Culture

The discovery of genetic drivers of cancer can have critical implications for the diagnosis and treatment of cancer patients, yet genome analysis has focused primarily on only 1-2% of the whole genome - the part that contains the code for making proteins. What about the rest? Does it also play a role in driving the disease?

As part of the Pan-Cancer project, scientists have analysed whole-genome sequencing data. To do this, the scientists had to develop new statistical methods suitable for analysing the non-coding genome.

Joachim Weischenfeldt - now a group leader at the Biotech Research & Innovation Centre at the University of Copenhagen, and Rigshospitalet, Copenhagen - was a postdoc in the Genome Biology Unit at EMBL Heidelberg at the time of the research. He explains the rationale for the investigation: "Decades of work has been focused on identifying the consequences of changes in the protein-coding part of the genome. Many cancers have no important mutations in the protein-coding part, but something is driving the cancer. By inference, we suspect the non-coding part is playing an important role in these unexplained cases."

The analysis focused on identifying driver point mutations - mutations that affect only one or very few letters of the DNA code - and structural variants, or rearrangements, in the non-coding regions of the genome. In addition to identifying new drivers, the analysis confirmed some previously reported drivers and, importantly, invalidated others. It also identified novel putative driver rearrangements near genes called the AKR1C genes. This correlated with increased gene expression across lung and liver cancers.

Mutations and structural variants driving cancer were found to be less frequent in non-coding genes and sequences than in the protein-coding part of the genome, but this could partly be due to the relatively small number of patient datasets available to analyse for some tumour types. "We probably need an order of magnitude more genomes to really have a comprehensive understanding of all the mutations that drive cancer, and the complex mechanisms by which they form," says Weischenfeldt. "As cancer is a disease of the genome, we ultimately want to be able to explain as many cancers as possible using genetics."

Thanks in large part to the work carried out during the Pan-Cancer project, about 95% of the cancers studied could be explained genetically by a driver mutation. One of the key outputs of the project is a catalogue that clinicians and researchers can use to look up specific tumour types and identify the drivers of the disease.

The Pan-Cancer project

The Pan-Cancer Analysis of Whole Genomes project is a collaboration involving more than 1300 scientists and clinicians from 37 countries. It involved analysis of more than 2600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was the starting point for 16 working groups to study multiple aspects of cancer development, causation, progression, and classification.

With water scarcity intensifying, wastewater treatment and reuse are gaining popularity. But some methods for killing microbes in wastewater create disinfection byproducts (DBPs) that could be harmful to human health. Now researchers have found that ozone treatment and subsequent chlorination can convert trace amounts of some pharmaceuticals in wastewater into DBPs called halonitromethanes. They report their results in Environmental Science & Technology.

The combination of ozone and chlorine kills most bacteria and viruses in wastewater. Compared with chlorine treatment alone, ozone also reduces the formation of many DBPs. Recently, however, scientists have discovered that ozone can increase the formation of potentially toxic halonitromethanes, such as chloropicrin, in chlorine-treated wastewater. Jiaming Lily Shi and Daniel McCurry wanted to determine which molecules in the wastewater were being converted to chloropricin and how.

To find out, the researchers collected wastewater samples from three treatment plants in Southern California. The team discovered that ozone treatment produced nitromethane, which could have been formed from some nitrogen-containing drugs in the wastewater, including stimulants such as ephedrine and methamphetamine and certain antidepressants. Then, chlorination transformed the nitromethane into chloropricin. The pharmaceuticals, which enter wastewater through sewage, are not removed completely by conventional wastewater treatment. Future work should address how effectively processes that occur after ozone treatment can remove the nitromethane intermediate, the researchers say.

Research Highlights:

Heart-healthy lifestyle habits are always recommended whether blood pressure or cholesterol medications are prescribed or not, yet many patients let healthy habits slip after starting the prescription drugs.

In a Finnish study, people who started blood pressure or cholesterol medications were more likely to gain weight and exercise less compared to those who didn't take these medications.

DALLAS, February 5, 2020 -- Heart-healthy lifestyle modifications are always recommended whether blood pressure or cholesterol medications are prescribed or not. However, a new study found that many patients let these healthy habits slip after starting the prescription medications, according to new research published today in the Journal of the American Heart Association, the open access journal of the American Heart Association.

Finnish researchers found patients at risk for heart disease and stroke who took cholesterol or blood pressure lowering medications were more likely to reduce their activity levels and gain weight.

"Medication shouldn't be viewed as a free-pass to continue or start an unhealthy lifestyle. Our research sought to determine if people who started medications were making the lifestyle changes necessary to see health benefits," said Maarit J. Korhonen, Ph.D., lead author of the study and senior researcher at the University of Turku in Finland.

Researchers studied more than 40,000 public-sector workers (average age 52, more than 80% female) in Finland who had not been previously diagnosed with heart disease or stroke. Participants were given two or more surveys in 4-year intervals from 2000?2013. The surveys included a baseline and follow up questionnaire to assess BMI, physical activity, alcohol consumption and smoking history. Pharmacy data of participants was also obtained to determine if they began taking the prescribed high blood pressure or statin medications.

Participants' medication use was categorized by those who began the preventive medications between the baseline and 4-year follow-up surveys, and those who did not start medications. The researchers found that compared to those who did not start medications, those who did:

Were more likely to reduce their physical activity and were 8% more likely to become physically inactive;

Were 82% more likely to become obese or have an increase in body mass index;

Were 26% more likely to quit smoking; and

Reduced their alcohol consumption.

While people often gain weight when they stop smoking, this did not explain the BMI increase found in the study. Participants who took their medications and stopped smoking gained more weight than those who didn't take medications and stopped smoking.

"People starting on medications should be encouraged to continue or start managing their weight, be physically active, manage alcohol consumption and quit smoking," Korhonen said.

The analysis was limited by the lack of additional details about the respondents' diets, blood pressure measurements and cholesterol levels. This study was in Finland, where a large public health effort aimed at preventing and managing diabetes was initiated during the study period and may not be generalizable to people in countries without comparable programs and resources. In addition, participants in this study were white and predominantly female public-sector workers, therefore, the results may not be generalizable to more diverse populations.

Researchers at ETH Zurich and ETH spin-off Inositec have developed a new substance to prevent vascular calcification, which affects many patients suffering from chronic kidney disease. As their metabolism is impaired, calcium salts may deposit in soft tissues, such as blood vessels or even the heart valves, causing them to stiffen. This often leads to severe, potentially fatal cardiovascular diseases. However, before patients can benefit from the substance further research and tests must be carried out.

"Calcification occurs when calcium phosphate crystals are deposited in tissue," explains Jean-Christophe Leroux, Professor of Drug Formulation and Delivery at ETH Zurich. "The compound adheres to calcium phosphate crystals, inhibiting their growth."

Derivative of a natural substance

The new molecule is structurally related to inositol hexakisphosphate, also known as IP6. Occurring naturally in legumes and cereals, IP6 binds phosphate and various minerals, such as calcium, magnesium and iron. The plants use the molecule in their seeds to provide the seedlings with a sufficient supply of these substances.

It has been known for some time that IP6 also has an effect in the human bloodstream. The molecule has to be injected as it cannot be absorbed after oral ingestion. Other scientists are currently conducting clinical trials to study how effectively IP6 prevents vascular calcification.

Screening the collection of molecules

"The problem, though, is that IP6 is not particularly stable and is metabolised by the body very quickly," Antonia Schantl says. A doctoral student in Leroux's group, she is the lead author of the paper that has been published in the journal Nature Communications. In order to overcome this problem, Leroux and his colleagues sought to stabilise the molecule by making specific chemical modifications. They developed a series of related molecules, which ETH then patented. To be able to market one or more of these derivatives as medication in the future, ETH Professor Leroux and others involved founded the spin-off Inositec, which acquired the licence from ETH to use the molecule family.

Leroux's group at ETH subsequently collaborated with Inositec and researchers from other universities to screen this collection of molecules in a project that was co-financed by the Swiss innovation agency Innosuisse. The scientists conducted in vitro experiments to study the molecules' ability to inhibit the growth of calcium phosphate crystals in the blood and check their stability. They also tested their effect in a disease model in rats. The studies singled out one of the molecules in the collection as particularly suitable.

For the next stage, the ETH scientists will work with Inositec and third parties to clarify various issues, such as drug safety and the optimal dosage.

For this project, the researchers from ETH Zurich and Inositec collaborated with researchers at Lausanne University Hospital, the Universities of Antwerp and Edinburgh and McGill University in Montreal.

Higher levels of mercury in the blood were linked with a higher prevalence of non-melanoma skin cancer, the most common human malignancy, in a study published in the British Journal of Dermatology.

For the study, researchers analyzed 2003-2016 data on 29,413 participants in the National Health and Nutrition Examination Survey. The team examined blood levels of different forms of mercury: total mercury, inorganic mercury, and methyl mercury. Compared with individuals with low total mercury, those with high total mercury had nearly double the odds of being diagnosed with non-melanoma skin cancer. Similarly, participants with high methyl mercury had a 1.7-times greater odds of non-melanoma skin cancer compared with those with low methyl mercury. Inorganic mercury levels were non-significantly but positively associated with non-melanoma skin cancer.

Most individuals in the United States are exposed to mercury through consumption of contaminated fish and shellfish.

Self-perception of aging--or attitudes toward one's aging experience--may affect older individuals' risk of dying early after being diagnosed with cancer, according to results from a study published in Cancer Medicine.

In the study of 140 individuals aged 65 years and older who were diagnosed with non-metastatic cancer and were followed for up to six years, participants with more negative self-perception of aging were 3.62 times more likely to die than those with a more positive self-perception of aging, after adjusting for potential influential factors.

"This research highlights the importance of self-perceptions of aging for our health, and remind us of the need to change our attitudes towards older people," said corresponding author Sarah Schroyen, PhD, of the University of Liège, in Belgium.

New research published in Health Economics indicates that after US states passed medical marijuana laws, workers' compensation claims declined.

The results indicate that medical marijuana may allow workers to better manage symptoms associated with workplace injuries and illnesses and, in turn, reduce the need for workers' compensation. The reductions in workers' compensation claims after states passed medical marijuana laws were very modest, however.

"The findings suggest additional benefits to expanded access to medical marijuana: increased work capacity and less reliance on social insurance programs among workers," said corresponding author Johanna Catherine Maclean, PhD, of Temple University. "Policy makers may wish to consider these benefits when considering medical marijuana regulation."

Mindfulness meditation with a focus on nonjudgment of emotions may help perfectionists recover from stress, according to a study published in Psychophysiology.

The study used high frequency heart rate variability to measure recovery from stress during mindfulness meditation sessions in 120 university students who scored high on a screening tool for perfectionism--the need to be or appear perfect.

Mindfulness meditation sessions that incorporated a nonjudgment element--or awareness and acceptance--led to better recovery compared with general mindfulness meditation sessions.

"This study extends the findings of mindfulness researchers and suggests the potential importance of nonjudgment of emotions and experiences during mindfulness practice for perfectionists," said lead author Hannah Koerten, MA, of Bowling Green State University.

Bees are an important factor for our environment and our sustenance. Without insect pollination, many plant species - including various crops - cannot reproduce. "Bee mortality therefore affects food supply for human beings," stated Professor Sara Leonhardt, who specializes in plant-insect interactions. All of the worldwide more than 20,000 bee species need to be considered. Among these, bumble bees are of particular importance besides the famous honey bee.

"Bees obtain most of their nutrients from their main food sources, which are nectar and pollen. While nectar is mainly a source of carbohydrates, pollen contains most of the other necessary nutrients: proteins, fat, minerals and vitamins. Until today, most bee researchers assumed that bees, like other herbivores, mainly consider the protein content when choosing their food," Professor Leonhardt explained.

Using a two-step mechanistical approach that included learning and feeding experiments, the group established a new way to literally keep a close eye on the feeding habits of insects.

Learning experiments with bumble bees (Bombus terrestris)

Which nutrients can bumble bees taste in pollen? As a first step, learning experiments helped the scientists to establish the bumble bees' preference for certain nutrients - in this case fat and protein.

Fabian Rüdenauer, main author of the study, explained: "We are focusing on fatty and amino acids, which represent the two essential pollen macro nutrients and which are likely to be perceived and thus tasted by bees."

In this context, a small amount of fatty acids was added to pollen to increase its fat content. The researchers found that bumble bees could clearly differentiate between normal pollen and pollen with increased fat content and did show a clear preference for normal pollen. Surprisingly, the bumble bees made no clear distinction when the pollen amino acid content was altered in the same way.

What is a bumble bee's preferred taste?

Which nutrients actually affect the bumble bees' foraging behavior and what are the consequences for their survival and reproductive capabilities? Those were the central questions guiding the subsequent feeding experiments.

"The more fat the pollen contained, the less the bumble bees consumed that pollen," Leonhardt concluded. Bumble bees actually accepted death over having to consume the high-fat pollen. The work group therefore concluded that fat in pollen adversely affects the bumble bees' reproductive capabilities and survival, which is why it is being avoided.

Similar to the learning experiment, variations in the amino acid content of pollen did not affect the bees' feeding habits, survival or reproduction.

Help for bees and bumble bees

"Our study highlights the importance of fat for foraging bumble bees. It also shows that there is a correlation between nutrient perception, nutritional regulation and reproductive fitness," stated Dr. Johannes Spaethe from the University of Würzburg, who also led the study. "The bees can taste what is good for them and collect their food accordingly," said Leonhardt, summarizing the results.

Currently, the researchers are creating a dataset on pollen nutritional chemistry in order to obtain an overview across the wide spectrum of different plant species. They are also examining the nutritional needs of other species of bees. "In the future, this may lead to better understanding the effect of variation in flowering plant species on bees, and it may improve protective measures such as flower strips in agricultural landscapes," predict the researchers.

Since the 1980s, the all-cause mortality rate in the U.S for rural residents has exceeded that of urban dwellers. In a recently completed study, researchers from the F. Marie Hall Institute for Rural and Community Health at the Texas Tech University Health Sciences Center (TTUHSC) sought to determine why this disparity exists in general, and why specifically this imbalance varies so much between states.

The results from their study, "Higher U.S. Rural Mortality Rates Linked To Socioeconomic Status, Physician Shortages, And Lack Of Health Insurance," were published in the December issue of Health Affairs Journal.

Gordon Gong, M.D., Ph.D., an associate professor of rural and community health who recently retired from TTUHSC, authored the study. Scott Phillips, editor in chief for TTUHSC's Rural Health Quarterly magazine and a co-author to the study presented the results Dec. 4 at the Health Affairs Rural Health Forum hosted by the National Press Club in Washington D.C.

Phillips said the study spun off of a U.S. rural health report card that he, Gong and others have been putting together since 2016. They started the report card by trying to answer one question: how well does Texas stack up to other states when it comes to providing quality rural health care?

"We couldn't really answer that question, and we found that no one else had really tried," Phillips said. "We created this data set of every rural and urban county in the U.S. so we could see the disparities."

Developing the report card allowed the TTUHSC team to rank states based upon their grades for outcomes and access, but it made no attempt to explain the disparities.

"This latest study is the next step where we try to explain why rural areas do so much worse than urban areas when it comes to health outcomes, and why the disparities are so widely spread among the states," Phillips said. "We noticed some patterns in the early days of working on the report card that gave us a good starting place for this study."

According to Phillips, the study focused on five explanatory variables within each county: socioeconomic deprivation (e.g., poverty status, access to housing and education, employment), uninsured rates, the supply of and access to primary care physicians, the percentage of racial or ethnic groups and the number of rural and urban residents.

However, after compiling all of the data, the TTUHSC researchers discovered that only three of their explanatory variables were applicable: socioeconomic deprivation, percentage of uninsured and the primary care physician supply. Phillips said those three variables accounted for 81.8% of the total variance of mortality.

"That's an impressive finding and a very large number for this kind of study," Phillips said. "The caveat is that correlation is not necessarily causation, but it's certainly a very strong hint that this is the direction where we need to marshal our resources and pay more attention."

In the end, Phillips said, the remaining variables -- the percentage of racial and ethnic groups and the number of rural or urban residents -- were not significantly associated with mortality.

"The number of rural-urban residents within a county is just a binary measure for the model we applied to the study because it classifies each individual as either rural or urban," he explained. "We used the rural-urban continuum codes put out by the USDA. It's not perfect, but it gives us a good way to break down and divide by counties, and because the health data tends to be by counties, this helps us make sure we're comparing apples to apples."

Phillips said the race-ethnicity variable initially indicated that the percentage of African Americans is positively associated with mortality. However, after adjustments for socioeconomic deprivation, uninsured rates and supply-access to primary care physicians were factored in, the percentage of African Americans was no longer significantly associated with mortality.

"That was fascinating and unexpected, but I want to be real clear about it," Phillips said. "We're not saying that African Americans across the country don't have higher rates of mortality because they absolutely do. What we are saying, and what we discovered with this study, is that other disparities that African Americans face, particularly socioeconomic status and access to care, account for the higher African American mortality rates across the country."

The study also showed the percentage of Hispanic Americans is negatively associated with mortality. Phillips said that could be attributed to what is known as the Hispanic paradox, an accepted epidemiological finding that Hispanic Americans tend to have health outcomes that are comparable to, and often better than those of non-Hispanic whites, even though Hispanic Americans on average tend to have lower socioeconomic status.

"There's a raging debate on why that's the case," Phillips said. "There are various explanations from immigration patterns and diet to genetics and many other factors."

Phillips said the study implies that rural residency in and of itself does not appear to negatively affect mortality. Instead, the study suggests that rural residency tends to favor lower mortality.

"We didn't expect that, but it seems to be getting a lot of attention from people so far," Phillips said. "What it indicates is that rural dwellers would have lived longer than their urban counterparts had their socioeconomic conditions and access to health care been similar. That's a pretty exciting and novel finding as far as this study goes, and I think that's one of the things that really got the attention of Health Affairs Journal."

Armed with the information from this study, Phillips said the TTUHSC team wants to analyze the three states that proved to be exceptions to those findings: Colorado, Montana and Wyoming.

"Those three contiguous states in the Mountain West have higher urban mortality than rural mortality and we want to find out why," Phillips said. "We've got a pretty good theory, but it's going take some heavy lifting to prove it."

Microbiological communities, which include bacteria, single-celled organisms and nematodes, reveal a great deal of information about the state of soils. All around the world, a lot of research is being performed on this biodiversity at a genetic level but third parties are not always able to put these research results to the best possible use. The reason for this: The information recorded in databases varies in terms of quality. UFZ researchers have now built up a new metadata-database for terrestrial metagenomes with over 15,000 datasets, which is intended to make work easier for scientists. This was published in the scientific journal Nucleic Acids Research.

More than 202,000 metagenomes, i.e. the entire genetic information contained in a given soil sample, can be found in the two most important databases in which microbiologists can archive research data: the MG-Rast and Sequence Read Archive (SRA) repositories. Here, international researchers have recorded where they performed investigations into microbiological communities or genome sequencing on the seabed, in forests, in grassland or on rocks, and their findings. By doing so, they enable other researchers to use this data in their own research activities and compare it to their own findings. And it saves them from having to repeat time-consuming work on questions that may have already been answered. The researchers do, however, come across obstacles to their work time and time again: the datasets are often incomplete and not uniformly marked. "This makes it more difficult for interested users to further process the data," says Dr Ulisses Nunes da Rocha, microbiological ecologist at the UFZ and one of the study's lead authors. This starts with minor details, such as the temperature. Temperature can be recorded in different ways using Fahrenheit, Kelvin or Celsius; the way in which the units are abbreviated varies in addition. But there is also uncertainty with regard to what may seem to be basic issues; for example, some scientists around the world have different understandings of the exact definition of a biome (the scientific term for a large-scale habitat). All this, says Dr da Rocha, makes it more difficult to use the data efficiently.

Dr Ulisses Nunes da Rocha and his team have now filtered the metagenome data out of the MG Rast and SRA datasets collected by researchers in the terrestrial environment around the world. In contrast, they screened out data collected from the seas and oceans. Exactly 15,022 metagenome datasets from forests or grasslands or from the subsoil originating in 84 countries were brought together in the new metadata-database. They did not develop any new scientific standards for the exact description of this metadata, such as the geographical coordinates, the pH value or the temperatures involved but used an existing method of standardisation. "The metadata-database helps researchers whose work centres on the terrestrial environment and who want to incorporate data of this kind into their own work," says the UFZ researcher. Instead of performing complex laboratory experiments for the purpose of CO2 fixation or establishing the effect of pesticides on microbiological communities, to name two examples, researchers can consult the database to see if researchers somewhere around the world have already performed similar experiments on this topic and have made their data available.

The UFZ's freely accessible "TerrestrialMetagenomeDB" metadata-database went online at the beginning of November. Users can initially use six filters, such as the origin of the biome, sample type or the data source to search the database and, if necessary, track down more specific data by means of a further 33 filters. Secondly, another approach provides an interactive map of the world that users can use to look for datasets according to geographical features. Three video tutorials offer additional user support on how to best conduct research and download the data. The metadata-database is automatically updated twice a year - in January and July. As part of this process, new or corrected datasets are automatically retrieved from the MG-Rast and SRA repositories, assuming that groups of scientists have adapted the attributes of their own data to the standards of the new database. There is great potential: there are another 100,000 or so datasets on hold containing data on terrestrial metagenomes that could not be standardised to date because the data had not been entered precisely enough. For Dr Ulisses Nunes da Rocha and his UFZ "Microbiological Systems Data Science" working group, this is only the first step in a process of facilitating big data analyses of microbiological communities in terrestrial systems on a global scale.

Some of the first biological evidence of the incongruence transgender individuals experience, because their brain indicates they are one sex and their body another, may have been found in estrogen receptor pathways in the brain of 30 transgender individuals.

"Twenty-one variants in 19 genes have been found in estrogen signaling pathways of the brain critical to establishing whether the brain is masculine or feminine," says Dr. J. Graham Theisen, obstetrician/gynecologist and National Institutes of Health Women's Reproductive Health Research Scholar at the Medical College of Georgia at Augusta University.

Basically -- and perhaps counterintuitively -- these genes are primarily involved in estrogen's critical sprinkling of the brain right before or after birth, which is essential to masculinization of the brain.

Variants investigators identified may mean that in natal males (people whose birth sex is male) this critical estrogen exposure doesn't happen or the pathway is altered so the brain does not get masculinized. In natal females, it may mean that estrogen exposure happens when it normally wouldn't, leading to masculinization.

Both could result in an incongruence between a person's internal gender and their external sex. The negative emotional experience associated with this incongruence is called gender dysphoria.

"They are experiencing dysphoria because the gender they feel on the inside does not match their external sex," Theisen says. "Once someone has a male or female brain, they have it and you are not going to change it. The goal of treatments like hormone therapy and surgery is to help their body more closely match where their brain already is."

"It doesn't matter which sex organs you have, it's whether estrogen, or androgen, which is converted to estrogen in the brain, masculinizes the brain during this critical period," says Dr. Lawrence C. Layman, chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics in the Department of Obstetrics and Gynecology. "We have found variants in genes that are important in some of these different areas of the brain."

These brain pathways are involved in regions of the brain where the number of neurons and how connected the neurons are typically differ between males and females.

They note that while this "critical period" for masculinizing the brain may seem late, brain development actually continues well after birth and these key pathways and receptors already need to be established when estrogen arrives.

While it's too early to definitively say the gene variants in these pathways result in the brain-body incongruence called gender dysphoria, it is "interesting" that they are in pathways of hormone involvement in the brain and whether it gets exposed to estrogen or not, says Layman.

He and Theisen are co-corresponding authors of the study in the journal Scientific Reports.

"This is the first study to lay out this framework of sex-specific development as a means to better understand gender identity," Theisen says. "We are saying that looking into these pathways is the approach we are going to be taking in the years ahead to explore the genetic contribution to gender dysphoria in humans."

In fact, they already are exploring the pathways further and in a larger number of transgender individuals.

For this study, they looked at the DNA of 13 transgender males, individuals born female and transitioning to male, and 17 transgender females, born male and transitioning to female. The extensive whole exome analysis, which sequences all the protein-coding regions of a gene (protein expression determines gene and cell function) was performed at the Yale Center for Genome Analysis. The analysis was confirmed by Sanger sequencing, another method used for detecting gene variants.

The variants they found were not present in a group of 88 control exome studies in nontransgender individuals also done at Yale. They also were rare or absent in large control DNA databases.

Reproductive endocrinologist/geneticist Layman says his experience with taking care of transgender patients for about 20 years, made him think there was a biological basis. "We certainly think that for the majority of people who are experiencing gender dysphoria there is a biologic component," says Theisen. "We want to understand what the genetic component of gender identity is."

While genetics have been suggested as a factor in gender dysphoria, proposed candidate genes to date have not been verified, the investigators say. Most gene or gene variants previously explored have been associated with receptors for androgens, hormones more traditionally thought to play a role in male traits but, like estrogen in males, also are present in females.

MCG investigators and their colleagues decided instead to take what little is known about sex-specific brain development -- that estrogen bath needed in early life to ensure masculinization of the brain-- to hone in on potential sites for relevant genetic variances. Extensive DNA testing initially revealed more than 120,000 variants, 21 of which were associated with these estrogen-associated pathways in the brain.

Animal studies have helped identify four areas of the brain with pathways leading to development of a male or female brain, and the investigators focused on those likely also present in humans. Laboratory studies have indicated that disrupting these brain pathways in males and females during this critical period results in cross sex behavior, like female rodents mounting and thrusting and males taking on a more traditional female posture when mating. These cross sex behaviors, which also have been documented in non-human primates, emerge during the natural sex hormone surge of puberty.

While sex specific brain development has not been thoroughly evaluated in humans, as with animals, the effects typically play out most at the time of puberty, a time when sex hormones naturally surge, when the general awareness of our sexuality really begins to awaken and when the complex state of gender dysphoria may become easier for adolescents to articulate, the investigators say. Layman notes that many individuals will report experiencing gender incongruent feelings as early as age 5.

Theisen notes that we all are full of genetic variants, including ones that give us blue eyes versus brown or green, and the majority do not cause disease rather help make us individuals. "I think gender is as unique and as varied as every other trait that we have," Theisen says.

The investigators suggest modification of the current system for classifying variants that would not imply that a variant means pathogenic, or disease causing.

Last year, the World Health Organization said that gender incongruence is not a mental health disorder and six years before that The Diagnostic and Statistical Manual of Mental Disorders, replaced gender identity disorder with general dysphoria.

About 0.5 to 1.4% of individuals born male and 0.2 to 0.3 % of individuals born female meet criteria for gender dysphoria. Identical twins are more likely than fraternal twins to both report gender dysphoria.

Gender affirming therapies, like hormone therapies and surgeries along with mental health evaluation and support, help these individuals better align their bodies and brains, the physician-scientists say.

Transgender individuals experience increased rates of discrimination, sexual violence and are at increased risk of depression, substance abuse and attempted suicide. About 26% report use of alcohol or other drugs to help cope; 19% have been denied medical care by a physician or other provider, some report verbal harassment in a medical environment and insurance companies do not consistently cover the cost of gender affirming hormone or surgical therapies.

A problem, the investigators say, is an overall lack of understanding of the biologic basis of gender dysphoria.

While their study of 30 individuals -- they now have data on more than 30 others -- appears to be the largest to date, the sample size prompted them to classify the published findings as preliminary.

Astronomers using the Atacama Large Millimeter/submillimeter Array (ALMA), in which ESO is a partner, have spotted a peculiar gas cloud that resulted from a confrontation between two stars. One star grew so large it engulfed the other which, in turn, spiralled towards its partner provoking it into shedding its outer layers.

Like humans, stars change with age and ultimately die. For the Sun and stars like it, this change will take it through a phase where, having burned all the hydrogen in its core, it swells up into a large and bright red-giant star. Eventually, the dying Sun will lose its outer layers, leaving behind its core: a hot and dense star called a white dwarf.

"The star system HD101584 is special in the sense that this 'death process' was terminated prematurely and dramatically as a nearby low-mass companion star was engulfed by the giant," said Hans Olofsson of the Chalmers University of Technology, Sweden, who led a recent study, published in Astronomy & Astrophysics, of this intriguing object.

Thanks to new observations with ALMA, complemented by data from the ESO-operated Atacama Pathfinder EXperiment (APEX), Olofsson and his team now know that what happened in the double-star system HD101584 was akin to a stellar fight. As the main star puffed up into a red giant, it grew large enough to swallow its lower-mass partner. In response, the smaller star spiralled in towards the giant's core but didn't collide with it. Rather, this manoeuvre triggered the larger star into an outburst, leaving its gas layers dramatically scattered and its core exposed.

The team says the complex structure of the gas in the HD101584 nebula is due to the smaller star's spiralling towards the red giant, as well as to the jets of gas that formed in this process. As a deadly blow to the already defeated gas layers, these jets blasted through the previously ejected material, forming the rings of gas and the bright bluish and reddish blobs seen in the nebula.

A silver lining of a stellar fight is that it helps astronomers to better understand the final evolution of stars like the Sun. "Currently, we can describe the death processes common to many Sun-like stars, but we cannot explain why or exactly how they happen. HD101584 gives us important clues to solve this puzzle since it is currently in a short transitional phase between better studied evolutionary stages. With detailed images of the environment of HD101584 we can make the connection between the giant star it was before, and the stellar remnant it will soon become," says co-author Sofia Ramstedt from Uppsala University, Sweden.

Co-author Elizabeth Humphreys from ESO in Chile highlighted that ALMA and APEX, located in the country's Atacama region, were crucial to enabling the team to probe "both the physics and chemistry in action" in the gas cloud. She added: "This stunning image of the circumstellar environment of HD101584 would not have been possible without the exquisite sensitivity and angular resolution provided by ALMA."

While current telescopes allow astronomers to study the gas around the binary, the two stars at the centre of the complex nebula are too close together and too far away to be resolved. ESO's Extremely Large Telescope, under construction in Chile's Atacama Desert, "will provide information on the 'heart' of the object," says Olofsson, allowing astronomers a closer look at the fighting pair.

About 29 million Americans use over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) to treat pain. Every year in the United States, NSAID use is attributed to approximately 100,000 hospitalizations and 17,000 deaths. In addition, the U.S. Food and Drug Administration recently strengthened its warning about risks of non-aspirin NSAIDs on heart attacks and strokes. While each over-the-counter and prescription pain reliever has benefits and risks, deciding which one to use is complicated for health care providers and their patients.

To provide guidance to health care providers and their patients in their clinical decision-making, researchers from Florida Atlantic University's Schmidt College of Medicine have published a review in the Journal of Cardiovascular Pharmacology and Therapeutics addressing cardiovascular risks and beyond, which include gastrointestinal and kidney side effects of pain relievers. They examined the benefits and risks of over-the-counter and prescription drugs for pain relief such as aspirin, ibuprofen (Motrin or Advil), naproxen (Aleve), and prescription drugs such as diclofenac (Voltaren), a non-aspirin NSAID, and selective cyclooxygenase-2 inhibitors such as celecoxib (Celebrex) as well as acetaminophen (Tylenol).

NSAIDs include aspirin, traditional non-aspirin NSAIDs such as ibuprofen, (Motrin or Advil), naproxen, (Aleve) and diclofenac, (Voltaren) as well as selective cyclooxygenase 2 inhibitors (COXIBs), such as celecoxib (Celebrex), and acetaminophen (Tylenol).

All of these drugs have benefits and risks. Aspirin decreases inflammation as well as coronary events and stroke, but increases gastrointestinal symptoms and bleeding, however, without adverse hepatic or renal consequences. Non-aspirin NSAIDs decrease inflammation, but have been associated with adverse major coronary events and stroke with long-term use as well as major upper gastrointestinal and kidney side effects, as well as electrolyte imbalances such as high sodium or potassium and even heart failure.

Cyclooxygenase 2 (COX2) inhibitors were developed primarily because of their more favorable gastrointestinal side effect profile relative to aspirin and traditional non-aspirin NSAIDs, but confer adverse cardiovascular as well as hepatic and renal effects. Acetaminophen has no clinically relevant anti-inflammatory properties and accounts for more than 50 percent of drug overdose related liver failure and about 20 percent of liver transplant cases, as well as kidney disease.

"With respect to the benefits and risks of pain relievers, the totality of evidence suggests that health care providers and their patients should make individual clinical judgements based on the entire risk factor profile of the patient," said Manas Rane, M.D., first author and a third-year internal medicine resident in FAU's Schmidt College of Medicine. "The judicious individual clinical decision-making about the prescription of NSAIDs to relieve pain based on all these considerations has the potential to do much more good than harm."

This manuscript has been selected by the editorial board of the Journal of Cardiovascular Pharmacology and Therapeutics for inclusion in the newly launched "Editor's Choice Collection" - a collection of high-quality and potentially high-impact publications, which will be featured prominently on the journal's website and promoted to their readership.

"The factors in the decision of whether and, if so, which drug to prescribe for relief of pain and inflammation, should not be limited to risks of cardiovascular or gastrointestinal side effects. These considerations should also include potential benefits including improvements in overall quality of life resulting from decrease in pain or impairment from musculoskeletal pain syndromes," said Charles H. Hennekens, M.D., Dr.P.H., corresponding author, first Sir Richard Doll Professor and senior academic advisor in FAU's Schmidt College of Medicine.

Widespread poaching in tropical biodiversity hotspots is causing unprecedented declines in wildlife populations, known as defaunation. A new study published in the journal Diversity & Distributions, provides evidence that large-scale systematic surveys and novel methods of data collection and analysis, are necessary to assess the extent and distribution of poaching and its impact on biodiversity in forest exposed to severe defaunation. Mapping biodiversity in this way will provide information critical to protecting rare species that may still exist in these landscapes. The research was conducted in the Annamite mountains on the border of Laos and Vietnam, an area with an exceptionally high occurrence of endemic species that is threatened by illegal poaching through the setting of wire snares. The research team, led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW), comprised scientists, conservationists and government counterparts, including representatives from WWF-Vietnam and WWF-Laos.

High levels of unsustainable hunting have decimated wildlife populations in many forests in the Annamites. This situation is not unique to Vietnam and Laos - tropical rainforests in other parts of Southeast Asia are also experiencing a similar fate. To protect wildlife communities in these areas, the researchers argue that limited conservation resources must be utilized effectively and that understanding where rare and threatened species still occur will be an important first step to identify priority areas for targeted conservation activities.

The authors provide evidence that surveying biodiversity in defaunated landscapes may require novel approaches. "By conducting systematic surveys at the landscape-scale, we were able to get a better overview of the wildlife communities and a deeper understanding of the underlying factors which influence species distribution," said Andrew Tilker of the Leibniz-IZW and lead author of the study. "We also found that using two complementary survey methods - camera-traps and vertebrate DNA extracted from parasitic blood-sucking leeches - improved our ability to detect species, which is especially important for rare and elusive animals. We then used these data and applied advanced statistical techniques to produce maps of species distributions across the landscape - the first for the Annamites." Ultimately, the researchers expect that biodiversity baselines established through such scientifically-robust approaches will help conservation managers to protect rare and endangered species still present in these landscapes.

"The threat posed by illegal snares to the survival of endemic wildlife cannot be overstated," said Benjamin Rawson, Conservation and Program Development Director of WWF-Vietnam. "WWF is deploying probably the largest effort in the region to get these snares out of the forest and provide wildlife a fighting chance, but the sheer number of wire snares set in the Annamites is alarming."

"With evidence from landscape-level surveys we will now deploy snare-removal teams to freshly identified areas of high biodiversity," says Adrian Klocke, Project Manager of the KfW Development Bank in Germany, which supports the Carbon and Biodiversity Phase 2 project (CarBi II) in the Annamites. CarBi II is implemented by WWF through KfW as part of the International Climate Initiative (IKI) of the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU). "Additionally, the results of this study help us identify areas that are not currently protected but which are important for rare species," Klocke adds. "For instance, one interesting result was that a mostly unpatrolled forest area in Laos called the Palé area is a hotspot for numerous endemic and threatened species. We hope that as a part of CarBi II, this area can be protected."

Amphone Phommachak, WWF-Laos Landscape Manager for the Central Annamites, agrees that this type of scientific study is highly valuable. "We need to develop and implement evidence-driven conservation strategies to protect the remarkable biodiversity of the Annamites. There is no doubt that the Central Annamites have been hit hard by intensive snaring, but fortunately, rare and endemic species are still hanging on. There is still time to protect species like the Annamite striped rabbit, but the window of opportunity is rapidly closing. Focusing snare-removal efforts and protecting new areas will hopefully help us prevent further extinctions in the Annamites."