Culture

Philadelphia, April 15, 2021--Researchers at Children's Hospital of Philadelphia (CHOP) have identified a key target that may be responsible for treatment failure in about 30% of patients with hemophilia A. The target, known as B cell activating factor (BAFF), appears to promote antibodies against and inhibitors of the missing blood clotting factor that is given to these patients to control their bleeding episodes. The findings, published in the Journal of Clinical Investigation, raise the possibility of using anti-BAFF therapies, potentially in combination with immune tolerance therapies, to tame the immune response in some patients with severe hemophilia A.

Hemophilia A is the most common inherited bleeding disorder, affecting 1 in 10,000 men worldwide. The condition is the result of a missing coagulation factor known as factor VIII (FVIII), which leads to uncontrolled bleeding episodes, joint disease, and increased risk of death. To control the disease, patients receive infusions of the FVIII protein to replace the missing coagulation factor, but for reasons scientists haven't fully understood, approximately 30% of patients with severe hemophilia A develop neutralizing antibodies known as FVIII inhibitors that prevent the treatment from working, which negatively affects disease management.

Some patients resistant to FVIII protein replacement therapy receive immune tolerance induction (ITI), wherein high doses of FVIII are given over a period of one to two years to build up tolerance. However, ITI is demanding on patients and families, and the treatment - which is both costly and invasive - isn't always effective.

To both uncover the mechanism behind the anti-FVIII immune response and expose a potential target, the researchers explored the possible role of BAFF in regulating FVIII inhibitors. Prior studies have shown that high plasma BAFF levels are implicated in some autoimmune diseases, as well as antibody-mediated transplant rejections. Using both adult and pediatric hemophilia A patient samples and hemophilia A mouse models, the researchers explored their hypothesis that BAFF may play a role in the generation and maintenance of FVIII antibodies.

The research team, led by CHOP and Indiana University School of Medicine, found that BAFF levels were elevated in pediatric and adult patients who were resistant to FVIII replacement therapy; after successful ITI, those BAFF levels decreased to levels similar to non-inhibitor patients. In patients for whom ITI was unsuccessful, BAFF levels remained elevated. Working in mouse models, the researchers found that giving the mice prophylactic anti-BAFF therapy before FVIII treatment prevented inhibitors. In mice with established inhibitors, the researchers found that treating the mice with both anti-BAFF and rituximab, a chimeric antibody that depletes mature B cells, dramatically reduced FVIII inhibitor titers by, at least in part, reducing FVIII-specific plasma cells.

"Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors, as well as anti-FVIII B cells," said co-senior author Valder R. Arruda, MD, PhD, a researcher in the Division of Hematology at CHOP and director of CHOP's NIH-funded Center for the Investigation of Factor VIII Immunogenicity. "Given that an FDA-approved anti-BAFF antibody is currently used to suppress the immune response in autoimmune diseases, future research should explore the use of this treatment in combination with rituximab to achieve better outcomes for hemophilia A patients resistant to FVIII protein replacement therapy."

April 15, 2021 - Decades after their days on the gridiron, middle-aged men who played football in high school are not experiencing greater problems with concentration, memory, or depression compared to men who did not play football, reports a study in Clinical Journal of Sport Medicine. The journal is published in the Lippincott portfolio by Wolters Kluwer.

"Men who played high-school football did not report worse brain health compared with those who played other contact sports, noncontact sports, or did not participate in sports during high school," according to the new research, led by Grant L. Iverson, PhD, of Harvard Medical School. The study offers reassurance that playing high-school football is not, in itself, a risk factor for cognitive or mood disorders or other problems that have been linked to a history of repeated concussions in professional football players.

No increase in cognitive, mood, or pain problems in high-school football players

The researchers analyzed responses to an online survey completed by 407 men aged 35 to 55 years. Of these, 123 reported playing football in high school. The study excluded men with recent concussions or those who played semi-professional football.

Rates of a wide range of brain health problems were assessed for the ex-football players, compared to men who played other contact sports, non-contact sports, or no sports. Men who played contact sports, especially football, had more concussions than the other two groups: more than 80 percent of men who played high-school football reported at least one concussion.

Overall, the former football players were no more likely to have problems with brain health in their mid-thirties to mid-fifties. High-school sports experience was unrelated to problems with depression, anxiety, or anger; concentration or memory problems; or headaches, migraines, neck or back pain, or chronic pain. For football and other contact sports, rates of brain health problems were unrelated to years playing sports.

There were a few significant differences between groups. Men who played high-school football were more likely to report sleep problems: 39 percent, compared to about 20 to 30 percent of the other groups. Ex-football players were also more likely to be prescribed medications for headaches or chronic pain.

The study identified several factors that predicted an increased rate of memory problems, including sleep difficulties, anxiety, history of concussions, and feeling depressed. Although some of these factors were more common among former football players, playing football itself was not a significant predictor.

Reports of long-term neurological abnormalities among former National Football League (NFL) players have raised concerns over the brain health of men who played football at the high-school level. Previous studies have found no increase in mental health, cognitive, or mood problems in former high-school football players. The new research - partly supported by the NFL - is the first to focus on middle-aged men.

Dr. Iverson and colleagues emphasize that, "without question," some men who played high-school football will develop problems with psychological health and cognitive function later in life. However, these risks "do not seem to be greater than the rates in men who did not play football."

The researchers note that there are strong associations between depression and anxiety, headaches and migraine, chronic pain, and memory problems, which commonly occur together and are "mutually amplifying." Dr. Iverson and colleagues conclude, "[E]vidence-based treatment and rehabilitation for these problems can substantially reduce symptoms and improve functioning and quality of life."

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high fatality rate. Currently, chemotherapy is the major treatment option, but the clinical result is unsatisfactory. A research team led by biologists at City University of Hong Kong (CityU) has identified and characterised a set of specific super-enhancers that stimulate the activity of the related critical cancer genes. The research has also discovered that the deletion of certain specific super-enhancers can reduce tumour cell growth. The latest findings may help discover new effective drug targets for TNBC patients to improve their survival chance.

Traditionally, cancer research has been focused on identifying gene mutations in different types of breast cancer. In contrast, how the epigenetic circuit affects cancers remains poorly characterised.

Epigenetic change: another way to induce cancers

While genetic mutation is a change in one or more parts of the DNA sequence, an epigenetic change also changes a gene's DNA, but not at the sequence level. Instead, special marks, called epigenetic marks, are added to or removed from the DNA sequence to change how a protein works in the body. And specific epigenetic marks are contained in super-enhancers. Deregulation, meaning abnormal regulation, of super-enhancers can therefore induce high production of cancer driver proteins and promote cancer formation.

To find out how these super-enhancers can affect TNBC cells, Dr Rebecca Chin Yuet-ming, a cancer biologist, and Dr Wang Xin, a computational biologist, both from the Department of Biomedical Sciences at CityU, joined hands together to lead the study. Their findings were published in the scientific journal Nature Communications, titled "Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling".

Integrating multi-level epigenomic sequencing data for 21 cell lines with gene expression data and clinical information for over 4,000 patient samples, Dr Wang's team used the method of multiomic profiling to perform in-depth data mining and built a specific super-enhancer-target regulatory network for all types of breast cancer.

A key regulator of cancer growth

"Our integrated analyses reveal that the clustering of super-enhancers is sufficient to characterise different subtypes of breast cancer," said Dr Wang. "Importantly, based on the regulatory network, we identify the gene FOXC1 as a key regulator of cancer growth and metastasis which is driven by a TNBC-specific super-enhancer. The FOXC1 is predictive of patients' survival and help develop therapeutic strategies targeting epigenetic circuits."

A number of key cancer driver genes (oncogenes), including FOXC1 and MET, are known to promote cancer growth and are associated with worse survival in TNBC patients. However, very little is known about how these genes being specifically highly expressed in TNBC. "Our network biology analysis uncovers FOXC1 as the master regulator of a large set of genes in metastasis. Using CRISPR/Cas9 technology, we further directly demonstrate that super-enhancer drives FOXC1 expression, and importantly, enhances cancer growth in mouse models," said Dr Chin.

By performing analysis on in-house clinical samples, the teams also learnt that FOXC1 upregulation is associated with higher tumour grade, cell division rate, and tumour-infiltrating immune cells.

Another TNBC-specific gene

The researchers went a step further and applied the integrated method to discover another new TNBC-specific gene ANLN. ANLN has been shown to be correlated with TNBC recurrence and poor survival rate in previous studies. In this study, the team found that the deletion of super-enhancer of ANLN could reduce the protein expression and tumour cell growth. "These findings demonstrate the power of leveraging epigenetic landscape to identify novel players in TNBC, paving the way to discover more effective therapeutic targets for this aggressive form of breast cancer," Dr Chin said.

Breast cancer is the most common type of cancer in women, with about 4,600 new cases of breast cancer being diagnosed in Hong Kong each year. Among all breast cancers, TNBC accounts for about 10-15%. Different from other types of breast cancer, TNBC does not express hormone receptors (namely estrogen receptors and progesterone receptors) and a protein called Her2, and that's where its name "triple-negative breast cancer" comes from. So TNBC is quite "invisible", and it is also difficult to heal as the scientists have not found an effective "target" on the TNBC cancer cell for the drugs to attack.

TNBC usually develops between the ages of 40-50, younger than the average breast cancer patients. Also, the time for TNBC metastasis is shorter. Patients typically relapse within 5 years of treatment, and is considered to have a poorer prognosis than other breast cancer forms.

"We hope our findings can contribute to the development of effective drugs for TNBC patients to improve their chance of survival," said Dr Chin.

More than 30 years ago, wilderness areas - natural areas that have not been considerably modified by humans - were identified as priorities of conservation and protection actions. Only recently has there been a push to define how to measure wilderness, with a focus on intact habitats. The integrity of natural ecosystems has also been recognized by the UN Convention on Biological Diversity as an important goal in the post-2020 global biodiversity framework. "We know intact habitat is increasingly being lost and the values of intact habitat have been demonstrated for both biodiversity and people," says Dr Andrew Plumptre from the Key Biodiversity Areas Secretariat in Cambridge, lead author of the study, "but this study found that much of what we consider as intact habitat is missing species that have been hunted by people, or lost because of invasive species or disease."

Defining intactness

Currently, there is no common definition of intactness. Past assessments, which focused on mapping human influence on habitat intactness, created maps of anthropogenic impact that independently estimated that between 20% and 40% of the planet's terrestrial surface remains free from major human disturbance (such as human settlements, roads, and light and noise pollution).

In the new study, Plumptre and colleagues took a different approach. Instead of focusing on human impact, they made a scoping of Key Biodiversity Areas (KBA) Criterion C sites, which states that an intact ecological community has the full complement of species known to occur in a particular site in their natural abundances (ie no known loss of animals in that area), relative to a regionally appropriate benchmark. As a benchmark, the authors chose the year 1500 CE, as this is the baseline date for assessing species extinctions within the IUCN Red List of Threatened Species. In addition to habitat intactness, the authors also assessed faunal intactness (ie, without any loss of animal species) and functional intactness (no loss of animal densities below a level that would affect the healthy functioning of an ecosystem).

Restoring intact habitats

The authors explored how applying these 3 measures of intactness reduces the number of sites that might qualify under KBA Criterion C. They found that only between 2% an 3% of Earth's terrestrial surface qualifies if Criterion C is defined as sites which are functionally intact, 10 times lower than previously estimated. Worryingly, only 11% of the measured sites are covered by protected areas. Many of the identified areas coincide with territories managed by indigenous communities, who play a crucial role in maintaining them. "Areas identified as functionally intact included east Siberia and northern Canada for boreal and tundra biomes, parts of the Amazon and Congo basin tropical forests, and the Sahara Desert," according to the authors.

However, there is hope. The authors say that up to 20% of the planet's land surface could be restored to faunal intactness through reintroductions of only a few species into remaining intact habitat. Plumptre says: "The results show that it might be possible to increase the area with ecological intactness back to up to 20% through the targeted reintroductions of species that have been lost in areas where human impact is still low, provided the threats to their survival can be addressed and numbers rebuilt to a level where they fulfil their functional role."

In the future, identifying areas under KBA Criterion C can help focus attention on these sites for conservation and restoration, according to Plumptre, "It has been shown that intact habitat has important benefits for both wildlife and people and as a result needs to be a critical target of the ongoing negotiations of the Convention on Biological Diversity post-2020 global biodiversity framework. Recognition of these special places within intact habitat, where you have full functional intactness, is needed and plans to focus restoration in areas where ecological integrity might be recovered."

A new study in SLEEP, published by Oxford University Press, demonstrates the significant benefits of later school start times for middle and high school students' sleep schedules.

Sleep is essential to a student's overall health, social development, and academic achievement, yet lack of sleep is common among children and adolescents. Biological changes to sleep cycles during puberty make falling asleep early difficult for adolescents. This, coupled with early school start times, means that students often end up with insufficient sleep.

Approximately 28,000 elementary, middle, and high school students and parents completed surveys annually, before changes to school start times and for two years afterward. Participating elementary schools started 60 minutes earlier, middle, 40-60 minutes later, and high school started 70 minutes later. Student and parent surveys separately asked about students' typical bedtime and wake time on both weekdays and weekends. The surveys also asked respondents to report on students' quality of sleep and their experience of daytime sleepiness.

Researchers found that the greatest improvements in these measures occurred for high school students, who obtained an extra 3.8 hours of sleep per week after the later start time was implemented. More than one in ten high school students reported improved sleep quality and one in five reported less daytime sleepiness. The average "weekend oversleep," or additional sleep on weekends, amongst high schoolers dropped from just over two hours to 1.2 hours, suggesting that with enough weekday sleep, students are no longer clinically sleep deprived and no longer feel compelled to "catch up" on weekends. Likewise, middle school students obtained 2.4 additional hours of sleep per week with a later school start time. Researchers saw a 12% decrease in middle schoolers reporting daytime sleepiness. The percent of elementary school students reporting sufficient sleep duration, poor sleep quality, or daytime sleepiness did not change over the course of the study.

The benefits of later start times were similar across racial and socioeconomic groups, but survey results indicated differences in weekday bedtimes. The authors encourage steps to be taken to "identify and ameliorate systemic factors that contribute to these differences," recommending education programs developed in partnership with families to ensure that guidance for adjusting bedtimes and increasing sleep opportunities are sensitive to sociocultural and environmental factors.

Previous studies have not concurrently considered the impact of changing start times on sleep for students from Kindergarten through 12th grade, a key factor in policy outcomes due to the need for school districts to stagger start times to accommodate transportation schedules.

"This study is remarkable due to the large sample size, the inclusion of elementary and middle school students, the two-year follow-up, and both student and parent report. It also provides the strongest evidence to date that moving elementary school start times to 8:00 am caused no significant negative effect on student sleep or daytime sleepiness. As students return to in-person learning, it is important for districts to consider healthy start times for all students."

As females age, their bodies typically undergo two significant changes that generally occur during adolescence and middle age. The first, known as menarche, is the time during puberty when a girl begins having monthly menstruation cycles, which often tends to range from 8-13 years of age. She enters the second change, known as menopause, 12 months following her last menstruation cycle when her ovarian function ceases, usually sometime in her 40s or 50s.

The time after menarche and prior to menopause is known as a woman's reproduction life span and marks the years when she is most able to bear children. For many women, these events occur naturally. However, women can enter menopause earlier than expected due to other issues. Women that undergo radiation therapy for cancer typically stop menstruating, as do women who undergo surgical menopause procedures such as having their ovaries removed.

Because each woman experiences these life stages at different times, one woman's reproductive life span is generally shorter or longer than that of another, sometimes significantly so. Duke Appiah, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) Graduate School of Biomedical Sciences, said those differences can affect much more than a woman's reproductive health.

For instance, Appiah said, researchers have known a link exists between the duration of a woman's reproductive life span and her overall metabolic health, but they haven't known why. Part of that link, he opined, could be caused by a woman being naturally exposed to estrogen and various estrogen compounds. Estrogens can be beneficial because they can help protect or delay the onset of certain health issues. However, they also have been associated with some diseases, and women that normally have less estrogen and remain that way through menopause are more likely to develop heart disease or osteoporosis.

"If the reproductive life span is longer, then that means they still have exposure to the natural estrogens, which will also help delay some diseases like cardiovascular disease and osteoporosis, and to some extent, even cancer," Appiah said.

But why do some women who have longer reproductive life spans, and therefore longer exposure to estrogens, still develop metabolic issues?

It's a question Appiah and a group of collaborators set out to address in a research letter to the Journal of the American Medical Association (JAMA). The letter, "Trends in Age at Natural Menopause and Reproductive Life Span Among U.S. Women, 1959-2018," was published in JAMA's April 8 issue. Appiah's collaborators included Chike C. Nwabuo, M.D., MPH, from Johns Hopkins University; Imo A. Ebong, M.D., M.S., from the University of California, Davis; Melissa F. Wellons, M.D., MHS, from Vanderbilt University Medical Center; and Stephen J. Winters, M.D., from the University of Louisville.

Appiah, an assistant professor of public health at the TTUHSC and director of the university's master's program in public health, said women who enter menopause at age 40-45 years have a higher risk of developing cardiovascular disease, whereas those who become menopausal after the age of 50 experience a higher risk of breast cancer.

"These characteristics have clinical significance, but we wanted to see in the United States over the past 60 years, if there have been any changes in age at menopause, reproductive life span and to age at menarche," Appiah explained. "If it was changing, we wanted to find out what factors are possibly associated with these changes. Not many studies have been done in the U.S. to look at trends in age at menopause. If we can see some of the factors which are associated with or are driving having natural menopause at an earlier age, perhaps we can intervene."

Appiah said many of the previous studies are outdated and used data from shorter time periods such as 1910-1950. None of these studies investigate the link between age at menopause and the development of metabolic health issues. They also failed to address factors that may cause a woman to enter menopause earlier in her life.

To collect data for his study, Appiah used successive surveys spanning the 1959-1962 National Health Examination Survey I (NHES I) through the National Health and Nutrition Examination Survey (NHANES) for 2017-2018. The NHANES is a biennial survey conducted by the Centers of Disease Control and Prevention to generally evaluate the health of children and adults in the U.S. In addition to providing a significantly larger sample size, the NHANES provides a cross-sectional sample of the non-institutionalized U.S. adult population. It includes a detailed demographic and behavioral questionnaire, a physical examination, laboratory testing and a list of all prescription medications used by the respondent.

Using this data, Appiah was able to analyze 7,773 women aged 40 to 74 years at the time of the survey and who had reached natural menopause. From the 1959-1962 NHES I to the 2015-2018 NHANES, the mean age at which women reached natural menopause increased from 48.4 years to 49.9 years and the mean age at menarche fell from 13.5 years to 12.7 years. This resulted in an increase of the mean reproductive life span from 35.0 years to 37.1 years.

In multivariable adjusted models Appiah saw that race and ethnicity (Black and Hispanic), poverty, current and former smoking status and hormone therapy use were associated with earlier age at natural menopause and a shorter reproductive life span. Factors such as more years of education and use of oral contraceptives were associated with women who reached natural menopause at a later age and had longer reproductive life span.

Appiah said other factors not assessed in their study such as lifestyle and behavior factors, improved access to health care, nutrition, obesity and environmental factors may be related to the increasing trends in age at natural menopause and reproductive life span.

In past research, Appiah has shown that menopause is associated with metabolic conditions, which also influence the development of certain diseases. More importantly, he said, his work has shown that researchers tend to be more concerned about the age at which women reach menopause when they actually need to identify factors that are causing women to reach menopause at an earlier age because those factors tend to be more important.

"This study was to give some empirical evidence to some of my past studies, but then for future studies, I'm still looking at how age and menopause is associated with cardiac structure and function, for instance, how the heart beats, how the heart becomes bigger with age," Appiah said. "This paper has given perspective to some of my past work, and it's also given some direction to my future work, whereby I'll look at whether age at natural menopause and length of reproductive life span is a marker for overall health in women."

Little is known about azhdarchid pterosaurs, gigantic flying reptiles with impressive wingspans of up to 12 meters. Cousins of dinosaurs and the largest animals ever to fly, they first appeared in the fossil record in the Late Triassic about 225 million years ago and disappeared again at the end of the Cretaceous period about 66 million years ago. One of their most notable features for such a large flighted animal was a neck longer than that of a giraffe. Now, researchers report an unexpected discovery in the journal iScience on April 14: their thin neck vertebrae got their strength from an intricate internal structure unlike anything that's been seen before.

"One of our most important findings is the arrangement of cross-struts within the vertebral centrum," says Dave Martill of the University of Portsmouth, UK. "It is unlike anything seen previously in a vertebra of any animal. The neural tube is placed centrally within the vertebra and is connected to the external wall via a number of thin rod-like trabeculae, radially arranged like the spokes of a bicycle wheel and helically arranged along the length of the vertebra. They even cross over like the spokes of a bicycle wheel. Evolution shaped these creatures into awesome, breathtakingly efficient flyers."

Scientists previously thought the pterosaur's neck had a simpler tube-within-a-tube structure, he explains. But it raised an important question: how could their thin-walled bones, needed to reduce weight in the flying reptiles, still support their bodies and allow them to capture and eat heavy prey animals?

Cariad Williams, the study's first author, hadn't set out to answer that question. She wanted to examine the degree of movement between each vertebra of the pterosaur's neck.

"These animals have ridiculously long necks," Williams says, adding that, in some species, the fifth vertebra of the neck from the head end is as long as the animal's body. "It makes a giraffe look perfectly normal. We wanted to know a bit about how this incredibly long neck functioned, as it seems to have very little mobility between each vertebra."

While the Moroccan pterosaur bones they study are well preserved in three dimensions, the researchers still hadn't expected the scans to offer such a clear view of the vertebra's intricate internal structure.

"We did not originally CT scan it to learn about the inside; we wanted a very detailed image of the outside surface," Martill says. "We could have got this by ordinary surface scanning, but we had an opportunity to put some specimens in a CT scanner, and it seemed churlish to turn the offer down. We were simply trying to model the degree of movement between all the vertebrae to see how the neck might perform in life."

He adds, "What was utterly remarkable was that the internal structure was perfectly preserved--so too was the microhistology when we made some petrographic sections through the bone. As soon as we saw the intricate pattern of radial trabeculae, we realized there was something special going on. As we looked closer, we could see that they were arranged in a helix traveling up and down the vertebral tube and crossing each other like bicycle wheel spokes."

His team realized immediately that they needed to bring in engineers to understand how the biomechanics of this unusual neck would have worked. Those analyses suggest that as few as 50 of the spoke-like trabeculae increased the amount of weight their necks could carry without buckling by 90%. Together with the basic tube-within-a-tube structure, it explains how the relatively light-weight animals could capture and carry heavy prey items without breaking their necks.

"It appears that this structure of extremely thin cervical vertebrae and added helically arranged cross-struts resolved many concerns about the biomechanics of how these creatures were able to support massive heads--longer than 1.5 meters--on necks longer than the modern-day giraffe, all whilst retaining the ability of powered flight," Martill says.

While pterosaurs are sometimes thought of as evolutionary dead ends, Martill and colleagues say the new findings reveal them as "fantastically complex and sophisticated." Their bones and skeletons were marvels of biology--extremely light yet strong and durable.

The researchers say there's still much to learn in future work about pterosaurs, including seemingly basic questions about their flight abilities and feeding ecology.

Describing the genetic diversity of human populations is essential to improve our understanding of human diseases and their geographical distribution. However, the vast majority of genetic studies have been focused on populations of European ancestry, which represent only 16% of the global population. Scientists at the Institut Pasteur, Collège de France, and CNRS have looked at understudied human populations from the South Pacific, which are severely affected by a variety of diseases, including vector-borne infectious diseases such as Zika virus, dengue, and chikungunya, and metabolic diseases such as obesity and diabetes. Using genome sequencing of 320 individuals, the scientists have investigated how human populations have biologically adapted to the environments of the Pacific islands and how this has affected their current state of health. This study has also revealed hitherto unsuspected aspects of the history of human settlement in this region. This work is published in the April 14th, 2021 issue of Nature.

An international consortium of scientists organized by Etienne Patin (CNRS/Institut Pasteur) and Lluis Quintana-Murci (Collège de France/Institut Pasteur) was set up to characterize the genetic diversity of populations in the South Pacific, a region full of contrasts with its myriad islands that have been settled at very different time periods.

Indeed, shortly after humans left Africa, they settled Near Oceania (Papua-New-Guinea, the Bismarck Archipelago, and the Solomon Islands) approximately 45,000 years ago, while the rest of the Pacific, known as Remote Oceania (Vanuatu, the Wallis and Futuna Islands, Polynesia, etc.), remained uninhabited. It was only approximately 40,000 years later that Remote Oceania was peopled: it is currently accepted that a group of humans left Taiwan 5,000 years ago - a migration known as the 'Austronesian expansion' - passed through the Philippines, Indonesia, and the already-inhabited Near Oceanian islands to eventually settle Remote Oceania for the first time.

En route to these remote lands, the ancestors of South Pacific populations met with groups of archaic humans, with whom they interbred. While 2-3% of modern-day Oceanian populations' genetic material is inherited from Neanderthals (which all populations outside Africa also possess), up to 3% of their genomes is also inherited from Denisovans (relatives of Neanderthals thought to have originated in Asia). It was already known that modern humans inherited beneficial mutations from Neanderthals via admixture, which improved their ability to adapt to their environment, including resistance to viral infections (Cell, 2016 ). In this study published today, scientists from the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS ) in collaboration with various laboratories in France , Germany, Sweden, Switzerland, China, and Taiwan have sought to shed light on how ancient admixture helped Pacific populations to adapt to their specific island environments, including any pathogens encountered.

Historical events traced using genetics

Based on whole-genome-sequencing of over 320 individuals from Taiwan, the Philippines, the Bismarck Archipelago, the Solomon Islands, Santa Cruz Islands, and Vanuatu, this work published in the Nature journal has helped tracing the history of the human settlement of Oceania. First, the scientists have dated the settlement of the various islands of Near Oceania back to approximately 40,000 years, thus confirming archaeological records. They have also demonstrated that this initial settlement was followed by a period of genetic isolation between islands. "Our results confirm that humans were able to cross the seas to reach new lands from an early stage. However, they also suggest that these voyages were relatively infrequent at this distant period in history," explains Etienne Patin, a CNRS scientist within the Human Evolutionary Genetics Unit at the Institut Pasteur. Moreover, the results of the study reveal a major reduction in the size of these populations just before the settlement.

Second, the study challenges the theory, known as the Out-of-Taiwan model, that a population left Taiwan approximately 5,000 years ago to rapidly settle Near and Remote Oceania. "Our analyses suggest that humans left Taiwan more than 5,000 years ago, and that admixture between the Austronesian incomers and the populations of Near Oceania started only 2,000 years later. The expansions from Taiwan therefore took some time, and may have involved a maturation phase in the Philippines or Indonesia," comments Etienne Patin.

The heritage of Neanderthals and Denisovans in South Pacific populations

Through this work, it has been possible to estimate the proportions of Neanderthal and Denisovan material in the genomes of South Pacific populations. "We were surprised to note that, contrary to the Neanderthal heritage, which is very similar among the twenty populations studied (approximately 2.5%), the Denisovan legacy varies considerably between populations, from virtually 0% in Taiwan and the Philippines to up to 3.2% in Papua-New-Guinea and Vanuatu" comments Lluis Quintana-Murci, Professor at the Collège de France, holder of the Chair in Human Genomics and Evolution, and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS).

But this was not the only surprise. The study confirms that Neanderthals provided modern human populations with beneficial mutations associated with numerous phenotypes: skin pigmentation, metabolism, neuronal development, etc. However, the most surprising finding is that admixture with Denisovans has almost exclusively brought beneficial mutations related to immune response regulation. This suggests that the Denisovan heritage has been a reservoir of advantageous mutations, which have improved the Pacific populations' ability to survive local pathogens. Therefore, it appears that these populations have benefited from the advantages bestowed through admixture with both forms of archaic humans.

Furthermore, the study demonstrates that admixture with Denisovans did not occur at once, but over the course of at least four independent events. It shows that the Denisovans with whom the Pacific populations interbred were in fact highly diverse populations. This conclusion was impossible to deduce from the single genome of a Denisovan specimen found in Siberia: "One of the strengths of these analyses is that, by studying the 3% of archaic heritage present in the genomes of modern humans, one can 'resurrect' Denisovans' genomes, and thus show that they presented high levels of genetic diversity," comments Lluis Quintana-Murci.

Finally, besides the biological adaptation enabled by archaic admixture, the scientists have found that lipid metabolism, cholesterol in particular, was also a target of natural selection among Oceanian peoples. This insight will potentially improve our understanding of why recent changes in these populations' lifestyle may be associated with metabolic disorders.

By taking an evolutionary genetics approach, it is possible to shed light on the history of populations' biological adaptation to their environment, and provide the scientific community with valuable information on specific human traits. These large-scale genomic studies will eventually help us better understand the genetic causes of diseases affecting some regions of the globe, where medical research has hitherto been scarce.

What The Study Did: Data from the Ohio Department of Health were used to evaluate changes in drug overdose mortality in that state by type of drug and age of the user during the first seven months of the COVID-19 epidemic.

Authors: Janet M. Currie, Ph.D., of Princeton University in Princeton, New Jersey, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2021.7112)

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

What The Study Did: The association between severity of eczema among children and risk of being diagnosed with a learning disability was investigated in this study.

Authors: Joy Wan, M.D., M.S.C.E., of the University of Pennsylvania Perelman School of Medicine in Philadelphia, is the corresponding author.

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

(doi:10.1001/jamadermatol.2021.0008)

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A potential treatment for dementia and epilepsy could look to reduce the amounts of a toxic gas in the brain has been revealed in a new study using rat brain cells.

The research published in Scientific Reports today [Wednesday 14 April] shows that treatments to reduce levels of hydrogen sulfide (H2S) in the brain may help to ward off damage caused by the gas. By testing rat brain cells, the team of scientists from the University of Reading, University of Leeds and John Hopkins University in the USA found that H2S is involved in blocking a key brain cell gateway that helps the brain to communicate effectively.

Dr Mark Dallas, Associate Professor in Cellular Neuroscience at the University of Reading said:

"This is an exciting finding as it gives us new insights about the role of hydrogen sulfide in various brain diseases, such as dementia and epilepsy. There has been growing interest in the effect of hydrogen sulfide on the brain and this study shows how important the implications of its build-up on proper brain functioning may be.

"We saw that hydrogen suldife acts to disrupt the normal functioning of potassium channels. These channels regulate electrical activity across the connections between brain cells, and when these channels are blocked from working properly we see overexcitable brain cells which we believe is leading to nerve cell death.

"The implication for potential treatments is particularly exciting because finding drugs that target hydrogen sulfide production in our brains may have a host of benefits for diseases, and there are clear links between hydrogen sulfide build -up and other warning signs for diseases such as Alzheimer's."

In the study, cells taken from rat brains were charged with a H2S donor molecule, and then brain cell electrical signals were monitored. The resulting exposure to H2S increased the level of activity in brain cells, and the research was able to establish that the effect was specifically controlled by the potassium channel tested.

The team were also able to identify which part of the potassium channel was allowing this effect from H2S. They used a mutated form of the potassium channel, which has already been shown to protect nerve cells from a host of toxic stimuli, including amyloid beta and found that the mutation was resistant to the effect of H2S that was seen in natural cells.

The specific mutated channel now holds particular interest for research into Alzheimer's Disease, given the protective benefits against amyloid beta which is also implicated in dementia.

Dr Moza Al-Owais, Research Fellow at the University of Leeds said:

"This exciting study demonstrates the growing evidence that gasotransmitters play an important role as signalling molecules in the regulation of the physiological processes underlying Alzheimer's disease, which are relatively poorly understood, opening new avenues for investigation and drug discovery."

Chestnut Hill, Mass. (4/14/2021) -- Using abundant cobalt and a unique experimental approach to probe ways to speed a sluggish catalytic reaction to harvest hydrogen from water, researchers from Boston College and Yale University discovered a mechanistic switch in the oxygen evolution reaction, a significant step towards optimizing electrocatalysts for water splitting to produce clean energy.

The mechanism switches by varying the amount of voltage, or applied potential, the team reports in the journal Chem. At moderate potential, two oxygen atoms bound to the catalyst surface react to form the oxygen-oxygen bond. By contrast, at higher potentials, the oxygen-oxygen bond is formed by a water molecule attacking a surface-bound oxygen species.

The findings show that in this materials class, an electrocatalyst for this reaction should be chosen, or optimized, depending on the potential regime in which it is expected to operate in a reactor. In other words, a given catalyst may be particularly efficient in promoting one mechanism, but not the other.

"What surprised us was how steeply the switch occurs from one mechanistic regime to another with applied potential," said Boston College Professor of Chemistry Dunwei Wang, a lead author of the report. "Only about 100 mV are necessary to toggle between the two mechanisms. It is a reminder of how sensitive reaction mechanisms are. More broadly, the facile switch may be another indication of how photosynthesis can adapt to changes in reaction environment for optimized performance."

Researchers have been working to split water into molecular hydrogen and oxygen in an effort to provide abundant renewable energy in the form of transportable and storable hydrogen gas. The splitting can be accomplished with electrocatalysis, a process in which the hydrogen and oxygen evolution reactions occur in spatially separated compartments on electrodes. That makes electrocatalysis a highly promising means for producing clean hydrogen gas.

However, the oxygen evolution reaction (OER) is slow, said Wang. As a result, the rate of the overall water splitting reaction is limited by the sluggish OER. The reaction needs to be facilitated by catalysts, that is, materials that promote the reaction without being themselves consumed in the process. To date, economically viable electrocatalysts for the promotion of the oxygen evolution reaction have not been developed yet. Wang and his colleagues focused on the OER in promising electrocatalysts in an effort to better understand the reaction processes and use those insights to design more efficient and stable electrocatalysts for this reaction.

They focused on the reaction in a class of electrocatalysts that are based on oxides of cobalt, a cheap and earth-abundant material, attributes that would translate efficiently to use on an industrial scale, Wang said.

In the last decade, various cobalt-oxide-based electrocatalysts have emerged as promising candidates for promoting the OER. In a collaboration with colleagues at Yale University, Wang and his team studied the OER on two types of cobalt-oxide electrocatalysts with electrochemical techniques, infrared spectroscopy, and density functional theory.

Wang said the team controlled the concentration of water by using water-in-salt electrolytes, which feature a concentration of salt that is approximately ten times higher than that of seawater. As a result, the researchers could control the activity of water by adjusting the amount of salt in the electrolyte. They monitored how the rate of the reaction responded to different concentrations of water. This revealed the mechanism of the OER on cobalt-based electrocatalysts, Wang said. Co-author and BC Associate Professor of Chemistry Matthias Waegele and his research team used infrared spectroscopy, which relies on the interaction of infrared light with molecules, to detect reaction intermediates of the OER under operating conditions.

They were able to detect a key reaction intermediate, which was predicted by the calculations by Yale chemist Victor Batista and his research group. Gary Brudvig, an inorganic chemist at Yale, also advised the team during the project.

Wang said the team wanted to look closely at the oxygen evolution reaction, particularly the characteristic that it is a step-by-step process, not a single event. Water contains only one oxygen atom. The product of the OER is molecular oxygen, which contains two oxygen atoms. Therefore, during the OER an oxygen-oxygen bond is formed, he noted.

Wang said researchers in this field have focused on two central questions: how does this oxygen bond form and in what step? Two principal mechanisms have been proposed in prior studies, however researchers had yet to resolve under what experimental conditions -- temperature, or applied electrode potential, for instance -- the oxygen-oxygen bond forms and which of the mechanisms is the dominant one.

Wang and his colleagues decided to look closely at how the applied electrode potential dictates the mechanism of the oxygen-oxygen bond formation step since reactions in electrocatalysis are driven by an electric potential that is applied to the catalyst.

The findings suggest that the mechanistic switch might be general for oxide-based electrocatalysts, Wang said.

"We are very interested in learning if this observation also applied to other promising electrocatalysts," he said. "In particular, we are currently working on catalysts with atomically defined active centers. In contrast to the cobalt-based electrocatalysts, whose atomic structure at the active center remains unresolved, our new study platform contains catalytic centers that are atomically well-defined. It will be very interesting to see if the potential-induced mechanistic switch also occurs on those catalysts."

In the cell nucleus histones play a crucial role packaging DNA into chromatin. Histones are however very sticky to both DNA and RNA, so to ensure they are transported to the cell nucleus after synthesis and bind to the right portion of DNA to organize the chromatin, they are guarded by complexes of histone chaperones.

Histone chaperones are proteins that bind to histones to help protect them from non-specific binding events until they reach their goal. This process fails sometimes and histones get stuck during their supply to chromatin without any purpose.

In a study published in Molecular Cell, researchers have shown that the protein DNAJC9 holds an important role in safeguarding histones and thereby chromatin.

Active fixer joins passive bystanders

"Until now researchers have assumed that histone chaperones only act to passively shield histones. We have found out that DNAJC9 actively engages the cellular protein folding machinery - which means it actively recruits enzymes and molecular chaperones to redeploy histones that have been trapped," says assistant professor Colin Hammond, who has lead the study. Hammond is part of the Protein Memory Program in the Novo Nordisk Foundation Center for Protein Research at University of Copenhagen.

Once released from their trapped condition histones can re-engage histone chaperones like MCM2 and be assembled into nucleosomes to organize chromatin. When the protein DNAJC9 is mutated to lose its ability to recruit the protein folding machinery, the histones stay trapped and are thereby lost for proper chromatin deposition.

"This means that traditional histone chaperones cannot fully protect histone proteins from spurious interactions. Rather, the cell is dependent on the combined action of molecular chaperones and histone chaperones to safeguard these fundamentally important proteins during their dynamic lives," Colin Hammond underlines.

Strong collaboration necessary

The study is based on a strong international collaboration. Co-first author Hongyu Bao in Hongda Huang's lab and other partners from Southern University of Science and Technology in China, and Dinshaw Patel from Memorial Sloan Kettering Cancer Center, provided the structural discoveries of DNAJC9. The functional analysis was spear-headed by Colin Hammond in close collaboration with colleagues from the Proteomics Program at CPR, Ivo Hendriks and Michael Lund Nielsen, to dissect the function of the protein through in depth proteomic assays.

Relevant insights for cancer research

DNAJC9 is an essential protein in many cancer cell types and the levels of the protein correlate with the rates at which cancer cells proliferate. Chromatin in cancer cells may be more reliant on DNAJC9 compared to regular cells, and if this is the case DNAJC9 could be a target for the development of future cancer treatments.

"Although it's still early days, we hope this fundamental advance in our understanding of DNAJC9 biology helps to pinpoint a function essential for cancer cell viability with therapeutic potential," Colin Hammond says.

If you were to visit the Great Basin and Colorado Plateau a thousand years ago, you'd find conditions remarkably familiar to the present. The climate was warm, but drier than today. There were large populations of Indigenous people known as the Fremont, a who hunted and grew crops in the area. With similar climate and moderate human activity, you might expect to see the types of wildfires that are now common to the American West: infrequent, gigantic and devastating. But you'd be wrong.

In a new study led by the University of Utah, researchers found that the Fremont used small, frequent fires, a practice known as cultural burning, which reduced the risk for large-scale wildfire activity in mountain environments on the Fish Lake Plateau--even during periods of drought more extreme and prolonged than today.

The researchers compared lake sediment, tree ring data and archaeological evidence to reconstruct a 1,200 history of fire, climate, and human activity of the Fish Lake Plateau, a high-elevation forest in central Utah in the United States. They found that frequent fires occurred between the years 900 and 1400, a period of intense farming activity in the region. Prehistoric cooking hearths and pollen preserved in lake sediment show that edible plant species dominated the landscape during this period, indicating that Fremont people practiced cultural burning to support edible wild plants, including sunflowers, and other crops. Large-scale farming ceased after the year 1400. Hunters and foragers, ancestors of the Ute and Paiute, continued to burn, although less frequently than during the farming period. After Europeans made cultural burning illegal, the ecosystem returned to be dominated by a thick forest of trees.

"When you have people burning frequently, they're reducing the amount of surface fuels present on the landscape. It makes it much more difficult for a lightning fire to reach up to the canopy and burn down the entire forest," said Vachel Carter, postdoctoral research assistant at the U and lead author of the study. "Now we have an environment dominated by trees in a very dry environment, which are conditions prime for megafires. Is this a result of climate change? Definitely. But in the case at Fish Lake, it could also be attributed to a lack of cultural burning."

For millennia through the present, Indigenous people across North America have used cultural burning to drive game, ease travel, clear vegetation for fields and enhance regrowth of edible plants. European settlers banned the practice in favor of fire suppression, the strategy that's dominated forest management since the turn of the 20th century.

"All over North America, humans have always modified fire regimes to benefit themselves and their families," said Brian Codding, associate professor of anthropology at the U and senior author of the paper. "Cultural burning is something that needs to be considered when people are talking about how to manage forests, just like in the Fish Lake National Forest."

The paper published April 14, 2021 in the Nature journal Communications Earth and Environment.

It takes a village

The study is the first in the region to combine charcoal, pollen, tree ring and archeological site data together to assess human influence on prehistoric wildfires. The multiple disciplines allowed the researchers to make connections that would otherwise have been impossible.

"This is really showing us something that's kind of invisible otherwise," said Codding. "People have been trying to look at human impacts on fire regimes all over the place, and it's really hard. Because the changes might be really subtle, or our records just aren't fine-grained enough to record the types of changes that can reveal it."

Colleagues from Utah State University and Brigham Young University contributed tree ring data that document how the climate has shifted over time. Thick rings mean that the tree grew rapidly, indicating there was more moisture available. Narrow rings represent a slow growth year due to less moisture, a signature that can record periods of drought. For this study, they established a climatological timeline for the Fish Lake area.

Carter analyzed the contents of ancient sediments to reconstruct past worlds. Detritus from the local environment blows over the lake and settles at the bottom, building up layers as time passes. Each layer provides a snapshot of what the surrounding area was like at a particular time. She used charcoal as a proxy for fire abundance--more charcoal means more frequent fire--and analyzed pollen grains to determine what plant species dominated and compared how those changed over the last 1,200 years.

Codding and colleagues counted the number of sites that were occupied, using radiocarbon dates on items found at dwelling sites to establish when people were there. They also used food remnants in cooking hearths to establish the types of food people were eating. They analyzed sites within modern day Sevier County, the area around and including Fish Lake, the ancestral lands of the Ute and Paiute Tribes.

"From the cooking hearths found at Fish Lake, we got an indication of what people were eating, and when they were eating it. We knew that they were eating food in the sunflower family, the grass family, and the sedge family, all these plants that don't naturally dominate a high elevation forest," said Carter. "I counted the pollen from those species in the sediment cores and, sure enough, when the Fremont were present, those same plant species were present in much higher abundances than when the Fremont were absent."

"This piece really pulls the study together for linking how people living at this area, at higher densities, were actually modifying the environment to increase the resources that were available to them," Codding said.

Cultural burning for Pando

In Utah, many forests could benefit from frequent, smaller fires to mitigate wildfire risk. Perhaps one of the most urgent is in the Fish Lake National Forest that guards Pando, a stand of 47,000 aspen tree clones and the most massive organism on Earth. Pando has sat at the south end of Fish Lake for thousands of years, at least--some say the organism is a million years old. In recent years, the beloved grove has been shrinking. Low severity fires may help Pando, and other Utah forests, stay healthy.

"Fuels on the Fish Lake landscape are at the highest that they've been in the last 1,200 years. The climate is much warmer than it was in the past. Our droughts have not been as intense as we've seen in the past, but they're on their way," Carter said. "The Fremont likely created long-lasting legacies on the Fish Lake Plateau through their cultural burning. Moving forward, 'good fire,' like prescribed fire, will be needed to mitigate against wildfire risk."

Compared to newborns conceived traditionally, newborns conceived through in vitro fertilization (IVF) are more likely to have certain chemical modifications to their DNA, according to a study by researchers at the National Institutes of Health. The changes involve DNA methylation--the binding of compounds known as methyl groups to DNA--which can alter gene activity. Only one of the modifications was seen by the time the children were 9 years old.

The study was conducted by Edwina Yeung, Ph.D., and colleagues in NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Previous studies by the research team found no differences in growth and development for this group.

"Our study found only small differences in DNA methylation at birth and these were not seen in early childhood," Dr. Yeung said. "When considered along with our previous studies finding no differences in children's growth and development, our current study should be reassuring to couples who have conceived with fertility treatments and to those considering these methods."

IVF consists of collecting eggs and sperm, fertilizing the eggs in a lab, and then transferring the resulting embryo or embryos into the uterus. Another technique, intracytoplasmic sperm injection (ICSI), consists of injecting a sperm cell directly into the egg before placing the resulting embryo into the uterus.

Methylation changes were not associated with two other fertility treatments, ovulation induction (drug treatment to release the egg from the ovary) and intrauterine insemination (insertion of semen directly into the uterus).

According to a national report in 2018, almost 75,000 IVF-conceived infants (2.0% of all infants) were born in the United States. Of these, approximately 76% were conceived with ICSI. Another study found that 3 to 7% of births resulted from ovulation induction and intrauterine insemination.

When methyl groups are added to a gene, the gene is switched off and does not produce a protein. Methyl groups are added and removed from DNA throughout life, as genes are alternately switched on and off. Changes in methylation may occur in any step of IVF. These include exposure to hormones needed to bring the eggs to maturity so they can be collected or exposure to the culture medium in which the eggs are fertilized and embryos develop.

Previous studies have found associations between IVF and certain rare disorders. However, many of these studies were small and their results inconsistent. Also, many of the studies were conducted before ICSI was in widespread use.

For the current study, researchers evaluated data on DNA methylation differences in children beginning at birth and when they were 8 to 10 years old. The children were born in New York State from 2008 to 2010 and more than 70% of IVF birth were with ICSI.

Of the newborns, 157 were conceived with fertility treatments and 520 were conceived without treatments. Newborns conceived with IVF were more likely to have lower methylation levels in some parts of their DNA. The researchers did not find any methylation changes for newborns conceived by ovulation induction or intrauterine insemination.

Among the 152 children who provided DNA samples at 8 to 10 years old, 23 were conceived with IVF and 34 with ovulation induction or intrauterine insemination. For children conceived with IVF, lower methylation levels were seen for only one region, in the GNAS gene, which has been found in some previous studies but not others.

The study authors called for more research on how variations in fertility treatments could contribute to methylation differences in children, such as variations in the medium used to culture embryos.