime, avoiding sugary drinks and snacks between meals and seeing a dentist regularly are all small habits that can help boost the overall health of your teeth."

Scotland's Chief Dental Officer, Tom Ferris, said, "FiCTION highlights the importance of preventing tooth decay in our youngest children. I believe the key to success in prevention lies within families and communities; for this reason Scottish Government launched the Oral Health Community Challenge Fund for Third Sector organisations working alongside families living in our most disadvantaged areas. The activities from these projects complement our mainstream Childsmile work in education and health settings."

New UBC research suggests restoring habitat may not be enough to save threatened woodland caribou--an iconic animal that's a major part of boreal forests in North America and a key part of the culture and economy of many Indigenous peoples in Canada.

Caribou populations have declined rapidly in recent decades across much of western Canada, including the oil sands region of northeastern Alberta. The researchers placed hidden cameras, known as "camera traps", in the area to see if replanting seismic lines has helped protect caribou by separating them from predators and fellow prey moving through the area.

Seismic lines, which are narrow strips of land cleared to make way for oil and gas exploration, are thought to disturb caribou habitat and promote faster travel for predators and food competitors. These lines do not recover quickly naturally, but are now being restored through replanting with native trees and natural features like mounds and tree debris.

"In theory, restoration should have made it much more difficult for predators to travel across the caribou range, but our cameras showed us a different picture," said lead author Erin Tattersall, who did the work as a master's student in forest sciences at UBC.

Predators like black bears and wolves, and prey like moose, used the restored seismic lines about as much as they used unrestored lines. Only white-tailed deer--a key caribou competitor --showed less use of the restored lines. Caribou preferred to use lines located in low-lying wetland areas, as well as more isolated lines--whether they'd been restored or not.

"In other words, restoration did not do much to keep caribou apart from their predators and competitors, at least not in the short term," Tattersall said.

The work, published last week in Biological Conservation, is one of the first to challenge the assumed impacts of a caribou recovery strategy, and researchers say it makes the case for more rigorous analysis of conservation methods.

"It's possible caribou will eventually recover in the area we studied, and other restoration approaches in other regions could also prove more immediately effective for caribou recovery," said senior author Cole Burton, a professor of forestry who leads the Wildlife Coexistence Lab at UBC. "But our results clearly show that we can't simply assume the best--it's necessary to closely monitor the actual results of restoration."

And while the study focuses on Alberta caribou, it can also be important for discussions on saving B.C. caribou, Burton added.

"We are seeing steep declines in many of B.C.'s caribou populations, and even total losses of some," he said. "Effective restoration of already degraded habitats will ultimately be critical to recovering our caribou."

In a recent study using mice, lab-grown human retinal cells and patient samples, Johns Hopkins Medicine scientists say they found evidence of a new pathway that may contribute to degeneration of the light sensitive tissue at the back of the eye. The findings, they conclude, bring scientists a step closer to developing new drugs for a central vision-destroying complication of diabetes that affects an estimated 750,000 Americans.

The Johns Hopkins research team focused on diabetic macular edema, a form of swelling and inflammation that occurs in people with diabetes when blood vessels in the eye leak their fluids into the portion of the retina that controls detailed vision.

Current therapies for this disease block the protein VEGF, which contributes to abnormal blood vessel growth. However, because the treatment is not adequate for more than half of patients with diabetic macular edema, investigators have long suspected that more factors drive vision loss in these patients.

In the new study, the Johns Hopkins researchers say they found compelling evidence that angiopoietin-like 4 is at play in macular edema. The signaling protein is already well known to be a blood vessel growth factor with roles in heart disease, cancer and metabolic diseases, of which diabetes is one.

A report on the findings was published Sept. 23 in The Journal of Clinical Investigation.

Akrit Sodhi, M.D., Ph.D., associate professor of ophthalmology at the Johns Hopkins University School of Medicine and the Johns Hopkins Wilmer Eye Institute, in collaboration with Silvia Montaner, Ph.D., M.P.H., at the University of Maryland, led the research team and was intrigued by angiopoietin-like 4 after finding, in previous studies, elevated levels of this protein in the eyes of people with a variety of vision-related diseases.

In the new study, Sodhi and his team found that angiopoietin-like 4 acts both independent of, and synergistically with, VEGF activity, and they identified a potential way to block it.

The investigators made their discoveries by exposing human blood vessel tissue cells grown in the lab to low levels of VEGF and angiopoietin-like 4. Knowing that low levels of these factors individually did not generally create an effect, the researchers were surprised to find that in combination, low-level VEGF and low-level angiopoeitin-like 4 had a synergistic effect on vascular cell permeability, and doubled the leakage from retinal vessels in mice.

"This told us that you can have subthreshold levels of both molecules, where neither alone is enough to do anything, but together, produce a huge effect," says Sodhi.

The amplifying effect led the researchers to believe that VEGF and angiopoietin-like 4 might share a protein receptor within vascular cells.

However, similar experiments revealed that angiopoietin-like 4 also increases blood vessel formation independently of VEGF. "This could explain why some patients continue to experience vision loss despite treatment with current anti-VEGF therapies," says Sodhi.

To test this, the team looked to see whether the angiopoietin-like 4 protein bound to one of VEGF's receptors in lab-grown human vascular cells. They found that angiopoietin-like 4 did not bind to the classic VEGF receptor that is a target of current anti-VEGF medicines, but another less studied one called neuropilin.

With the newly identified receptor, the researchers next sought to learn whether a lab-grown version of the receptor could block angiopoietin-like 4 before it was able to interact with blood vessel cells.

To do that, they injected a soluble fragment of the neuropilin receptor into the eyes of mice pharmacologically treated to mimic human diabetes, resulting in a twofold increase in retinal vascular leakage. The treated diabetic mice showed approximately half of the blood vessel leakage as mice who did not receive the treatment, similar to the nondiabetic mice.

To further explore the new receptor-based treatment's potential value for human patients, the researchers grew human blood vessel cells in the lab in fluid samples collected from the eyes of patients with diabetic macular edema, to replicate the conditions and growth factors found naturally inside of the patients' eyes.

One group of such cells was exposed to the soluble receptor neuropilin. The researchers say they observed a marked decrease in the diabetic macular edema cells treated with the receptor compared to untreated cells.

"This gives us some confidence that this approach will work in human eyes as well," says Sodhi, although he cautions that clinical use of a treatment based on their findings will require many more years of research.

Next, the researchers hope to take a look at the molecular interactions between angiopoietin-like 4 and the neuropilin receptor. Doing so, says Sodhi, will allow them to create a refined match that can bind up as much vision-threatening angiopoietin-like 4 in the eye as possible.

Sodhi also hopes the team's discovery will have value in treating cancer and cardiovascular disease, the courses of which also are influenced by uncontrolled blood vessel growth.

A recent study authored by professors at two California State University campuses, including San Francisco State University, found that students' tolerance for cheating has a high probability of bleeding over into their careers later on. That's concerning to San Francisco State Professor and Chair of Marketing Foo Nin Ho, a co-author of the study. "If [students] have this attitude while they're in school -- that it's OK to cheat in school -- that attitude unfortunately will carry over to the corporate boardroom," he said.

The study tackles two questions: If students tolerate cheating in the classroom, will they also tolerate unethical behavior in their careers? And what's shaping these attitudes? Part of the researchers' intention behind the study was to give educators insight into what's happening in their classrooms so they can challenge and possibly change student beliefs about cheating.

The fear is that these lax attitudes, if left unchecked, could manifest later as turning a blind eye to unethical business behavior or participating in a cover-up, says the study's lead author, California State University San Marcos Professor of Marketing and Chair of Management Glen Brodowsky.

To conduct the study, the authors surveyed nearly 250 undergraduate marketing students from Cal State San Marcos and SF State. Students were asked to respond to statements about cheating and ethics such as "It's cheating to ask another student what was on the test" and "Within a business firm, the ends justify the means." They were asked to choose a response along a scale that ranged from strongly agree to strongly disagree.

The survey found that students who were more tolerant of cheating in a classroom also demonstrated an openness to unethical behavior on the job. The authors then went a step further and pinned down the underlying forces influencing these attitudes.

Ho and his collaborators modeled their study on older ones about cheating and ethical behavior. One previous study about ethical decision-making identified two traits, individualism and collectivism, as the biggest cultural factors in determining how people resolve conflicts in a way that's mutually beneficial. So they decided to measure whether being an individualist or a collectivist led students to be more or less tolerant of cheating.

The results revealed that group-oriented students, or collectivists, had a more laissez-faire attitude toward cheating than their more individualistic classmates. Collectivists want to maintain group cohesion, so they're more likely to be OK with unethical behaviors, Brodowsky says. "To save face they might count on cheating to make sure they all do well. They also won't rat each other out because that will make people look bad."

Brodowsky gave an example of how this could play out in a class: Some students face enormous pressure from their families to succeed in college, so those students may engage in cheating to avoid the shame of flunking out.

But Ho and Browdosky are quick to point out that just being from a collectivist or individualistic culture doesn't define who a student is. "Just because a student is part of one culture doesn't mean they'll be more tolerant of cheating," Ho added. Their survey measured individual attitudes shaped in part by culture -- an important distinction, they say.

Understanding the cultural forces at work could help professors develop culturally sensitive ways to minimize these unethical behaviors in their classrooms.

"As professors, we need to set the tone and say, 'This is what's not rewarded in the classroom' and train students that following ethical behavior leads to better outcomes," Brodowsky said. "So when they graduate and work for companies they will better equipped to evaluate that situation."

Robotic vehicles like Amazon delivery drones or Mars rovers can be hacked more easily than people may think, new research from the University of British Columbia suggests.

The researchers, based at UBC's faculty of applied science, designed three types of stealth attack on robotic vehicles that caused the machines to crash, miss their targets or complete their missions much later than scheduled.

The attacks required little to no human intervention to succeed on both real and simulated drones and rovers.

"We saw major weaknesses in robotic vehicle software that could allow attackers to easily disrupt the behaviour of many different kinds of these machines," said Karthik Pattabiraman, the electrical and computer engineering professor who supervised the study. "Especially worrisome is the fact that none of these attacks could be detected by the most commonly used detection techniques."

Robotic vehicles use special algorithms to stay on track while in motion, as well as to flag unusual behaviour that could signal an attack. But some degree of deviation from the travel plan is typically allowed to account for external factors like friction and wind -- and it's these deviations that attackers can exploit to throw the vehicles off course.

The UBC team developed an automated process that enables an attacker to quickly learn the allowed deviations of robotic vehicles running conventional protection systems. Hackers can then use the information to launch a series of automated attacks that the vehicle cannot detect until it's too late.

"Robotic vehicles are already playing an important role in surveillance, warehouse management and other contexts, and their use will only become more widespread in the future," says Pritam Dash, an electrical and computer engineering graduate student at UBC and the study's lead author. "We need safety measures to prevent rogue drones and rovers from causing serious economic, property and even bodily harm."

The researchers offer the basis for a few such countermeasures -- including self-adjusting deviation thresholds -- in a recent paper describing their findings. They will present their work at the Annual Computer Security Applications Conference in San Juan, Puerto Rico, next month.

Tsukuba, Japan - Embryonic stem cells have the potential to differentiate into any type of cell in the human body. Once differentiated though, the newly minted somatic cells live out the rest of their days as that specific cell type and never again have the capacity to differentiate. Or so the theory goes.

In a study published last week in Cell Reports, a team led by researchers from the University of Tsukuba describes how a newly discovered protein may help unlock the potential of somatic cells, allowing them to become pluripotent.

For several decades now, researchers have realized the enormous potential of being able to take any cell from the human body and reprogram it so that it displays the properties of an embryonic stem cell. Theoretically this isn't so farfetched--after all, almost all of our cells contain the same genetic blueprint, it's just how that blueprint is interpreted that allows some cells to form the heart while others produce the spinal cord. A key to this process is epigenetic changes, which are modifications that determine which part of the blueprint is interpreted, namely by turning genes on or off. Researchers have so far found several different ways to generate these induced pluripotent stem cells (iPSCs), but most hinge on the expression of four proteins called OCT4, SOX2, KLF4, and c-MYC. Production progresses through distinct phases of reprogramming associated with specific epigenetic changes.

"One of the most important steps in the reprogramming process is the silencing of retroviruses in the human genome, which, among other things, have a habit of inducing tumor formation," explains lead author of the study Phuong Linh Bui. "Retroviral silencing is essential for the production of high quality iPSCs because it shows the cells are undergoing proper epigenetic changes, but exactly when this occurs during reprogramming and what controls the silencing is somewhat of a mystery."

To better understand retroviral silencing, the researchers used a Sendai virus-based system that enabled expression of the four reprogramming proteins within the host cell cytoplasm and generated partially reprogrammed iPSCs, allowing the researchers to examine specific epigenetic changes at various stages throughout the process.

"We found that retroviral silencing occurred relatively early in the reprogramming process, before the development of pluripotency, and did not require KLF4," says co-lead author Ken Nishimura. "We then examined proteins bound at the primer binding site of silenced proviruses, which is where the silencing occurs, and identified a novel silencing component called TAF-Iα. Knockdown or overexpression of TAF-Iα resulted in diminished or enhanced retrovirus silencing, respectively, suggesting that it plays an important role in retroviral silencing during reprogramming."

By gaining a better understanding of the reprogramming process, researchers are one step closer to producing high quality iPSCs for use in fields such as regenerative medicine and stem cell therapy.

PITTSBURGH--Computational biologists at Carnegie Mellon University have devised an algorithm to rapidly sort through mountains of gene expression data to find unexpected phenomena that might merit further study. What's more, the algorithm then re-examines its own output, looking for mistakes it has made and then correcting them.

This work by Carl Kingsford, a professor in CMU's Computational Biology Department, and Cong Ma, a Ph.D. student in computational biology, is the first attempt at automating the search for these anomalies in gene expression inferred by RNA sequencing, or RNA-seq, the leading method for inferring the activity level of genes.

As they report today in the journal Cell Systems, the researchers already have detected 88 anomalies -- unexpectedly high or low levels of expression of regions within genes -- in two widely used RNA-seq libraries that are both common and not previously known.

"We don't yet know why we're seeing those 88 weird patterns," Kingsford said, noting that they could be a subject of further investigation.

Though an organism's genetic makeup is static, the activity level, or expression, of genes varies greatly over time. Gene expression analysis has thus become a major tool for biological research, as well as for diagnosing and monitoring cancers.

Anomalies can be important clues for researchers, but until now finding them has been a painstaking, manual process, sometimes called "sequence gazing." Finding one anomaly might require examining 200,000 transcript sequences -- sequences of RNA that encode information from the gene's DNA, Kingsford said. Most researchers therefore zero in on regions of genes that they think are important, largely ignoring the vast majority of potential anomalies.

The algorithm developed by Ma and Kingsford automates the search for anomalies, enabling researchers to consider all of the transcript sequences, not just those regions where they expect to see anomalies. This technology could uncover many new phenomena, such as the 88 previously unknown common anomalies found in the multi-tissue RNA-seq libraries.

But Ma noted that identifying anomalies is often not clear cut. Some RNA-seq "reads," for instance, are common to multiple genes and transcripts and sometimes get mapped to the wrong one. If that occurs, a genetic region might appear more or less active than expected. So the algorithm re-examines any anomalies it detects and sees if they disappear when the RNA-seq reads are redistributed between the genes.

"By correcting anomalies when possible, we reduce the number of falsely predicted instances of differential expression," Ma said.

CINCINNATI -- Stem cell therapy helps hearts recover from a heart attack, although not for the biological reasons originally proposed two decades ago that today are the basis of ongoing clinical trials. This is the conclusion of a Nov. 27 study in Nature that shows an entirely different way that heart stem cells help the injured heart - not by replacing damaged or dead heart cells as initially proposed.

The study reports that injecting living or even dead heart stem cells into the injured hearts of mice triggers an acute inflammatory process, which in turn generates a wound healing-like response to enhance the mechanical properties of the injured area.

Mediated by macrophage cells of the immune system, the secondary healing process provided a modest benefit to heart function after heart attack, according to Jeffery Molkentin, PhD, principal investigator, director of Molecular Cardiovascular Microbiology a Cincinnati Children's Hospital Medical Center and a professor of the Howard Hughes Medical Institute (HHMI).

"The innate immune response acutely altered cellular activity around the injured area of the heart so that it healed with a more optimized scar and improved contractile properties," Molkentin said. "The implications of our study are very straight forward and present important new evidence about an unsettled debate in the field of cardiovascular medicine."

The new paper builds on a 2014 study published by the same research team, also in Nature. As in that earlier study, the current paper shows that injecting c-kit positive heart stem cells into damaged hearts as a strategy to regenerate cardiomyocytes doesn't work. The findings prompted Molkentin and his colleagues to conclude that there is a need to "re-evaluate the current planned cell therapy based clinical trials to ask how this therapy might really work."

An Unexpected Discovery

The study worked with two types of heart stem cells currently used in the clinical trials--bone marrow mononuclear cells and cardiac progenitor cells. As the researchers went through the process of testing and re-verifying their data under different conditions, they were surprised to discover that in addition to the two types of stem cells, injecting dead cells or even an inert chemical called zymosan also provided benefit to the heart by optimizing the healing process. Zymosan is a substance designed to induce an innate immune response

Researchers reported that stem cells or zymosan therapies tested in this study altered immune cell responses that significantly decreased the formation of extra cellular matrix connective tissue in the injury areas, while also improving the mechanical properties of the scar itself. The authors concluded: "injected hearts produced a significantly greater change in passive force over increasing stretch, a profile that was more like uninjured hearts."

Molkentin and his colleagues also found that stem cells and other therapeutic substances like zymosan have to be injected directly into the hearts surrounding the area of infarction injury. This is in contrast to most past human clinical trials that for patient safety reasons simply injected stem cells into the circulatory system.

"Most of the current trials were also incorrectly designed because they infuse cells into the vasculature," Molkentin explained. "Our results show that the injected material has to go directly into the heart tissue flanking the infarct region. This is where the healing is occurring and where the macrophages can work their magic."

The researchers also noted an interesting finding involving zymosan, a chemical compound that binds with select pattern recognition receptors to cause an acute innate immune response. Using zymosan to treat injured hearts in mice resulted in a slightly greater and longer-lasting benefit on injured tissues than injecting stem cells or dead cell debris.

Looking to the Future

Molkentin said he and other collaborating scientists will follow up the findings by looking for ways to leverage the healing properties of the stem cells and compounds they tested.

For example, considering how heart stem cells, cell debris and zymosan all triggered an acute innate immune response involving macrophages in the current paper, Molkentin explained they will test a theory that harnesses the selective healing properties of macrophages. This includes polarizing or biologically queuing macrophages to only have healing-like properties.

Further testing of this, he said, could therapeutically be very important for developing future treatment strategies.

SUMMARY:

Images show how changes in a specific protein of the malaria parasite are causing a frontline treatment to lose effectiveness

Results show how antimalarial resistance could spread out of Southeast Asia

Study suggests way to restore antimalarial potency

Malaria parasites are rapidly developing resistance to front-line drugs across the world, threatening to undo years of progress in reducing deaths from the disease.

New pictures of a key mediator of drug resistance for the parasite captured with single-particle cryo-electron microscopy by a team of scientists at Columbia University Vagelos College of Physicians and Surgeon--are now giving researchers clues about how to combat resistance.

The study shows that drug resistance in the malaria parasite is linked to a specific protein and illustrates how mutations in the protein allow the parasite to expel the drug.

The new discovery may help scientists find ways to restore the drugs' potency and will allow health officials in other parts of the world to monitor for emerging resistance.

"The fight against malaria is stalling," says David Fidock, PhD, the C.S. Hamish Young Professor of Microbiology & Immunology, who led the effort with Filippo Mancia, PhD, associate professor of physiology & cellular biophysics, and Matthias Quick, PhD, associate professor of neurobiology (in psychiatry). "Uncovering the molecular underpinnings of resistance is essential to prolonging the effectiveness of current drugs and developing new ones."

The research was published Nov. 27 in the journal Nature.

Image shows how a frontline malaria drug is losing effectiveness--

For nearly 15 years, the drug piperaquine, or PPQ, has been used all over the world to treat people infected with the malaria parasite. The drug, in combination with artemisinin, has helped slash the number of deaths caused by the disease from over 1 million in 2004 to an estimated 435,000 in 2017. The disease strikes more than 220 million individuals each year across the globe, including Africa, Southeast Asia, the Western Pacific, and South America. Almost all fatal infections occur in young African children.

But resistance to PPQ has exploded recently in Southeast Asia. "In some areas, the frontline combination of PPQ with dihydroartemisinin (which also has succumbed to resistance) is now effective in only 13% of patients, making this an essentially useless drug in those regions," Fidock says.

This study in Nature shows that the source of PPQ resistance is a protein in the malaria parasite called PfCRT.

PfCRT is the same protein that had mediated resistance to the former first-line drug, chloroquine (CQ).

That coincidence may create new opportunities for treatment, since the new mutations, which are spreading like wildfire across Southeast Asia, often cause parasites to lose their chloroquine resistance. Combining antimalarials could treat drug-resistant and sensitive parasite infections.

Resistant parasites spit out drug

The antimalarial drugs CQ and PPQ work by entering the parasite's digestive vacuole (a compartment resembling a stomach) and altering it so that the parasite poisons itself on its own toxic waste product, formed from digested hemoglobin.

PfCRT is located in the vacuole's membrane, and the location of mutations--inside a central cavity of PfCRT-reaffirm the observation that resistant parasites use variant forms of this protein to expel the drug out of the vacuole.

"It looked like the protein spits the drug out of the parasite's stomach," says Mancia, "keeping it away from its target."

Though the images were evocative, biochemical testing of the PfCRT's transport properties was needed to confirm the researchers' suspicions. By making other mutations in the protein and testing their drug binding and transport abilities, Quick found that only mutations in the protein's central cavity give PfCRT the ability to expel the drug from the vacuole.

Scientists can now predict how resistance will arise in other parts of the world

With images of PfCRT in hand--combined with the location and properties of resistance-causing mutations--it is now possible to predict how PPQ resistance will arise in other parts of the world.

"The PfCRT gene is difficult to sequence, so it's been hard for people to monitor," Fidock says, "There are hundreds of locations in PfCRT that could be mutated, but now we can sayust look at these handful in the central cavity with specific structural and conservation properties. They are the only ones that can drive resistance."

Based on what's now known, Fidock says South America could be the next place where PPQ fails. Results presented in this report already show one such mutation in PfCRT that, should it appear and spread in South America, would lead to high-grade resistance and augment the risk of treatment failures.

"Getting ahead of the 'drug resistance curve' by knowing where to look in the parasite's genome will be critical to identifying where resistance arises and having time to move to alternative treatment strategies," Fidock says.

Fidock and Quick are now testing whether PfCRT mutations identified in Asian malaria parasites will also cause PPQ resistance in African parasites, which are genetically distinct and which cause the vast majority of the global malaria burden. Those experiments may also help officials in Africa who are planning to deploy PPQ more broadly in areas of high transmission and who need to know how to monitor for signs of emerging resistance.

Study suggests ways to restore the potency of antimalarial drugs

Parasites have enlisted PfCRT in their fight against antimalarials, but researchers could also co-opt PfCRT to restore the potency of PPQ and similar drugs.

"We may be able to restore the efficacy of these drugs with an agent that entirely blocks the capacity of this protein to transport anything," says Fidock, who is working with colleagues to develop parasite-based screens to identify potential candidate compounds.

"That would make PPQ and the earlier first-line drug chloroquine fully functional."

Limits of Nobel technique pushed to acquire images

The malarial protein (49 kDa) is one of the smallest molecules of its type to be visualized with cryo-electron microscopy (cryo-EM), which is typically limited to proteins of at least 100 kDa in size. PfCRT needed to be bulked up with an antibody fragment before it could be seen under the electron microscope. This fragment, which was found to bind to the PfCRT central cavity, allowed the researchers to see PfCRT from multiple angles, which was necessary to generate a 3D model.

PfCRT's small stature wasn't the only problem in obtaining clear images by cryo-EM. PfCRT is normally surrounded by lipids inserted in a biological membrane, so the protein required the use of detergents to be extracted and purified, creating an often destabilizing and non-natural environment to image the protein. The researchers sidestepped this problem by creating nanosized lipid discs to hold PfCRT in a nearly natural state without obscuring important details from view.

The UK National Health Service (NHS) shows pockets of good performance, but spending, patient safety, and population health are all below average to average relative to ten other high income countries, according to a study published by The BMJ today.

If the NHS wants to achieve comparable health outcomes, or even improve outcomes, it needs to spend more to increase staffing numbers, long term care, and other social services, they write.

The NHS, like many other healthcare systems, faces the challenge of having to meet growing demand while under pressure to reduce costs. However, comparative data on how the UK performs relative to other high income countries are lacking.

So a team of UK and US researchers set out to compare the UK health system with those of nine other high income countries, across seven key areas including spending, structural capacity, accessibility, quality, and health outcomes.

Their findings are based on data from international organisations such as Eurostat and the Organization for Economic Cooperation and Development (OECD) for the UK, Australia, Canada, Denmark, France, Germany, the Netherlands, Sweden, Switzerland, and the US.

The focus was on the most recent data available, typically 2017, as well as trends since 2010 when available and comparable.

These comparator countries were chosen because they are all high income countries that the UK tends to liken itself to, with populations that face similar burdens of illness, yet also have healthcare systems structured in different ways.

The results show that the UK spent the least per person on healthcare in 2017 ($3825; £2955; €3417) compared with an average $5700 for all other countries studied, and healthcare spending is growing at slightly lower levels (0.02% of GDP in the UK from 2014-17 compared with an average of 0.07%).

Although the UK has comparable numbers of people over the age of 65, it spends less of its already low total healthcare expenditure on long term care - and a greater proportion of this comes from private sources than it does in other healthcare systems.

When it comes to the healthcare workforce, the UK had among the highest proportion of foreign trained doctors (28.6%) and nurses (15%).

Despite this, the numbers of healthcare professionals (general practitioners, specialists, nurses) are some of the lowest of all countries studied (UK 2.8 doctors per 1000 population compared with 3.5 study average), and these numbers are declining.

As the migration of healthcare professionals has decreased since 2015, the existing staffing challenges facing the NHS "will likely be further exacerbated," note the authors.

Waiting times and access to care in the UK compared favourably to other countries, but utilisation (number of hospital admissions) was lower than average.

The UK had slightly below average life expectancy (81.3 years compared with an average of 81.7), the lowest survival rates for breast and colon cancer, and the second lowest survival rates for rectal and cervical cancer.

Although several outcomes were poor, such as death rates for heart attack and stroke, the UK achieved lower than average rates of deep venous thrombosis after joint surgery and fewer healthcare associated infections.

However, maternal death in the UK was higher than average, and is increasing, while the numbers of preventable and treatable deaths were the third highest and highest respectively.

This is an observational study, so can't establish cause, and the researchers point out that the data are purely descriptive, and the interpretation of the results is sensitive to the selection of comparator countries.

Nevertheless, they conclude that while the NHS shows pockets of good performance, spending, patient safety, and population health are all below average to average at best.

"Taken together, these results suggest that if the NHS wants to achieve comparable health outcomes at a time of growing demographic pressure, it may need to spend more to increase the supply of labour and long term care and reduce the declining trend in social spending to match levels of comparator countries," they conclude.

Boston, MA - Hospitalizations for several common diseases--including septicemia (serious bloodstream infection), fluid and electrolyte disorders, renal failure, urinary tract infections, and skin and tissue infections--have been linked for the first time with short-term exposure to fine particulate air pollution (PM2.5), according to a comprehensive new study led by Harvard T.H. Chan School of Public Health.

In addition, the study found that even small increases in PM2.5 exposure were linked with substantial health care and economic costs.

The study will be published online November 27, 2019 in BMJ.

"The study shows that the health dangers and economic impacts of air pollution are significantly larger than previously understood," said Yaguang Wei, a doctoral candidate at Harvard Chan School and lead author of the study.

Fine particulate air pollution is composed of tiny solids and liquids floating in the air that come from sources such as motor vehicles, coal-fired power plants, and wildfires. Previous studies have shown that, when inhaled, the particles can enter deep into the lungs and cause serious health problems. "For this study, we wanted to shed further light on the risks of exposure to short-term air pollution by searching for links between such pollution and all diseases that are plausible causes of hospitalizations," said Joel Schwartz, professor of environmental epidemiology at Harvard Chan School and senior author of the study.

Researchers classified the diseases into 214 disease groups. They then analyzed 13 years' worth of hospital admissions records, from 2000 to 2012, from more than 95 million inpatient hospital claims for Medicare beneficiaries aged 65 and older. To estimate daily PM2.5 levels across the U.S., researchers used a computer model that predicts exposure using satellite-based measurements and a computer simulation of air pollution. They then matched the PM2.5 data with the zip codes of study participants.

In addition to showing that short-term exposure to PM2.5 was associated with several newly identified causes of hospital admissions among older adults, the study confirmed previously identified associations between short-term exposure and hospitalization risk for a number of other ailments, including several cardiovascular and respiratory diseases, Parkinson's disease, and diabetes.

Notably, all of the associations remained consistent even on days when daily PM2.5 levels were below the WHO air quality guideline.

In an economic analysis, researchers found that each 1 μg/m3 increase in short-term exposure to PM2.5 was associated with an annual increase of 5,692 hospitalizations, 32,314 days in the hospital, and 634 deaths, corresponding to $100 million in annual inpatient and post-acute care costs, and $6.5 billion in "value of statistical life" (a metric used to determine the economic value of lives lost).

"These results raise awareness of the continued importance of assessing the impact of air pollution exposure. The strong evidence of a link between exposure to PM2.5 and many diseases, even at levels below the WHO guideline and, nationally, the National Ambient Air Quality Standards in the U.S., suggests that both sets of guidelines should be reviewed and updated," said Francesca Dominici, professor of biostatistics at Harvard Chan School and principal investigator of the study.

An editorial by Wei, Dominici, and Schwartz, highlighting the newly identified health dangers of air pollution, accompanied the study.

Other Harvard Chan School authors of the study included co-first author Yan Wang, Qian Di, Christine Choirat, Yun Wang, Petros Koutrakis, and Antonella Zanobetti.

Under a 2°Celsius warming scenario, 80 to 83% of language areas in New Guinea--home to the greatest biological and linguistic diversity of any tropical island on Earth--will experience decreases in the diversity of useful plant species by 2070, according to a new study. "This study is the first to evaluate the potential impact of climate change across New Guinea's ecosystems and indigenous lands, and to propose a climate-smart expansion of protected areas that accounts for both biodiversity and cultural traditions," says author Rodrigo Cámara Leret. The report is part of a final group of papers published in a Science Advances Special Collection that - through research published in 2018 and 2019 - illustrates the scientific community's increased understanding of interactions between biodiversity and climate. The collection's final installment this week comes on the eve of the 25th United Nations Climate Change summit (COP25), which will be held in Spain this December. "Evidence [in the studies in this collection] suggests that the negative impacts of climate change can be kept under control if we collectively act and, critically, use biodiversity as part of the solutions we invent," write Science Advances editors Pablo Marquet, Shahid Naeem, Jeremy Jackson, and Kip Hodges in a related editorial.

Also in this installment of the Special Collection, a study by Brian Enquist et al. uses a global plant observation dataset accounting for 435,000 species to measure the fraction of existing land plants considered rare. It finds that about 36.5% of the plant species are exceedingly rare, suggesting rare species are disproportionately at risk and greater global efforts are required to conserve the biodiversity hot spots where they tend to exist. A review by Derek Tittensor et al. concludes that the goals of marine protected areas (MPAs) must be adjusted to account for broader climatic changes, which are expected to hinder conservation efforts from maintaining ecosystems in their current states or restoring them to previous baselines. By analyzing the available literature, Peter Convey and Lloyd Peck find that the arrival of non-native species to Antarctica--which has so far been thwarted by the harsh environment--may pose a greater threat to Antarctic ecosystems than climate change itself. Additionally, a review by Francisco Pugnaire et al. observes that important gaps remain in research on how specific aspects of climate change and elevated atmospheric carbon dioxide levels will affect plant-soil interactions.

Two French researchers from the CNRS and Ecole nationale des chartes disprove the theory according to which Corneille was Molière's ghostwriter - a popular and century-old theory, defended by some academics and writers. According to their forthcoming study in Science Advances, Molière would most likely be the only author of his numerous masterpieces.

Was Pierre Corneille Molière's ghostwriter? The idea dates back to 1919, when French poet and writer Pierre Louÿs wrote a now famous article, attributing Amphitryon and a few other plays signed by Molière to Corneille. This suspicion grew further, to encompass all of Molière's plays: how would it be possible that a poorly educated actor, managing his own theatre company, and valet of the king's chamber, could have written so many masterpieces? Molière would only have been the main protagonist of the plays. Their actual author, Pierre Corneille, would have benefited from his fame and talent, without exposing himself to controversies nor tarnishing his reputation as a serious author.

This theory was revived in the early 2000s by researchers in linguistics, stating that Corneille and Molière's styles were extremely close - which would mean that Corneille actually wrote Molière's works.

Florian Cafiero and Jean-Baptiste Camps, two researchers in computational linguistics from the CNRS and the École nationale des chartes, used "authorship attribution" techniques to disprove this theory. They rely on an extensive statistical analysis of writing habits and speech mannerism to identify the author of a text. Each individual writes using a specific proportion of words, expressions, or grammatical sequences. Even when someone tries to consciously imitate another style, some elements betray him, like function words ( "from", "then", "of"...), that we use without even thinking.

The reliability of these techniques is remarkable. They are used by historians to identify the author of a medieval text, or by an intelligence agency to understand who wrote an anonymous threat. Using these methods, the authors of this study read and analysed these texts for three years, comparing among other thing the rhymes, grammar, vocabulary, or function words present in texts by Molière, Pierre Corneille, Scarron, Rotrou or Thomas Corneille. In this study of an unprecedented scale, it appeared that from any point of view, the characteristics found in Molière's text were without a doubt significantly different from any other author of the time. Pierre Corneille's plays are very often the most different, Scarron's or Thomas Corneille's works being always closer to Molière's. It is thus very likely that Molière's masterpieces would not have been written by Corneille, nor by another author... but more simply, by himself.

Scientists have identified a protein in fruit flies that can be targeted to reverse the effects of disease-causing mutations in mitochondrial genes. The discovery could provide clues about how to counteract human mitochondrial diseases, for which there is currently no cure.

Mitochondria, the powerhouses of the cell, are rod-shaped structures that generate almost all of the energy required by cells to perform their activities. Mitochondria carry their own DNA - mitochondrial DNA - which encodes 13 proteins essential for producing energy. This is distinct from the DNA in the cell nucleus - 'nuclear DNA' - which encodes the blueprint for the whole organism. While nuclear DNA is derived half from each parent when an egg is fertilised by a sperm, mitochondrial DNA (mtDNA) is inherited solely from the mother, through the egg.

A typical cell has two copies of the nuclear DNA, but often contains hundreds or even thousands copies of mtDNA. During development and ageing as mtDNA continues to replicate, mutations can occur to some of the copies. This means that individuals will carry a mixture of mutated and healthy mitochondrial genomes, which constantly compete with each other to alter their relative abundance.

Some of these mutations are potentially harmful. Often, these harmful mutations are present in low abundance when they first arise, and their proportion remains low in many healthy individuals. However, in some people, they increase in abundance over time.

When the proportion of harmful mutations goes beyond 60-80% of all the mtDNA copies in a cell, there is not enough energy to support the normal cellular activities, and disease symptoms will emerge. These disease symptoms can be further passed on to the next generation if mutant mitochondrial genomes are also present in high percentages in the mother's eggs.

To date, over 350 mutations in mtDNA have been reported to cause a spectrum of mitochondrial diseases that affect at least 1 in 5,000 individuals in the UK. Some of these conditions are fatal and there are currently no cures.

Researchers at the Wellcome Trust/ Cancer Research UK Gurdon Institute, University of Cambridge, have devised a model in the fruit fly to examine how the abundance of mutated mtDNA changes over time. This competition between healthy and mutated mitochondrial genomes is a fundamental feature of development and could be influenced by the nuclear DNA, but little is known about how.

The scientists created 'three-parent flies' which inherit some of their mtDNA from a second mother. This is done under the microscope using tiny tools where mitochondria from the second mother are transferred to fertilised fly eggs carrying genetic information from their original mother and father. The flies carry two competing mitochondrial genomes, one healthy and one mutated, that are normally balanced and co-transmitted to subsequent generations. However, a change in the nuclear DNA can tip the balance in favour of one mitochondrial genome at the expense of the other.

Using these three-parent flies in a 'genetic screen' allowed the scientists to measure the influence of every individual nuclear gene on the competition between healthy and diseased mitochondrial genomes.

The study identified multiple nuclear genes that could limit the harmful mitochondrial genome being passed on during development or to the next generation. One of these genes codes for a protein called mtDNA polymerase. Reducing the amount of mtDNA polymerase increases the percentage of healthy mtDNA from 20% to 75% in just one generation. This increase eradicated disease symptoms and the new flies were much healthier.

There is no equivalent mouse model or human cell line in which scientists can perform such a genome-wide genetic screen to look at the effect of nuclear genes on the manifestation of mitochondrial disease. This model, using three-parent flies, is designed to help understand why mutant mtDNA may cause problems of different severity among different people and between different tissues in the body. The new results show that reducing the activity of a nuclear gene can almost eliminate the harmful mtDNA mutations and could potentially be used to reverse mitochondrial disease symptoms. This could provide a target for drugs to treat mtDNA-linked diseases.

"To achieve this dramatic change in the proportion of healthy mitochondrial DNA, we're not changing an individual's nuclear DNA," says lead author Dr Hansong Ma, Group Leader at the Gurdon Institute. "All we are doing is reducing how much of certain proteins is produced. This could be achieved using drugs. Our fruit flies will help us rapidly screen potential drugs compounds."