Culture

A device to quickly capture and identify various strains of virus has been developed, according to researchers at Penn State and New York University.

Currently, virologists estimate that 1.67 million unknown viruses are in animals, a number of which can be transmitted to humans. Known viruses, such as H5N1, Zika and Ebola have caused widespread illness and death. The World Health Organization states that early detection can halt virus spread by enabling rapid deployment of countermeasures.

"We have developed a fast and inexpensive handheld device that can capture viruses based on size," said Mauricio Terrones, distinguished professor of physics, chemistry, and materials science and engineering at Penn State. "Our device uses arrays of nanotubes engineered to be comparable in size to a wide range of viruses. We then use Raman spectroscopy to identify the viruses based on their individual vibration."

This device, called a VIRRION, has a wide range of possible uses. For farmers, for example, early detection of a virus in the field can save an entire crop. Early detection of a virus in livestock can save a herd from illness. Humans also will benefit by the detection of viruses in minutes rather than in days with current methods. Because of its size and low cost, such a device would be useful in every doctor's office as well as in remote locations when disease outbreaks occur.

"Most current techniques require large and expensive pieces of equipment," Terrones said. "The VIRRION is a few centimeters across. We add gold nanoparticles to enhance the Raman signal so that we are able to detect the virus molecule in very low concentrations. We then use machine learning techniques to create a library of virus types."

According to Professor Elodie Ghedin, a virologist at NYU, "The VIRRION enables the rapid enrichment of virus particles from any type of sample -- environmental or clinical -- which jump-starts viral characterization. This has applications in virus emergence, virus discovery and in diagnosis. Eventually, we hope to use this device for the capture and sequencing of single virions, giving us a much better handle on the evolution of the virus in real time."

Added lead author Ying-Ting Yeh, an assistant research professor in the Terrones group, "We synthesized a gradient of aligned carbon nanotube forest arrays to capture different viruses according to their size and detect them in-situ using Raman spectroscopy. We designed and assembled a portable platform that enriches virus particles from several milliliters of clinical samples in a couple of minutes."

Cultural evolution has been the dominant driver of range contractions in megafauna taxa across China since the beginning of Common Era, with little or no direct importance of climate. A research team led by Aarhus University along with collaborators from Nanjing University analyzed maps of megafauna distribution dynamics and societal development based on Chinese archival records alongside data on climate across China from 2 to 1953 CE.

Human activities are now playing a dominant role in driving changes in Earth's biodiversity and are responsible for the incipient sixth mass extinction, but the historical processes leading to this situation are poorly understood, often without emphasis on cultural evolution as a potential key process underlying anthropogenic impacts. A team of researchers from Aarhus University and Nanjing University has now shown that cultural evolution overshadowed climate change in driving historical broad-scale biodiversity dynamics.

By mining the deep Chinese administrative records in relation to culturally important wild megafauna species as well as sociocultural development, the researchers identified the millennia-long spread of agricultural land and agricultural intensification, as well as the specific expansion of the Han culture, as the main cause of the extirpation of five megafauna species from much of China, with little or no direct importance of climate.

Cultural evolution, not climate change, as the main driver

"China's well-preserved written records for more than 2000 years provide a unique opportunity to reconstruct long-term dynamics of culture-nature interactions across large geographical extents," says senior author Professor Jens-Christian Svenning, director of Center for Biodiversity Dynamics in Changing World (BIOCHANGE), Aarhus University. The five studied megafauna taxa include Asiatic elephant (Elephas maximus), Asian rhinoceroses (Rhinoceros sondaicus, R. unicornis and Dicerorhinus sumatrensis), tiger (Panthera tigris), Asiatic black bear (Ursus thibetanus), and brown bear (Ursus arctos), all of which were widely distributed across the study area and have played an important role in ancient China's cultural activities.

"Ancient China used to host a highly biodiverse assemblage of large mammals even in its nowadays densely populated areas such as the North China Plain and the Middle-Lower Yangtze Plain. Our research shows that the relatively recent loss of this rich megafauna in large part can be attributed to the southward expansion of intensified agricultural practices with the Han culture, which originated in North China," explains postdoc Shuqing Teng from Aarhus University and Nanjing University, the first author of the study.

Regional extirpation of these taxa from the study area were consistent with the sociocultural dynamics described above, but inconsistent with climate change. There were at least two conspicuous cooling-warming cycles during the last two thousand years, including the Medieval Warm Period and the Little Ice Age, with fluctuations of mean annual temperature around 1 to 1.5 °C, but neither had a conspicuous effect on the megafauna range dynamics.

Importance of cultural filtering

The study provides clear evidence that cultural evolution historically has overshadowed past climate change in shaping broad-scale megafauna patterns, in contrast to the common belief that human societies were unimportant in driving biodiversity dynamics at such large spatiotemporal scales until recent time frames such as the Industrial Revolution or the Great Acceleration of the 20th century.

This finding highlights the importance of culture's role in filtering current ecological assemblages from historical species pools. Perspectives through the lens of cultural filtering should also stimulate thoughts on what is natural - notably helping to overcome the Shifting Baseline Syndrome, the tendency to accept an already degraded state as natural due to lacking recognition of earlier declines - and which natural world we aim to conserve or restore.

Furthermore, modification of cultural filters will be key to respond to the challenges of the Anthropocene biodiversity crisis, as it is fundamentally culturally driven, as shown by this study of historical China, and how to achieve this is an important research challenge.

ITHACA, N.Y. - Holiday celebrations often revolve around eating, but for those with food restrictions, that can produce an incongruous feeling when dining with friends and loved ones: loneliness.

People with restricted diets - due to allergies, health issues or religious or cultural norms - are more likely to feel lonely when they can't share in what others are eating, new Cornell University research shows.

"Despite being physically present with others, having a food restriction leaves people feeling left out because they are not able to take part in bonding over the meal," said Kaitlin Woolley, assistant professor of marketing in the Samuel Curtis Johnson Graduate School of Management and lead author of the research.

Across seven studies and controlled experiments, researchers found that food restrictions predicted loneliness among both children and adults.

The research also offers the first evidence, Woolley said, that having a food restriction causes increased loneliness. For example, in one experiment, assigning unrestricted individuals to experience a food restriction increased reported feelings of loneliness. That suggests such feelings are not driven by non-food issues or limited to picky eaters, Woolley said.

"We can strip that away and show that assigning someone to a restriction or not can have implications for their feeling of inclusion in the group meal," she said.

Further evidence came from a survey of observers of the Jewish holiday of Passover. When reminded during the holiday of the leavened foods they couldn't enjoy with others, participants' loneliness increased. Yet, within their own similarly restricted group, they felt a stronger bond.

Bonding over meals is an inherently social experience, Woolley notes. In previous research, she found that strangers felt more connected and trusting of each other when they shared the same food, and eating food from the same plate increased cooperation between strangers.

But when restricted from sharing in the meal, people suffer "food worries," Woolley said. They fret about what they can eat and how others might judge them for not fitting in.

Those worries generated a degree of loneliness comparable to that reported by unmarried or low-income adults, and stronger than that experienced by schoolchildren who were not native English speakers, according to the research. Compared with non-restricted individuals, having a restriction increased reported loneliness by 19%. People felt lonelier regardless of how severe their restriction was, or whether their restriction was imposed or voluntary.

The study concluded that food restrictions and loneliness are on the rise and "may be related epidemics," warranting further research.

To date, Woolley said, children have been the primary focus of research on the effects of food restrictions. A nationally representative survey she analyzed from the Centers for Disease Control did not track the issue among adults.

But increasingly, she said, food restrictions are being carried into adulthood, or adults are choosing restricted diets such as gluten-free, vegetarian and vegan for health or ethical reasons. Up to 30% of all participants in her research deal with restrictions, Woolley said.

"This is a problem that I don't think people are quite aware of," she said, "and that has implications for people's ability to connect with others over eating."

Drawing an object and naming it engages the brain in similar ways, according to research recently published in JNeurosci. The finding demonstrates the importance of the visual processing system for producing drawings of an object.

In a study by Fan et al., healthy adults performed two tasks while the researchers recorded brain activity using functional magnetic resonance imaging: they identified pieces of furniture in pictures and produced drawings of those pieces of furniture. The researchers used machine learning to discover similar patterns of brain activity across both tasks within the occipital cortex, an area of the brain important for visual processing. This means people recruit the same neural representation of an object whether they are drawing it or seeing it.

As the participants drew each object multiple times, the activity patterns in occipital cortex remained unchanged, but the connection between occipital cortex and parietal cortex, an area involved in motor planning, grew more distinct. This suggests that drawing practice enhances how the brain shares information about an object between different regions over time.

Anthracyclines remain a cornerstone of breast cancer therapy in combination with new-generation targeted drugs such as trastuzumab. Both types of drugs are major culprits in chemotherapy-induced heart disease. A recent study showed that being overweight or obese was a risk factor for cardiotoxicity in chemotherapy-treated patients with breast cancer, but it did not take into account related cardiac risk factors or other classic risk factors of cardiotoxicity produced by anthracycline and trastuzumab (e.g., older age, concomitant chemotherapy or previous radiation therapy, smoking, high blood pressure, or diabetes).

In a study published December 23 in the open-access journal PLOS Medicine, Elisé Kaboré of Centre Georges-François Leclerc and Charles Guenancia of University Hospital, Dijon, France, and colleagues address this gap in knowledge. They provide evidence that obesity is associated with a three-fold increased risk of cardiotoxicity in chemotherapy-treated patients with early-stage breast cancer, regardless of other predictors of cardiotoxicity. As noted by the authors, the results suggest that overweight and obese patients may benefit from careful cardiac screening and follow-up during and after chemotherapy.

The authors examined the association of body mass index and cardiotoxicity using prospective data collected from 2012 to 2014 in the French national breast CANcer TOxicity study (CANTO) of 26 cancer centers. The study included 929 patients with stage I to III breast cancer who were treated with anthracycline and/or trastuzumab.

At baseline, nearly half of the study population was overweight or obese. During a mean follow-up period of 22 months following chemotherapy, cardiotoxicity occurred in 29 patients (3.2%). Compared to the normal-weight group, the obese group was more prone to cardiotoxicity (8/466 vs. 9/171; p=0.01), regardless of other predictors of cardiotoxicity. In addition, cardiotoxicity was independently associated with obesity (OR, 3.02; 95%CI, 1.10-8.25; p=0.03) and trastuzumab administration (OR, 12.12; 51 95%CI, 3.6-40.4; p

The first rigorously controlled study of a 2016 California law that aimed to increase childhood vaccination rates by eliminating nonmedical exemptions has found the law worked as intended, although the researchers noted a small increase in the number of medical exemptions.

The study provides definitive evidence on the success of the California law, as policymakers across the United States and around the world debate similarly strict vaccine requirements.

"Vaccine hesitancy and the recent decline in vaccination rates is an increasing threat to public health and our patients," said Nathan C. Lo, MD, PhD, a medical resident at UC San Francisco and senior author of the study, published Monday, Dec. 23, 2019, in PLOS Medicine. "Our study shows that government policy has a role to address this, and that eliminating nonmedical exemptions is an effective way of increasing vaccination coverage."

The researchers estimated how many California children would have received a key vaccine -- measles, mumps and rubella, or MMR -- if the law had not gone into effect, and compared that to how many children actually were vaccinated following the law's enactment. The comparison group was created synthetically with data from 44 other states, so that it resembled California's demographics and trends.

The researchers did something similar at the county level, comparing overall vaccine coverage in California counties to vaccine coverage in similar counties from 16 other states. The state data covered the years 2011 to 2017 and the county data covered 2010 to 2017.

"The big strength of our study over previous analyses is that we designed a quasi-experimental study with control groups, to adjust for ongoing trends in vaccination," said Sindiso Nyathi, a PhD candidate in the Department of Epidemiology and Population Health at Stanford University School of Medicine, who was one of the first authors on the new paper. "This makes our results more reliable."

Both analyses showed that vaccination rates went up following the law's enactment. MMR coverage across the state increased 3.3 percent, compared to the "synthetic" state control; nonmedical exemptions decreased by 2.4 percent; and medical exemptions increased 0.4 percent.

In the county-level analysis, overall vaccination coverage went up on average 4.3 percent, nonmedical exemptions went down 3.9 percent and medical exemptions went up 2.4 percent. The averages masked much larger changes in vaccination coverage in some counties, which ranged from a 6 percent decrease to a 26 percent increase, with the largest increases happening in counties that had the lowest vaccine coverage before the law took effect.

"We did see an increase in medical exemptions, but in absolute terms the numbers remain small -- 1 to 2 percent, driven largely by a few counties -- and we can expect them to remain of similar magnitude in the near term," Lo said. "Overall vaccine coverage increased by 10 to 20 percent in the high-risk counties, far more than the increase in medical exemptions."

These changes were enough to bring the vaccination rate to 95 percent in almost all California counties, which is high enough coverage to create so-called herd immunity, which can prevent disease from spreading among vulnerable groups, like newborns and older children who cannot receive vaccinations for various medical reasons.

"The implication of our study is the law brought about protection through herd immunity," said Hannah Karpel, a student at New York University School of Medicine, and a first author of the paper. "Even small average increases can have a big effect."

When NASA's Aqua satellite passed over the Northwestern Pacific Ocean, water vapor data provided information about the intensity of Tropical Cyclone Phanfone. In the Philippines, the storm is known locally as Ursula.

Tropical Depression 30W formed early on Dec. 22 and strengthened into a tropical storm. By 4 a.m. EST (0900 UTC), the storm was renamed Phanfone.

NASA's Aqua satellite passed over Tropical Cyclone on Dec. 22 at 0445 UTC (Dec. 21 at 11:45 p.m. EST) and the Moderate Resolution Imaging Spectroradiometer or MODIS instrument gathered water vapor content and temperature information. The MODIS image showed highest concentrations of water vapor and coldest cloud top temperatures were around the center of circulation.

MODIS data also showed coldest cloud top temperatures were as cold as or colder than minus 70 degrees Fahrenheit (minus 56.6 degrees Celsius) in those storms. Storms with cloud top temperatures that cold have the capability to produce heavy rainfall.

Water vapor analysis of tropical cyclones tells forecasters how much potential a storm has to develop. Water vapor releases latent heat as it condenses into liquid. That liquid becomes clouds and thunderstorms that make up a tropical cyclone. Temperature is important when trying to understand how strong storms can be. The higher the cloud tops, the colder and the stronger the storms.

On Dec. 23 at 4 a.m. EST (0900 UTC), Tropical Storm Phanfone (Philippines designation Ursula) was located near latitude 9.8 degrees north and longitude 132.2 degrees east, about 717 nautical miles east-southeast of Manila, Philippines. Phanfone is moving to the west-northwest and had maximum sustained winds near 40 knots (46 mph/74 kph).

On Dec. 23 at 10 a.m. EST (1500 UTC), the GMI or Microwave Imager sensor aboard NASA and the Japan Aerospace Exploration Agency's Global Precipitation Measurement mission or GPM core satellite, showed an eye was developing in Phanfone's center.

Forecasters at the Joint Typhoon Warning Center expect Phanfone will move west-northwest toward and through the central Philippine archipelago and the Visayas and Mindanao regions on Dec. 24 and 25.

NASA's Aqua satellite is one in a fleet of NASA satellites that provide data for hurricane research.

Typhoons and hurricanes are the most powerful weather event on Earth. NASA's expertise in space and scientific exploration contributes to essential services provided to the American people by other federal agencies, such as hurricane weather forecasting.

LEBANON, NH - Breast density is an important risk factor for breast cancer but no study had asked women what they know or think about breast density in relation to screening they have had. A number of states do have notification laws about breast density, but these laws vary. In a new qualitative study, a team of scientists at Dartmouth and Dartmouth-Hitchcock's Norris Cotton Cancer Center and the Breast Cancer Surveillance Consortium led by Karen Schifferdecker, PhD, MPH, and Anna Tosteson, ScD, sought to explore women's knowledge and perceptions of breast density and experiences of breast cancer screening across three states with and without notification laws.

The focus group study found that women from all states had varying knowledge about their own breast density and breast density in general. A number of women were aware of the difficulty of detecting cancer with dense breasts, but only one woman knew that density increased breast cancer risk. "We found that very few women received information about breast density during healthcare visits although some were encouraged to get supplemental imaging or to pay for new types of mammography such as breast tomosynthesis," says Schifferdecker. "Women who were offered more imaging or different technology usually thought these were 'better,' even though they were given little information about the effectiveness or harms."

The study also found, importantly, that women from all states expressed a strong desire for more information about breast density. All of these results are in the article, "Knowledge and Perception of Breast Density, Screening Mammography, and Supplemental Screening: in Search of 'Informed'" newly published in the Journal of General Internal Medicine. "The findings in this paper are exciting because no research on dense breasts has explored women's knowledge and experiences in their own words and compared this across different states," says Schifferdecker. "We partnered with the national Breast Cancer Surveillance Consortium to identify and recruit women who had a recent screening and also had dense breasts. In this way, we knew all women had dense breasts and could explore what they knew or did not know, including their own personal breast density."

The conclusions also identify opportunities for improvements in educating women so they may make informed decisions related to mammography and supplemental screening. "Women want--and deserve--more usable information about breast cancer risk, "says Schifferdecker. "More research needs to be done to understand how the medical community can better assist women in making informed decisions related to breast density and screening."

Atomic clocks are used around the world to precisely tell time. Each "tick" of the clock depends on atomic vibrations and their effects on surrounding electromagnetic fields. Standard atomic clocks in use today, based on the atom cesium, tell time by "counting" radio frequencies. These clocks can measure time to a precision of one second per every hundreds of millions of years. Newer atomic clocks that measure optical frequencies of light are even more precise, and may eventually replace the radio-based ones.

Now, researchers at Caltech and the Jet Propulsion Laboratory (JPL), which is managed by Caltech for NASA, have come up with a new design for an optical atomic clock that holds promise to be the most accurate and precise yet (accuracy refers to the ability of the clock to correctly pin down the time, and precision refers to its ability to tell time in fine detail). Nicknamed the "tweezer clock," it employs technology in which so-called laser tweezers are used to manipulate individual atoms.

"One of the goals of physicists is to be able to tell time as precisely as possible," says Manuel Endres, an assistant professor of physics at Caltech who led a new paper describing the results in the journal Physical Review X. Endres explains that while the ultra-precise clocks may not be needed for everyday purposes of counting time, they could lead to advances in fundamental physics research as well as new technologies that are yet to be imagined.

The new clock design builds upon two types of optical atomic clocks already in use. The first type is based on a single trapped charged atom, or ion, while the second uses thousands of neutral atoms trapped in what is called an optical lattice. In the trapped-ion approach, only one atom (the ion) needs to be precisely isolated and controlled, and this improves the accuracy of the clock. On the other hand, the optical lattice approach benefits from having multiple atoms--with more atoms there are fewer uncertainties that arise due to random quantum fluctuations of individual atoms.

The atomic clock design from Endres' group essentially combines the advantages of the two designs, reaping the benefits of both. Instead of using a collection of many atoms, as is the case with the optical lattice approach, the new design uses 40 atoms--and those atoms are precisely controlled with laser tweezers. In this regard, the new design benefits not only from having multiple atoms but also by allowing researchers to control those atoms.

"This approach bridges two branches of physics--single-atom control techniques and precision measurement," says Ivaylo Madjarov, a Caltech graduate student and lead author of the new study. "We're pioneering a new platform for atomic clocks."

Madjarov explains that, in general, the atoms in atomic clocks act like tuning forks to help stabilize the electromagnetic frequencies, or laser light. "The oscillations of our laser light act as a pendulum that counts the passage of time. The atoms are a very reliable reference that makes sure that pendulum swings at a constant rate."

The team says that the new system is ideally suited for future research into quantum technologies. The atoms in these systems can become entangled, or globally connected, and this entangled state can further stabilize the clock. "Our approach can also build a bridge to quantum computation and communication architectures," says Endres. "By merging different techniques in physics, we've entered a new frontier."

To disarm toxic substances, many organisms - including humans - possess enzymes called flavin-containing monooxygenases (FMOs). Despite their importance, the structure of the enzymes has not been resolved, as the protein is too unstable to study in detail. University of Groningen enzyme engineer Marco Fraaije and colleagues from Italy and Argentina reconstructed the ancestral genetic sequences for three FMO genes and subsequently studied the enzymes. The ancestral enzymes proved to be stable enough to study and revealed how FMOs metabolize toxic substances. The results were published on 23 December in Nature Structural & Molecular Biology.

FMOs are present in animals, plants and bacteria. In humans, our five different FMOs are not only involved in metabolizing toxic substances but also in drug activation, while mutations in FMO genes may cause illnesses. 'These enzymes are studied in detail by pharmaceutical companies but we still had no detailed structure available,' says Fraaije. Human FMOs are membrane-bound proteins, which proved to be impossible to crystallize for standard structural analysis by X-ray diffraction. 'My group published the structure of a bacterial FMO, some fifteen years ago, but this was not a membrane-bound protein.'

Phylogenetic tree

Several developments prompted Fraaije and his co-workers to have another go at the structure: 'Over the last couple of years, the gene sequences for a large number of different FMOs were published. This allows you to build a phylogenetic tree, but also to reconstruct ancestral gene sequences for the FMOs.' These gene sequences are used to create artificial DNA, which is then translated to proteins in bacterial systems. 'Previous work has shown that such ancestral proteins are generally more stable than the modern ones,' says Fraaije.

Colleagues from the Universidad Nacional de San Luis in Argentina reconstructed the DNA sequences, the University of Groningen group produced and characterized the proteins, while scientists at the University of Pavia in Italy determined the structures. The international team managed to analyse the ancestral forms of three of the five human FMOs.

Tunnel

'The results are fascinating,' says Fraaije. 'The membrane-bound part of the enzyme forms a kind of tunnel through which substances can be transported to the active site.' Many toxic compounds are fatty substances that will accumulate in the fatty cell membrane. 'The FMO enzymes can take them from the membrane and oxidize them.' This makes the toxins more hydrophilic, which makes it easier for the cell to excrete them. Whereas the active site is the same in the three FMOs, they have slightly different tunnels, probably suited to different classes of toxic compounds. 'We knew that different FMOs metabolize different substances and now we can explain why this is so.'

The approach using reconstructed ancestral genes has paid off. 'The amino acid sequence of ancestral proteins and contemporary proteins are 90 percent identical, while their functions are completely identical,' says Fraaije. Scientists and pharmaceutical companies are now finally able to see how the FMOs work. 'This could help in the design of drugs that are activated by these enzymes. And the observation that the ancestral protein is more stable is also of interest. Understanding why this is the case could help us to design more stable enzymes for industrial use.'

Fish odour syndrome

Finally, it is now possible to reconstruct the effect of disease-causing mutations in FMO genes. One of those mutations causes fish odour syndrome, where a mutation in FMO3 results in the inability to metabolize the substance trimethylamine. This substance, which has a strong fish odour, consequently builds up in the body and is released in sweat, urine and breath, among other things. Fraaije: 'This was a high-risk project, as we didn't know if the ancestral protein would be stable enough. But it has paid off.'

Using a new microscopic "fishing" technique, scientists at the Montreal Clinical Research Institute (IRCM) and Université de Montréal have successfully snagged thousands of proteins key to the formation of the cell skeleton.

Led by UdeM cell biologist Jean-François Côté, the team threw 56 "baits" into human cells they were incubating in their laboratory, catching more than 9,000 proteins in the process. The results are published today in the journal Nature Cell Biology.

The goal was to identify the proteins that attach to those of the Rho family, famous in the cell biology world since the discovery in the early 1990s that they dictate how pieces of the cell skeleton -- the "cytoskeleton" -- are assembled.

In humans, the 20 members of the Rho family are scattered on the inner surface of cell membranes and act like small switches. When a signal from outside or inside the cell activates them, they stimulate other proteins to force the cytoskeleton to add or remove parts to its framework.

Out of all these proteins, only three, to date, have been thoroughly studied by researchers: Cdc42, Rac1 and RhoA. Cdc42 acts as the lead protein: it indicates the path that white blood cells must take to find a site of infection. Rac1 activates the engines that drive a non-muscular cell forward. RhoA stimulates the formation of fibres that allow cells to contract or form resistant tissues as they come together to produce, for example, the wall of a blood vessel.

But what are the other proteins doing? And what other proteins do they interact with? To find out, Coté and his team went fishing for answers.

Two-headed proteins

Into human cells growing in incubators in their lab, they cast their baited lines, forcing these cells to produce proteins with two heads, one containing a single side of a protein in the Rho family, the other a "biotin ligase" enzyme. The latter acts like an elite sniper in the cell, luring and labelling every passing protein with the help of its partner, a member of the Rho family. Every protein that approached the bait was thus labeled with biotin. Next, Côté and his team had to shred the cells to identify, one by one, each labelled protein.

Using 28 two-headed proteins and presenting the GTPases - a superfamily of enzymes that function as 'molecular switches' and are involved in regulating many cellular processes - in both active and inactive configurations, the team caught a total of 9,939 proteins. Some were already known to the scientists, including the GTPases' activators and deactivators. But the researchers also discovered hundreds of individual proteins with yet-to-be-defined roles.

These discoveries include the missing link of the cytoskelton Rho process identified in the early '90s. Back then, researchers noticed that the RhoA protein indirectly activates another protein, ERM, causing it to stabilize the cytoskeleton. But they didn't know the precise mechanism behind this process. On their "fishing expedition," Côté and his team found the answer: what forges the link between RhoA and ERM is a protein called SLK.

In their study, the IRCM team also looked at other proteins that, until now, were virtually unknown to biologists, namely GARRE and PLEKHG3. The scientists demonstrated that these proteins naturally attach to the active forms of Rac1 and RhoG, respectively. What's left to understand is the exact function of these associations. To accelerate the process, the team revealed characteristics of other molecules they caught in their experiments -- enough to give raw material to dozens of laboratories worldwide.

Through their research, Côté and his team have not only cleared up a whole area of cell biology, but have also demonstrated the effectiveness of their unique "fishing" method. Côté now plans to use it to better understand how other molecular switches work, especially those in the Ras family, proteins that lie at the centre of many types of cancer.

AMHERST, Mass. ¬ - Though climate change is becoming one of the greatest threats to the Earth's already stressed ecosystems, it may not be the most severe threat today for all species, say authors of a new report on the effects of deforestation on two lemur species in Madagascar.

Writing in the current issue of Nature Climate Change, Toni Lyn Morelli at the U.S. Geological Survey's Northeast Climate Adaptation Science Center at University of Massachusetts Amherst and her international team of co-authors point out that species across the globe now face concurrent pressures on many fronts. These include habitat degradation and fragmentation, overharvesting, overhunting, invasive species and pollution in addition to climate change - though the latter receives special attention because of its "global reach, ability to reshape entire ecosystems and potential to impact areas that are otherwise 'protected.'"

To understand these threats, they modeled the effects of deforestation and climate change on the two critically endangered ruffed lemur species in the genus Varecia over the next century. "Because of their essential role as some of Madagascar's last large-bodied seed dispersers and their sensitivity to habitat loss, ruffed lemurs serve as critical indicators of rainforest health," says co-author Andrea Baden of Hunter College CUNY, New York. "Ruffed lemurs and rainforests rely on each other. Remove one and the system collapses."

Undertaking what Morelli calls "a massive effort," she and her 21 colleagues combined 88 years of data to report on how deforestation will affect ruffed lemurs. Morelli, who did her doctoral work in Madagascar, says team members conducted research at thousands of sites on this island off the southeast coast of Africa with a wide range of government, foundation and academic support.

They estimate that suitable rainforest habitat could be reduced by as much as 59 % from deforestation, as much as 75 % from climate change alone, and almost entirely lost from both before 2080. Thus, protecting protected areas is a key conservation strategy, research ecologist Morelli says. She and co-authors write, "Maintaining and enhancing the integrity of protected areas, where rates of forest loss are lower, will be essential for ensuring persistence of the diversity of the rapidly-diminishing Malagasy rainforests."

Morelli adds, "Madagascar is facing devastating rates of forest loss, and lemurs are only found there and nowhere else. At this rate, even without climate change we're going to lose the rainforest and its lemurs, but with climate change we'll lose them even faster. If we can slow the deforestation, we can save some of them. Not all of them, but some of them."

Morelli adds, "This is not just about Madagascar, though it's a really special place, recognized as one of the world's biodiversity hotspots, and people really care about it. But there is a broader message. This research reminds us that there are other threats to biodiversity. We show that deforestation continues to be an imminent threat to conservation."

Baden says that the problem is not that people have not been trying to preserve habitat to save the lemurs. "There are already protected areas," she says. "If we want to save habitat and species, in the face of climate change, we have to do a better job of enforcement. But even with well-enforced protected areas, the outlook is pretty grim." The authors also discuss the likelihood that climate change will alter local residents' ability to grow and gather food, perhaps forcing further encroachment on protected lands.

Overall, "We challenge the conservation community to contemplate what should be done if nearly all of Madagascar's rainforest habitat were to be lost," they write. "To date, most conservation on the island has focused on establishment of protected areas, but even these are being eroded, albeit at a slower rate. If protected areas are not able to serve their intended purpose, how can we ensure that the perpetuation of the richness of Madagascar's biodiversity?"

Journal

Nature Climate Change

Writing in Nature Medicine, an international team headed by researchers at University of California San Diego School of Medicine describe a new way to effectively deliver a gene-silencing vector to adult amyotrophic lateral sclerosis (ALS) mice, resulting in long-term suppression of the degenerative motor neuron disorder if treatment vector is delivered prior to disease onset, and blockage of disease progression in adult animals if treatment is initiated when symptoms have already appeared.

The findings are published in the December 23, 2019 online issue of the journal Nature Medicine. Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine, is senior author of the study.

ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord. Motor neurons responsible for communicating movement are specifically harmed, with subsequent, progressive loss of muscle control affecting the ability to speak, eat, move and breathe. More than 5,000 Americans are diagnosed with ALS each year, with an estimated 30,000 persons currently living with the disease. While there are symptomatic treatments for ALS, there is currently no cure. The majority of patients succumb to the disease two to five years after diagnosis.

There are two types of ALS, sporadic and familial. Sporadic is the most common form, accounting for 90 to 95 percent of all cases. It may affect anyone. Familial ALS accounts for 5 to 10 percent of all cases in the United States, and is inherited. Previous studies show that at least 200 mutations of a gene called SOD1 are linked to ALS.

The SOD1 gene normally serves to provide instructions for making an enzyme called superoxide dismutase, which is widely used to break down superoxide radicals -- toxic oxygen molecules produced as a byproduct of normal cell processes. Previous research has suggested that SOD1 gene mutations may result in ineffective removal of superoxide radicals or create other toxicities that cause motor neuron cell death, resulting in ALS.

The new approach involves injecting shRNA -- an artificial RNA molecule capable of silencing or turning off a targeted gene -- that is delivered to cells via a harmless adeno-associated virus. In the new research, single injections of the shRNA-carrying virus were placed at two sites in the spinal cord of adult mice expressing an ALS-causing mutation of the SOD1 gene, either just before disease onset or when the animals had begun showing symptoms.

Earlier efforts elsewhere had involved introducing the silencing vector intravenously or into cerebrospinal fluid in early symptomatic mice, but disease progression, while delayed, continued and the mice soon died. In the new study, the single subpial injection (delivered below the pia matter, the delicate innermost membrane enveloping the brain and spinal cord) markedly mitigated neurodegeneration in pre-symptomatic mice, which displayed normal neurological function with no detectable disease onset. The functional effect corresponded with near-complete protection of motor neurons and other cells, including the junctions between neurons and muscle fibers.

In adult mice already displaying ALS-like symptoms, the injection effectively blocked further disease progression and degeneration of motor neurons.

In both approaches, the affected mice lived without negative side effects for the length of the study.

"At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS," said senior author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine.

"In addition, effective spinal cord delivery of AAV9 vector in adult animals suggests that the use of this new delivery method will likely be effective in treatment of other hereditary forms of ALS or other spinal neurodegenerative disorders that require spinal parenchymal delivery of therapeutic gene(s) or mutated-gene silencing machinery, such as in C9orf72 gene mutation-linked ALS or in some forms of lysosomal storage disease."

The research team also tested the injection approach in adult pigs, whose spinal cord dimensions are similar to humans, for safety and efficacy. Using an injection device developed for use in adult humans, they found the procedure could be performed reliably and without surgical complications.

Marsala said next steps involve additional safety studies with a large animal model to determine the optimal, safe dosage of treatment vector. "While no detectable side effects related to treatment were seen in mice more than one year after treatment, the definition of safety in large animal species more similar to humans is a critical step in advancing this treatment approach toward clinical testing."

The causes of autism spectrum disorder or ASD are not fully understood; researchers believe both genetics and environment play a role. In some cases, the disorder is linked to de novo mutations that appear only in the child and are not inherited from either parent's DNA.

In a study published December 23, 2019 in Nature Medicine, an international team of scientists, led by researchers at University of California San Diego School of Medicine, describe a method to measure disease-causing mutations found only in the sperm of the father, providing a more accurate assessment of ASD risk in future children.

"Autism afflicts 1 in 59 children and we know that a significant portion is caused by these de novo DNA mutations, yet we are still blind to when and where these mutations will occur," said co-senior author Jonathan Sebat, PhD, professor and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. "With our new study, we can trace some of these mutations back to the father, and we can directly assess the risk of these same mutations occurring again in future children."

Recent studies suggest gene-damaging de novo mutations are involved in at least 10 to 30 percent of ASD cases, with the number of mutations rising with the father's age at time of conception. De novo mutations occur spontaneously in parents' sperm or eggs or during fertilization. The mutation is then present in each cell as the fertilized egg divides. Studies now point to male sperm as a particularly important source of these mutations, with the chance of the mutation recurring within the same family generally estimated at 1 to 3 percent.

"However, such estimates are not based on actual knowledge of the risk in an individual family, but instead are based on frequencies in the general population," said co-senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children's Institute for Genomic Medicine. "When a disease-causing mutation occurs for the first time in a family, the probability that it could happen again in future offspring is not known. Thus families must make a decision with a great deal of uncertainty."

For their study, Gleeson, Sebat and colleagues analyzed the sperm of eight fathers who were already parents of children with ASD. The goal was to look for the presence of multiple, genetically different material in cells in the same person, a phenomenon called mosaicism. Using deep whole genome sequencing, they found variants in offspring that were matched only in the fathers' sperm.

"While medical textbooks teach us that every cell in the body has an identical copy of DNA, this is fundamentally not correct. Mutations occur every time a cell divides, so no two cells in the body are genetically identical," said first author Martin Breuss, PhD, an assistant project scientist in Gleeson's lab.

"Mosaicism can cause cancer or can be silent in the body. If a mutation occurs early in development, then it will be shared by many cells within the body. But if a mutation happens just in sperm, then it can show up in a future child but not cause any disease in the father."

The researchers determined that disease-causing mutations were present in up to 15 percent of the fathers' sperm cells, information that could not be determined through other means, such as blood samples.

"My laboratory has a long-standing interest in understanding the origins of pediatric brain disease, and how mutations contributes to disease in a child," said Gleeson. "We previously showed that mosaicism in a child can lead to diseases like epilepsy. Here, we show that mosaicism in one of parents is at least as important when thinking about genetic counseling."

If developed into a clinical test, the researchers said fathers could have their sperm studied to determine their precise risk of recurrence in future children. The methods might also be applied to men that haven't had children yet, but who want to know the risk of having a child with a disease.

"Our new method to study genetic variations in individual cells could transform the field of mutation detection," highlights Ashley Sanders, one of the lead authors of the study, working at EMBL Heidelberg, Germany. The method she and her colleagues developed - termed scTRIP (single cell tri-channel processing) - allows them to study genetic variations within the DNA of a single cell and measure genetic variations directly as they form in new cells. In contrast to existing methods that were able to detect only large-scale changes in the genome, scTRIP can detect small-scale changes, along with many types of genetic variations that were invisible using other single cell methods.

The researchers tested their method in studying patient-derived leukaemia cells. In their sample, the team found four times more variants in the patient than were detected by standard clinical diagnostics. These included a missed clinically relevant translocation that drove the overexpression of a cancer-causing gene. They also observed a catastrophic chromosome rearrangement that was missed in the initial leukaemia diagnosis. It probably occurred when a single chromosome shattered and was then glued back together in a rearranged order.

"These first results show that our method is outperforming existing ones significantly. Our method is much faster and cheaper than methods currently in use to uncover genetic variants in single cells. This might be very useful for clinical applications," summarises Tobias Marschall, from the Center for Bioinformatics at Saarland University and the Max Planck Institute for Informatics. The team has begun to expand their use of the method to analyse different forms of leukaemia and evaluate its potential clinical utility.

As the heterogeneity of a sample can best be studied at a single-cell level, researchers all over the world - including several groups at EMBL - are working on the development of technologies to improve the information received. "While existing techniques show how different cells can behave or respond to manipulation or treatment, research and application have so far centred on measuring the RNA within a cell. However, measuring the DNA in a single cell has so far received much less attention," explains Tobias Marschall. As it is expected that looking at the DNA will provide a new level of understanding in how these genetic changes drive different cell behaviours, the new method addresses the needs of both researchers and medical doctors.

scTRIP is based on a technology Ashley Sanders co-developed during her PhD in Vancouver. "scTRIP combines signals from three distinct channels of information from within the genomic code of the individual cell," explains Jan Korbel, group leader at EMBL Heidelberg. "Doing so, our method allows us to uncover the full spectrum of DNA rearrangements in individual cells."

Now, using scTRIP, the researchers are continuing their research on a very basic question: How much does one cell in the body differ from any other cell, in the context of cancer as well as in normal cells? Until now, they were unable to address this question because they lacked the technology to do so. "Using scTRIP we can now directly measure the mutational processes that act in cells to generate new genetically distinct populations," says Ashley Sanders. For the next steps in their research, the team plans to study mutational processes in different human cell types, and to assess the consequences these differences have in terms of human diseases.