Culture

A network of over 100 herbaria spread out across the southeastern United States recently completed the herculean task of fully digitizing more than three million specimens collected by botanists and naturalists over a span of 200 years. The project, which was funded by the National Science Foundation, is part of a larger, ongoing effort by natural history institutions worldwide to make their biological collections easily accessible to researchers studying broad patterns of evolution, extinction, range shifts, and climate change.

In a new study published in the journal Applications in Plant Sciences, researchers involved in the project analyzed the rate at which specimens could be reliably photographed, digitized, and databased to assess how much similar efforts might cost in the future.

"Everybody who was interested in this recognized very early on just how much labor and money we were talking about," said senior author Joey Shaw, associate professor of biology and herbarium curator at the University of Tennessee at Chattanooga.

Although digitization efforts had been underway at large institutions since the turn of the century, to date, no one had developed a robust framework for determining how much it cost to bring a set of collections online, noted Shaw.

"No one had really been doing it at any sort of scale to understand how many specimens you could catalog per minute."

Such information can be vitally important for smaller institutions that rely on a dwindling fraction of administrative funding to maintain their collections. At universities and liberal arts colleges, these efforts are also heavily reliant on students, who perform the work for college research credit or as student employees, which comes with its own associated set of benefits and pitfalls.

Digitizing specimens is often the first direct experience students have with natural history, and, for many, it blossoms into a lifelong appreciation for biology. For some, as was the case for four authors on the study, this appreciation later culminates in graduate studies and careers in the natural sciences.

Student employment, however, is by nature transient, and resources invested in training students is often duplicated when they graduate or move on to other projects. So, at the outset of the project's conception, Shaw and his colleagues wanted to integrate into their analyses the lag associated with student training along with the subsequent increase in productivity as students gained experience.

The resulting estimates were incredibly precise, to the extent that Shaw and his colleagues could pinpoint exactly when classes let out by analyzing the rates at which specimen photographs were uploaded.

"The students ended up being so efficient that the computer and internet speed actually starting slowing down the process when classes let out, when there's a surge of people picking up their phones," Shaw said.

With hundreds of thousands of specimens now freely accessible online, Shaw hopes that their data will help inform workers at other herbaria hoping to replicate their results. All of the partnering institutions in this study are members of the SouthEast Regional Network of Expertise and Collections (SERNEC), which supports more than 200 herbaria in the region that house a combined 15 million specimens, the majority of which have yet to be digitized.

With increasing amounts of habitat loss due to urbanization and deforestation, herbaria offer researchers a valuable window into ecosystems long-since developed or demolished. Many collections include specimens that are now extinct in the wild, while others have yielded the discovery of entirely new species. And as average global temperatures continue to rise, scientists are increasingly turning to herbaria collection data to analyze the effects climate change has already had on plant communities.

"Biologists have accumulated species data from all over the world, in the form of biological specimens, since at least the Renaissance, and we continue this practice today," Shaw said. "Our recent work has been to convert the data of these biological specimens into a freely accessible online database. It will be the largest dataset assembled on Earth's biodiversity, and we are only at the beginning of dreaming up research, conservation, and land management questions that will be answered with this database."

Levels of omega-3 fatty acids in the blood are as good a predictor of mortality from any cause as smoking, according to a study involving the Hospital del Mar Medical Research Institute (IMIM), in collaboration with The Fatty Acid Research Institute in the United States and several universities in the United States and Canada. The study, published in The American Journal of Clinical Nutrition, used data from a long-term study group, the Framingham Offspring Cohort, which has been monitoring residents of this Massachusetts town, in the United States, since 1971.

Researchers have found that omega-3 levels in blood erythrocytes (the so-called red blood cells) are very good mortality risk predictors. The study concludes that "Having higher levels of these acids in the blood, as a result of regularly including oily fish in the diet, increases life expectancy by almost five years", as Dr. Aleix Sala-Vila, a postdoctoral researcher in the IMIM's Cardiovascular Risk and Nutrition Research Group and author of the study, points out. In contrast, "Being a regular smoker takes 4.7 years off your life expectancy, the same as you gain if you have high levels of omega-3 acids in your blood", he adds.

2,200 people monitored over eleven years

The study analysed data on blood fatty acid levels in 2,240 people over the age of 65, who were monitored for an average of eleven years. The aim was to validate which fatty acids function as good predictors of mortality, beyond the already known factors. The results indicate that four types of fatty acids, including omega-3, fulfil this role. It is interesting that two of them are saturated fatty acids, traditionally associated with cardiovascular risk, but which, in this case, indicate longer life expectancy. "This reaffirms what we have been seeing lately", says Dr Sala-Vila, "not all saturated fatty acids are necessarily bad." Indeed, their levels in the blood cannot be modified by diet, as happens with omega-3 fatty acids.

These results may contribute to the personalisation of dietary recommendations for food intake, based on the blood concentrations of the different types of fatty acids. "What we have found is not insignificant. It reinforces the idea that small changes in diet in the right direction can have a much more powerful effect than we think, and it is never too late or too early to make these changes", remarks Dr Sala-Vila.

The researchers will now try to analyse the same indicators in similar population groups, but of European origin, to find out if the results obtained can also be applied outside the United States. The American Heart Association recommends eating oily fish such as salmon, anchovies or sardines twice a week because of the health benefits of omega-3 acids.

An international collaborative study led by University of Helsinki has conducted a holistic study to investigate the effects of COVID-19 restrictions on several air quality pollutants for the Po Valley region in northern Italy. The area is well known to have one of the worst air quality standards in Europe and is highly influenced by anthropogenic (human-led) activities. The study was done between research groups in Finland, Italy and Switzerland and the results were published in the journal Environmental Science: Atmospheres.

Scientists have combined air quality measurements and computer simulation data over several locations in the region. The resulting studies show that reduced emissions from traffic lead to a strong reduction of nitrogen oxides, while have had limited impact on aerosol concentrations, contributing to a better understanding of how the air pollution is formed in the Po Valley.

The studies show that despite the large reduction in mobility of people and emissions from cars (which raise for instance nitrogen oxides concentrations), aerosols concentrations remained almost unchanged compared to previous years. Secondary formed pollutants like ozone, on the other hand, showed an increase in concentrations. These findings were confirmed by a computer model simulation that simulates the COVID-19 restriction on traffic, indicating that the increased overall oxidation capacity of the atmosphere might have enhanced the formation of new aerosols.

Furthermore, model simulations indicated that as nitrogen oxides emissions were largely reduced, chemical reactions of organic gases against atmospheric oxidants increased, slightly favoring the formation of new organic particles.

"You can think of the Po Valley region as a massive batch reactor with all sort of chemicals. Altering one of the "ingredients" can trigger non-linear responses in air pollutants concentrations", says Dr Federico Bianchi from the Institute for Atmospheric and Earth System Research (INAR) of University of Helsinki.

These studies shade new lights on the formation of air pollutants in the Po Valley region and on their sources. The conclusion is that the reduction in traffic emissions had little impact on particulate matter concentrations, possibly highlighting the importance of other emissions sources in the Po Valley area.

Carefully characterizing the evolution of such emission categories are of a vital importance to improve the understanding of the air pollution and to reduce the uncertainties in future air quality scenarios.

SAN FRANCISCO, CA--July 22, 2021--To speed up a chemical reaction, a chemist might place the reactants over a Bunsen burner. Adding heat increases the degree of random movements and collisions of particles, accelerating the reaction.

In cell biology, one important "reaction" is the transformation of stem cells into all the other cells in the body, a process known as differentiation. Gladstone Institutes researchers have now discovered a molecular mechanism that acts like a Bunsen burner to "turn up the heat" and accelerate differentiation.

However, instead of boosting temperature, this process amplifies random fluctuations in levels of gene expression--or which genes are turned on or off within a cell. Boosting these fluctuations, also known as "noise," appears to aid the switch from one cell type to another.

"Researchers have studied and characterized these fluctuations, or 'noise' in gene expression, for decades," says Leor Weinberger, PhD, William and Ute Bowes Distinguished Professor, and director of the Center for Cell Circuitry at Gladstone. "But it was unclear if this noise was simply an unavoidable by-product of gene expression, which was widely assumed, or if it played some functional role."

Now, as reported in the journal Science, he and his team have discovered a pathway they named discordant transcription through repair (DiThR, pronounced "dither"). The DiThR pathway appears to boost the noisiness of gene expression in stem cells and enhance their ability to differentiate.

A New Fundamental Mechanism

The discovery of the DiThR pathway arose from the team's earlier work on HIV.

"We'd been tackling a long-standing problem in HIV, namely how to alter HIV's ability to persist in a long-lived latent state in patients," says Weinberger, who is also a professor of biochemistry and biophysics, and pharmaceutical chemistry at UC San Francisco (UCSF). "We discovered that molecules that alter viral expression noise also reduced HIV persistence."

"It was pretty startling when these same molecules worked in stem cells," he adds. "And, trying to understand how these molecules work turned into a search for a fundamental biological mechanism."

When a gene is turned on, or expressed, the information stored in the gene is used to build substances that a cell needs to function. But the vast majority of genes do not stay on all the time.

Most genes toggle--or switch between active and inactive states, turning on and off--every few minutes to every few hours. This creates noise in gene-expression levels. HIV, once it infects a cell, acts very much like a human gene and exhibits similar noise properties.

While studying HIV, Weinberger's team uncovered the existence of molecules that could enhance noise, or switch the expression machinery between active and inactive states, but, curiously, without affecting the average level of expression. They called them noise-enhancer molecules. These molecules acted like Bunsen burners for gene expression and increased the efficiency of drugs designed to wake HIV from a silent state, which is part of a strategy to cure patients.

But how these noise-enhancer molecules could boost noise without altering expression levels was completely unknown.

On a whim, the scientists examined what happened when noise-enhancer molecules were applied to embryonic stem cells without HIV. Amazingly, these molecules had the same effect on stem cells as they did on HIV, amplifying noise without changing the expression level. They also accelerated the stem cells' ability to transform into other cell types.

The team's main findings were that the mechanism by which noise-enhancer molecules boost noise involves a process for repairing certain errors in DNA that may arise when genes are turned on. A key component of this DNA repair process is a protein known as AP endonuclease 1 (Apex1).

"We found that Apex1 directly alters the shape of the DNA double helix in a way that first impedes and then accelerates gene expression," says the study's first author, Ravi Desai, an MD/PhD student in the UCSF Medical Scientist Training program in Weinberger's lab.

The team showed that Apex1 is the critical factor in this new DiThR pathway, which increases noise across the entire array of genes in the genome.

Making Differentiation More Efficient

Next, because some noise-enhancer molecules are found naturally in stem cells, the team asked how the newly discovered mechanism might affect the transformation of stem cells into other cell types. They treated mouse embryonic stem cells with both noise-enhancer molecules and substances that prompt differentiation into other types of cells.

They found that the increased noise imparted by DiThR allowed the stem cells to differentiate more efficiently, like the Bunsen burner does for chemical reactions.

What's more, the mechanism also worked in the opposite direction. It improved the efficiency of a process that turns differentiated cells back into pluripotent stem cells, which have the potential to become several different cell types--a finding that earned Gladstone scientist Shinya Yamanaka, MD, PhD, a Nobel Prize in 2012.

"Our findings suggest that the DiThR pathway makes cells more responsive to the signals that guide their fate," says Desai. "That means this mechanism may play a fundamental biological role in the development of embryos."

Looking ahead, the research team plans to further map out the various components of the DiThR pathway.

"Our goal now is to understand how DiThR is regulated and if associated noise-control pathways exist," Weinberger says. "Ultimately, approaches to harness these pathways could dramatically improve cellular engineering and stem cell-based therapies."

CHAPEL HILL, North Carolina--Researchers at the UNC Lineberger Comprehensive Cancer Center demonstrated in a clinical trial in Malawi that a five-drug combination chemotherapy provided curative benefit compared to current standard-of care-therapy in people diagnosed with lymphoma, and now they have determined this option is also cost-effective. The economic finding appeared July 22, 2021, in Lancet Global Health.

The clinical trial results, reported May 19, 2021, in Lancet Global Health involved 37 people with diffuse large B-cell lymphoma (DLBCL). The majority of patients were also HIV-positive, which greatly increased their risk of DLBCL; all HIV-positive patients were treated with anti-viral drugs. The trial participants received a standard four-drug chemotherapy combination known as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) along with rituximab, an antibody therapy. After two years of follow-up, 55 percent of the patients were still alive, an outcome that is higher than CHOP alone based on earlier studies.

With the trial results in hand, the researchers wanted to know if either CHOP or CHOP plus rituximab were cost-effective treatments in a resource-limited setting. Demographically, Malawi is a sub-Saharan country in Africa with roughly 19 million residents. The healthcare resources available in the 2017-2018 government budget for Malawi were $170 million dollars (about $9 per person); external donors contribute approximately another $350 million annually to health expenditures.

UNC Lineberger's Matthew Painschab, MD, lead author of the economic analysis and co-lead author of the treatment efficacy study, said cost-effectiveness analyses allow comparisons across diverse diseases so that limited resources can be optimally allocated.

"Without such analyses, relatively expensive upfront costs for cancer medicines will often seem prohibitively costly for a relatively small number of patients compared to other available public health interventions," said Painschab, assistant professor in the Division of Hematology at UNC School of Medicine and a member of UNC-Project Malawi. "We demonstrated that an upfront, time-limited expense followed by decades of healthy life may be a prudent investment, relative to other accepted interventions such as daily, lifelong antiretroviral treatment for HIV."

On a per-patient basis, comparing supportive care (no chemotherapy) to chemotherapy with CHOP, chemotherapy prevented more than seven disability-adjusted life years (DALYs) at a cost of $193 per DALY prevented. One DALY is a year of life lived in perfect health and therefore losses represent both years lost from dying early as well as quality life-years lost to disability. Adding rituximab to CHOP prevented about three DALYs at a cost of $1,145 per DALY.

"Our analysis has important implications for saving lives," said Painschab. "Though precise estimates of cancer incidence are lacking, we estimate it would cost about one million dollars annually to treat all cases of DLBCL in Malawi with CHOP, saving an estimated 252 lives. For two million dollars more annually, we could add rituximab, which costs about $500 a dose in Malawi, and the five-drug regimen could save an additional 100 lives."

In addition to the recently published studies, the researchers are conducting some of the first molecular profiling studies for HIV-associated lymphoma in the world. They hope that greater biologic understanding of DLBCL in Malawi may lead to more targeted, safe and effective treatment strategies. They note there is still much work to be done in this area, both in the U.S. and Malawi.

"Proving that treating DLBCL in Malawi can be cost-effective was not necessarily intuitive, as upfront costs of treating cancer patients often seem daunting for countries facing many competing health priorities," noted Stephen Kimani, MD, a fellow in Hematology/Oncology at UNC-Chapel Hill and research fellow at UNC Project Malawi and first author of the study that found the combination therapy was effective. "Investments in high-quality, potentially curative cancer care may be very prudent when short-term costs result in a normal life expectancy thereafter. These sorts of demonstrations will hopefully spur a treatment access movement for cancer that is analogous to what has occurred for HIV."

ROCHESTER, Minn. -- A new study by Fergus Couch, Ph.D., of Mayo Clinic Cancer Center, along with collaborators from the CARRIERS consortium, suggests that most women with breast cancer diagnosed over 65 should be offered hereditary cancer genetic testing. The study was published Thursday, July 22, in the Journal of Clinical Oncology.

Dr. Couch says that women over 65 rarely qualify for hereditary cancer genetic testing based on current testing guidelines because they are thought to exhibit low rates of genetic mutations in breast cancer genes.

"Most studies of breast cancer genes have not looked at older women, those who were diagnosed over the age of 65," says Dr. Couch. He says these studies have mainly tested women with a strong family history of breast or ovarian cancer rather than those in the general breast cancer population. By studying older women from the general breast cancer population, the investigators aimed to determine if these women should be routinely offered genetic testing.

"We were not sure what this study of the older breast cancer population would yield, but our results support broader testing, regardless of age or family history," says Dr. Couch.

The researchers evaluated women with breast cancer diagnosed after 65 and matched unaffected women from the large population in the CARRIERS study for age, race, and ethnicity.

"We found that mutations in actionable breast cancer risk genes were present in 3.2% of the women with breast cancer," says Dr. Couch.

When the researchers considered only high-risk breast cancer genes, including BRCA1, BRCA2 and PALB2, they found that 1.35% of women with breast cancer exhibited mutations and that more than 2.5% of women with estrogen receptor-negative breast cancer had high-risk mutations, regardless of their age.

"As 2.5% mutation frequency is often used to trigger genetic testing, these results suggest that all women with estrogen receptor-negative breast cancer ? and perhaps all women with breast cancer, including those diagnosed over age 65 ? should be offered hereditary breast cancer testing," says Dr. Couch.

Dr. Couch also notes that women over 65 with high-risk mutations may benefit from targeted therapies and improved risk assessment for secondary breast cancers. He adds that family members of these women also may benefit from risk assessment.

Osaka, Japan - Gross chromosomal rearrangements—where portions of the genome become moved, deleted, or inverted—can lead to cell death and diseases such as cancer in complex multicellular organisms. However, the details of how exactly these occur remain unknown. Now, studies in a single-celled organism called fission yeast have found evidence for the involvement of a protein called Rad8.

When DNA replicates or repairs itself, three copies of a protein called PCNA bind together and form a ring-like structure surrounding the DNA strand. This ring structure acts like a clamp and slides along the DNA strand. The team showed that Rad8 attaches a small molecule called ubiquitin to this PCNA protein at the amino acid in the 107th position. This amino acid is a lysine molecule, termed "lysine 107," located at the interface between the different PCNA molecules.

Ubiquitin attachment is a common biological process serving a variety of functions. "In this case, the attachment of ubiquitin at lysine 107 weakens the interactions between PCNA molecules and changes the structure of the ring of proteins," says lead author of the paper Jie Su. This then alters how PCNA functions and leads to the formation of gross chromosomal rearrangements instead of accurate DNA repair.

Rad8 is a ubiquitin ligase, the molecule that is responsible for attaching a ubiquitin to a particular place on another protein. "We found that Rad8 works together with another protein called Mms2-Ubc4, a ubiquitin conjugating enzyme," says Takuro Nakagawa, senior author. "Mms2-Ubc4 brings in the ubiquitin molecule, and Rad8 then transfers the ubiquitin to lysine 107 of PCNA." The combined action of Rad8 and Mms2-Ubc4 is therefore responsible for causing gross chromosomal rearrangements.

But how does this information on a single-celled organism like yeast relate to cancer in complex organisms such as humans? Not much is known about HLTF, the human equivalent to Rad8, but it is seen to be activated and upregulated in cancer. Inhibition of HLTF, or inhibiting the attachment of ubiquitin to PCNA at the human equivalent of the lysine 107 position, could therefore be a very promising new strategy for cancer therapies.

UNIVERSITY PARK, Pa. -- Infection with dengue virus makes mosquitoes more sensitive to warmer temperatures, according to new research led by Penn State researchers. The team also found that infection with the bacterium Wolbachia, which has recently been used to control viral infections in mosquitoes, also increases the thermal sensitivity of the insects. The findings suggest that global warming could limit the spread of dengue fever but could also limit the effectiveness of Wolbachia as a biological control agent.

"Dengue fever, a potentially lethal disease for which no treatment exists, is caused by a virus, spread by the bite of the mosquito Aedes aegypti. This mosquito is also responsible for transmitting a number of disease-causing viruses, including Zika, chikungunya and yellow fever," said Elizabeth McGraw, professor and head of the Department of Biology, Penn State. "Aided by increasing urbanization and climate change, this mosquito's range is expected to overlap with 50% of the world's population by 2050, dramatically increasing the number of people who could potentially be exposed to these viruses."

In recent years, research groups around the world have attempted to control these viruses by infecting Ae. aegypti with the bacterium Wolbachia pipientis and then releasing the mosquitoes into the environment, McGraw explained.

"Wolbachia have been shown to prevent viruses, including dengue, from replicating inside mosquitoes," she said. "Importantly, Wolbachia are passed down to the mosquitoes' offspring, making them a self-propagating and lower-maintenance approach to disease control in the field."

McGraw noted that both dengue virus and Wolbachia infect a variety of tissues throughout a mosquito's body, and although they are not toxic, they do evoke an immune stress response.

"Since mosquitoes that are infected with dengue virus and/or Wolbachia are already suffering a stress response, we thought that they would be less well equipped to deal with an additional stressor, such as heat," she said.

To investigate the effects of heat on dengue and Wolbachia-infected mosquitoes, the team placed infected mosquitoes in sealed vials and then submerged the vials into a water bath heated to 42°C -- a realistic temperature extreme that a mosquito might encounter in the wild. The researchers then measured how long it took for the mosquitoes to become immobilized and compared the time to uninfected control mosquitoes. Their findings appear today (July 22) in the journal PLOS Neglected Tropical Diseases.

"After a lot of trial and error, we were successfully able to adapt a heat-based physiological assay commonly used in Drosophila [a model fruit fly species] to our mosquito species to examine the impact of both dengue virus and Wolbachia infections on thermal sensitivity," said Fhallon Ware-Gilmore, graduate student in the Department of Entomology and Center for infectious Disease Dynamics at Penn State who led the project.

The team found that mosquitoes infected with dengue virus showed greater sensitivity to heat; they became immobilized almost three times faster than uninfected mosquitoes when placed in the hot water bath. Similarly, mosquitoes infected with Wolbachia became immobilized four times faster than uninfected mosquitoes.

Interestingly, Ware-Gilmore said, the two agents -- dengue virus and Wolbachia bacteria -- did not have an additive effect on mosquito thermal tolerance.

"You might expect that mosquitoes infected with both dengue virus and Wolbachia might become immobilized even faster than mosquitoes infected with only one or the other microbe, but we did not find an additive effect," she said. "We are, however, the first to show that viral infection can affect mosquito thermal tolerance, specifically by reducing mosquito survival during exposure to high heat. And, while there are some known interactions between heat and Wolbachia, particularly in immature stages, this is also the first study to show that adult infected-mosquitoes have reduced survival during heat stress."

Ware-Gilmore noted that future climate models point to increasing frequencies of extreme temperature events, making short exposures to high temperatures a threat to the survival of dengue and Wolbachia infected mosquitoes.

"At lower temperatures, we know that dengue virus may fail to replicate fast enough to make it through the mosquito body and be transmitted, thereby reducing transmission risk," she said. "At higher temperatures, while the virus may replicate faster, our work suggests that a corresponding reduction in mosquito thermal tolerance may act as a counterforce on mosquito survival that could help to reduce transmission and potentially human disease incidence in hotter, more climate-variable regions. Similarly, our work suggests that Wolbachia may fail to work as a biocontrol agent in hotter regions given its effect on mosquito survival."

The discovery of a Roman road submerged in the Venice Lagoon is reported in Scientific Reports this week. The findings suggest that extensive settlements may have been present in the Venice Lagoon centuries before the founding of Venice began in the fifth century.

During the Roman era, large areas of the Venice Lagoon which are now submerged were accessible by land. Roman artefacts have been found in lagoon islands and waterways, but the extent of human occupation of the lagoon during Roman times has been unclear.

Mapping the lagoon floor using sonar, Fantina Madricardo and colleagues discovered 12 archaeological structures aligned in a northeasterly direction for 1,140 metres, in an area of the lagoon known as the Treporti Channel. The structures were up to 2.7 metres tall and 52.7 metres long. Previous surveys of the Treporti Channel uncovered stones similar to paving stones used by Romans during road construction, indicating that the structures may be aligned along a Roman road. The researchers also discovered an additional four structures in the Treporti Channel that were up to four metres tall and 134.8 metres long. Based on its dimensions and similarity to structures discovered in other areas, the largest of these structures is thought to be a potential harbour structure, such as a dock. Previously collected geological and modelling data indicates that the road is located on a sandy ridge that was above sea level during the Roman era but is now submerged in the lagoon.

The findings suggest that a permanent settlement may have been present in the Treporti Channel during the Roman era. The authors propose that the road may have been linked to a wider network of Roman roads in the Italian Veneto Region and may have been used by travellers and sailors to journey between what is now the city of Chioggia and the Northern Venice Lagoon.

Newly-hatched pterosaurs may have been able to fly but their flying abilities may have been different from adult pterosaurs, according to a study published in Scientific Reports.

Pterosaurs were a group of flying reptiles that lived during the Triassic, Jurassic and Cretaceous Periods (228 to 66 million years ago). Due to the rarity of fossilised pterosaur eggs and embryos, and difficulties distinguishing between hatchlings and small adults, it has been unclear whether newly-hatched pterosaurs were able to fly.

Darren Naish and colleagues modelled hatchling flying abilities using previously obtained wing measurements from four established hatchling and embryo fossils from two pterosaur species, Pterodaustro guinazui and Sinopterus dongi. The authors also compared these wing measurements with those of adults from the same species and compared the strength of the humerus bone, which forms part of the wing, of three hatchlings with those of 22 adult pterosaurs.

The researchers found that hatchling humerus bones were stronger than those of many adult pterosaurs, indicating that they would have been strong enough for flight. The authors also found that while hatchlings had long, narrow wings suited to long-distance flight, their wings were shorter and broader than those of adult pterosaurs, with a larger wing area relative to hatchling mass and body size. These wing dimensions may have may have made hatchlings less efficient than adult pterosaurs at long-distance travel, but may have resulted in them being more agile fliers, enabling them to suddenly change direction and speed.

The authors speculate that the agile flying style of hatchling pterosaurs may have enabled them to rapidly escape predators and made them better suited to chasing nimbler prey and flying amongst dense vegetation than adult pterosaurs. This could indicate that pterosaurs occupied dense habitats as hatchlings and open environments as adults, according to the authors.

Geneticists from Trinity College Dublin have discovered how a specific genetic mutation called H3K27M causes a devastating, incurable childhood cancer, known as diffuse midline glioma (DMG), and - in lab studies working with model cell types - successfully reverse its effects to slow cancer cell growth with a targeted drug.

Their landmark work - just published in leading international journal, Nature Genetics and supported by Worldwide Cancer Research and The Brain Tumour Charity - translates crucial new understanding of the genetics of DMG progression into a highly promising, targeted therapeutic approach and offers significant hope of improved treatments in the future.

The scientists now call for clinical trials to begin imminently, in which an already approved class of drugs called "EZH2 inhibitors" can be assessed. These drugs target the same key biological pathway involved in DMG as they do successfully in lymphomas and sarcomas -- two cancers common in adults.

Key findings and implications

The scientists behind this important work discovered:

How a specific genetic mutation called H3K27M causes DMG

How to target this cancer-causing gene with a drug that slows cancer cell growth

They have also established a specific model cell line for evaluating further targeted DMG approaches

Adrian Bracken, Professor in Trinity's School of Genetics and Microbiology, led the exciting research.

He said: "We've taken a huge step forward in our study of DMG tumours and hope that the insights will help us design and implement precision oncology-based treatment approaches in DMG patients in the future. Crucially, 'EZH2 inhibitor' drugs have already received approval from the United States Food and Drug Administration for the treatment of two types of adult cancer. We propose these drugs could be impactful for children with DMG and, as a result, call for clinical trials to begin next.

"Ultimately, we hope that our work - together with that of others focused in this area - will lead to curative clinical approaches for what is a truly terrible disease that can devastate families and for which there are currently no therapeutic options."

Paediatric gliomas - harrowing, devastating cancers

Paediatric gliomas like DMG are among the most devastating of childhood cancers. Tumours typically arise in the brain and are very challenging to treat, with prognosis extremely poor. As such, effective therapeutic options are urgently needed.

Dr Jane Pears, paediatric consultant oncologist at Our Lady's Children's Hospital, Crumlin, who treats children with this disease said: "Despite combined best efforts, these tumours remain a devastating diagnosis for children and their families. The best treatment we can currently offer may extend survival for a few months but is not curative. We are now entering an exciting era of expansion of our knowledge of this disease at a molecular level, which in turn will lead us towards more targeted treatments. Thanks to collaborative translational efforts between scientists, such as Prof. Bracken and his team working in the laboratory, and doctors in the clinical setting, this will hopefully lead to the improved outcomes that we all so dearly wish to see."

Speaking to the importance of the work, Maeve Lowery, Professor of Translational Cancer Medicine at Trinity, and Academic Director of the Trinity St James's Cancer Institute (TSJCI) said: "These findings have the potential to transform the treatment landscape of DMG tumours and improve outcomes for children with this challenging disease. Importantly, this pivotal work illustrates the success of a precision oncology approach - where understanding how cancers develop on a genomic level can accelerate the development of more effective treatments with less side effects. The Precision Oncology Research Program at TSJCI, led by Prof Bracken, will build on this success to continue to develop new and innovative treatment strategies for adult and childhood cancers."

Dr Becky Birch, Head of Research at The Brain Tumour Charity, which helped fund the study, said: "This is a really promising discovery that we hope will now pave the way for new and targeted treatments to be developed for children with diffuse midline gliomas (DMGs). With average survival still heartbreakingly short at less than 12 months, we urgently need to find new options to help slow the growth of this rare and often-inoperable cancer and give children diagnosed more time to live. It's really exciting that we now better understand how a specific genetic mutation may be driving the disease, and even more so that drugs that may inhibit this process have already been tested in other cancers. If further research can now design EZH2 inhibitors to more effectively target DMG cells, we hope these drugs can be quickly advanced into clinical trials for children diagnosed with this devastating disease."

Developing cancer treatments - why this research is different

Ordinarily, developing effective cancer treatments can take decades; indeed, it can take years before scientists are able to develop model systems in relevant cell types that afford them the chance to "look under the genetic bonnet".

Such investigations can first help us understand how cancers function. That information then provides the all-important clues as to how we can fight them. Further lab-based studies can hone these approaches, ultimately opening the doors to clinical trials and, if we're lucky, improved treatments.

The scientists behind this study have therefore taken great strides in the battle against DMG, having discovered key aspects of this disease at a genetic level; proposed an available strategy to target it; and created a model of the disease that can be used in continued work to advance further improved treatment strategies.

NOTICE: This summary has been updated to correct misspellings of the last names of both Perspective authors. The Perspective authors are Sanne Cottaar and Paula Koelemeijer. We apologize for our error.

The first direct seismic observations from NASA’s InSight lander, presented in three studies in this issue, provide clues to the composition of Mars. Researchers across these studies report preliminary findings from the Insight mission and begin to map – for the first time – the interior of a planet apart from Earth. “These three studies provide important constraints on the present-day structure of Mars and are also key for improving our understanding of how the planet formed billions of years ago and evolved through time,” write Sanne Cottaar and Paula Koelemeijer in a related Perspective. Studying a planet’s interior layers – its crust, mantle and core – can reveal key insights into its formation and evolution, as well as uncovering any geomagnetic and tectonic activity it hosts. Such deep interior regions can be probed by measuring the waves that travel through the planet’s body following seismic events like a quake. Such methods have been instrumental in surveying the internal characteristics of Earth.

In early 2019, NASA’s Martian lander InSight (Interior Exploration using Seismic Investigations, Geodesy and Heat Transport) began to detect and record marsquakes from its position on the surface of Mars, including several subcrustal quakes that resemble tectonic events on Earth. Brigitte Knapmeyer-Endrun and colleagues used marsquakes and ambient seismic noise to image the structure of the Martian crust below the InSight landing site, finding evidence for a multi-layered crust with either two or three interfaces. Extrapolating this data to the entire planet, Knapmeyer-Endrun et al. show how the average thickness of Mars’ crust lies between 24 and 72 kilometers (km). Amir Khan et al. used direct and surface reflected seismic waves from eight low-frequency marsquakes to probe deeper and reveal the structure of Mars’ mantle to a depth of nearly 800 km. Their findings suggest that a thick lithosphere lies close to 500 km below the surface and, like the Earth, likely has a low-velocity layer beneath it. According to Khan et al., Mars’ crustal layer is likely highly enriched in heat-producing radioactive elements, which heats this region at the expense of the planet’s interior. Deeper still, Simon Stähler and colleagues used the faint seismic signals reflected off the Martian core-mantle boundary to investigate the Martian core. They found that Mars’ relatively large liquid metal core has a radius of nearly 1,830 kilometers and begins roughly halfway between the surface and the center of the planet, suggesting that the planet’s mantle consists of only one rocky layer, rather than two, like in Earth. According to Stähler et al., the findings indicate that the iron-nickel core is less dense than previously thought and enriched in lighter elements. “Direct seismic observations on Mars represent a major leap forward in planetary seismology,” write Cottaar and Koelemeijer. “Over the coming years, as more marsquakes are measured, scientists will refine these models of the red planet and reveal more of Mars’ enigmatic mysteries.”

Journal

Science

DOI

10.1126/science.abf2966

Of the nearly 100 SARS-CoV-2 vaccines currently undergoing clinical trials, only seven are delivered intranasally - despite this vaccine type's long success in providing protection from influenza. In a Perspective, Frances Lund and Troy Randall argue that intranasal vaccines could be beneficial in the continued fight against COVID-19, especially considering respiratory viruses like SARS-CoV-2 predominantly enter the nasal passage first. Currently authorized COVID-19 vaccines are delivered via intramuscular injection, where they elicit systemic immune responses and central immune memory. While several versions are currently being administered worldwide, many more are in development. However, according to the authors, given the respiratory propensity of the virus, it is surprising that so few intranasal vaccines, which deliver their antigens directly to the site of infection, are being considered. Here, Lund and Randal discuss the potential of intranasal COVID-19 vaccines, highlighting their advantages, drawbacks and rationale for use over intramuscular options. In addition to being needle-free, intranasal vaccines provide two additional layers of protection compared to intramuscular vaccines. Intranasal vaccine-elicited immunoglobulin A (IgA) and resident memory B and T cells in the nasal passages and upper airways provide a barrier to infection, impede viral replication and reduce viral shedding. Lund and Randall note that effective vaccination strategies need not be restricted to a single delivery system and suggest that an ideal vaccination strategy may consist of an intramuscular vaccine combined with an intranasal booster.

Like dreaming of walking through a world they've not yet experienced, the retinas of neonatal mice practice for what mature eyes must later process by generating spontaneous patterns of activity that mimic the perception of directional movement through space, according to a new study. Essential functions in the mammalian visual system, including the ability to locate objects and detect motion, are present even at the first onset of vision. Optic flow, the perceived relative motion of objects and surfaces that seemingly stream by a field of vision during movement, is one of these functions. However, how the visual system organizes its functional characteristics before visual sensory experience is even possible remains unclear. And, while previous studies have revealed spontaneous retinal activity prior to functional vision, the role of this spontaneous activity in visual system development is unknown. Xinxin Ge and colleagues examined the spontaneous activity of ganglion cells in mice at multiple ages throughout development in vivo and discovered an intrinsic mechanism in the developing retina that prepares the downstream visual system for motion detection before the newborn mice can see. According to Ge et al., spontaneous waves of retinal activity during this transient window flow in the same pattern as would be produced if the mouse was physically moving through the environment. This patterned, spontaneous activity effectively trains the visual system and the associated brain circuits to process directional information and to interpret movement through space at eye opening.

Advances in microscopy have enabled researchers to picture loops of DNA strands for the first time. The images reveal how the human genome organises itself in three-dimensional space at much higher resolution than previously possible.

The findings, published in a new study in the journal Molecular Cell, also reveal that the process of DNA being copied into RNA - transcription - indirectly shapes the architecture of the genome. An international team led by Pia Cosma at the Centre for Genomic Regulation (CRG) in Barcelona and Melike Lakadamyali at the Perelman School of Medicine at the University of Pennsylvania in the United States found that transcription generates a force that moves across DNA strands like ripples through water.

Known as supercoiling, the force causes structural proteins known as cohesins to 'surf' across DNA strands, changing the scaffold's architecture and morphing the overall shape of the genome. While it is known that genome organization regulates gene transcription, it is the first-time researchers have found transcription to impact genome organization the other way round through supercoiling.

According to the researchers, the discovery of this new force may have future implications for the understanding of genetic diseases such as Cornelia de Lange syndrome, which is caused by mutations in genes encoding for cohesin or cohesin regulators. The findings may also be relevant for developmental disorders linked to how chromatin folds, as well as opening new avenues of research in genome fragility and cancer development.

The researchers studied the biological mechanisms that enable two metres of DNA to be squeezed into a tight space in each human cell. In this condensed state, the DNA, also known as chromatin, contains many loops that bring together different regions of the genome that would normally be far apart. The resulting physical proximity is important for transcribing DNA into RNA which then makes proteins, making chromatin looping a fundamental biological mechanism for human health and disease.

According to Vicky Neguembor, Staff Scientist at the CRG and first author of the paper, "Chromatin looping is what allows individual cells to switch different information on and off, which is why for example a neuron or a muscle cell with the same genomic information can still behave so differently. Loops are also one of the ways the genome gets compacted to fit into the nucleus."

"What we have found is important because it shows the biological process of transcription plays an additional role beyond its fundamental task of creating RNA that eventually turn into proteins. Transcription indirectly compacts the genome in an efficient manner and helps different regions of the genome talk to each other."

Previous techniques used to study this process could predict where loops were located but not their actual shape or how they look like within the cells. To improve image resolution, the researchers used a special type of microscopy that use high-power lasers under specific chemical conditions to track the blinking of fluorescent molecules. The technique provides ten times higher resolution than conventional microscopy, and combined with advanced imaging analysis techniques the researchers were able to identify chromatin loops, and the cohesins that hold the structure together like paper clips, within intact cells.