Earth

Healthy octogenarians have high cholesterol efflux capacity

Many scores designed to help doctors predict whether a patient is at risk for cardiovascular disease are not accurate in elderly adults. As life expectancy grows longer around the world, the search is on for new ways to measure risk beyond the traditional cholesterol test and life history. In a recent study in the Journal of Lipid Research, Francesca Zimetti and colleagues at the University of Parma in Italy and the State University of Campinas, Brazil, set out to determine if cholesterol efflux capacity, or CEC, should be considered a risk factor in healthy adults aged 80 or older. CEC is shorthand for the ability of arterial macrophages to release excess cholesterol, preventing it from accumulating on artery walls. In younger adults, high CEC correlates with a reduction in early signs of atherosclerosis. While this association did not hold in a group of Brazilian adults who had reached their 80s in good health, the octogenarians had significantly higher cholesterol efflux capacity than their middle-aged counterparts. The authors caution that the healthy elderly patients should be compared to patients over 80 with cardiovascular disease to be certain, but suggest that high CEC may promote longevity.

DOI: 10.1194/jlr.P079525

MicroRNAs promote fat cell apoptosis

Weight loss can be hard to sustain. The total mass of adipose tissue depends both on the number of fat cells, or adipocytes, and their average size. During weight loss, the amount of fat stored in each cell drops, but the total number of cells stays the same, making it easy to regain weight when a caloric surplus is available. Therefore, being able to selectively kill adipocytes or their precursor cells, preadipocytes, is a target for making weight loss last. In a paper in the Journal of Lipid Research, Zhenzhen Zhang and colleagues at Northwest A&F University in Shaanxi, China, report that in a model for apoptosis in fat cells, two microRNAs are important drivers of the programmed cell death pathway. These microRNAs, miR-103 and 107, suppress the production of a protein called wnt3a that reduces apoptosis. Overall, the microRNAs led to more programmed cell death. Targeting these microRNAs could someday become a route to killing adipocytes.

DOI: 10.1194/jlr.M082602

Eicosanoid fluctuations drive signaling in cultured cells

Cultured cells depend on media for many essential nutrients, among them polyunsaturated fatty acids. Researchers observed that cells' production of signaling lipids derived from PUFAs by cultured macrophages changes over time between media changes, as the cells exhaust the available essential PUFAs. In an article in the Journal of Lipid Research, Okuno and colleagues from Jutendo University in Japan and the University of Colorado in Denver quantified the changes to various lipids. In addition to fluctuating lipid levels, they observed that the number of days since the previous media change dramatically altered tumor necrosis factor secretion in response to lipopolysaccharide, an inflammation mediator. The study suggests that cell feeding schedules may introduce variability between in vitro experiments, which could be reduced by flow-through culture.

DOI: 10.1194/jlr.M083030

The average hippo weighs more than 3,000 pounds and consumes about 100 pounds of vegetation daily. This naturally results in large quantities of dung being deposited into the rivers and lakes where hippos spend their days.

In general, the nutrients delivered via hippo dung to such aquatic ecosystems are perceived to be beneficial. For millennia, they provided a natural source of fertilizer that appears to fuel life in aquatic food webs. That may be changing.

In sub-Saharan Africa, deforestation, water-intensive agriculture and now climate change are significantly altering water cycles and causing many rivers to begin to dry. A new study by UC Santa Barbara community ecologist Keenan Stears, with colleagues at UC Berkeley and Sokoine University of Agriculture in Tanzania, examines how these forces of global change are redefining the way hippos -- and their dung -- shape the ecology of freshwater ecosystems. The findings appear in the Proceedings of the National Academy of Sciences.

"This work explores how hippo dung shapes freshwater chemistry and links these changes to associated patterns of aquatic biodiversity change," said Stears, a postdoctoral researcher in UCSB's Department of Ecology, Evolution, and Marine Biology (EEMB). "It also illustrates that the net impact of hippos on river ecosystems is dynamically controlled by river hydrology and reveals the capacity of human disturbances on river flow to drastically alter the role of ecosystem-linking species."

Stears and his team studied river flow and hippo density in the Great Ruaha River in Tanzania's Ruaha National Park, which protects an area about the size of Connecticut and is home to large populations of some of Africa's most iconic species. The Great Ruaha River is the backbone of life in this dry region. Since 1993, however, the once constantly flowing river has ceased to flow during the dry season. The researchers tested nearly a dozen attributes of water quality and measured the diversity and abundance of aquatic life in hippo pools over multiple years, both when river flow was high and during dry periods when the river stopped flowing.

"During the dry season when there was no flow, the pools were completely separated," Stears explained. "We found a huge buildup of hippo dung, and therefore nutrient concentrations within high-density hippo pools. The high influx of nutrients caused the dissolved oxygen concentration to decline to sublethal levels for most fish species."

EEMB assistant professor Douglas McCauley, a senior researcher on the project, called these results an alarm bell for African wildlife. "Hippos are to Africa what polar bears are to the Arctic," he said. "Everything we thought we knew about how African ecosystems worked appears to be changing. Global change has turned productive hippo pools, once teeming with fish and life, into fetid black cesspools."

Only a few species of fish and insects are able to survive in the hippo pools when the river dries, because of extreme losses of dissolved oxygen in these pools. Stears and his colleagues noted large reductions in fish diversity and abundance inside the pools that were overfueled by dung when river flow ceased.

When the rains returned and the river resumed its flow, the researchers saw a reset in many impacts of hippo dung on water quality and biodiversity detected during the dry season.

"This suggests some kind of resilience within the system that allows it to recover after the hydrological disturbance every dry season," Stears said. "This resilience signifies that there is hope for this system, but without intervention soon, the chronic stress caused by river drying and overfertilizing of hippo dung may cause long-term species loss in this river system."

According to Stears, the findings from this study highlight the value of accelerating more efficient water-management policies and land-management practices not only for the conservation of hippos but also to ensure the sustained health and functioning of African watersheds in a changing environment.

"A lot of our results directly assess how changing river flow alters the hippos' influence on the ecological diversity and functioning of watersheds," Stears said. "However, these findings also call attention to the profound ways in which the dry-season impacts of hippos may influence local communities that rely on rivers as a food source. Tilapia are a commonly consumed fish throughout Africa and, during the dry season, we found that the presence of hippos reduced tilapia abundance by 41 percent across the watershed. That's not only bound to have ecological consequences but will also impact the human populations that rely on these rivers."

A new study in the Journal of Urban Ecology, published by Oxford University Press, indicates that the number of wild animals killed by motor vehicles may be much higher than is generally reported or understood.

Roads can have negative impacts on wildlife through direct effects such as fatal collisions with vehicles and through indirect effects such as changing and fragmenting animal habitats. There are millions of wildlife deaths on British roads every year, and the resulting carcasses represent a substantial amount of food for scavengers. By removing roadkill in urban areas, scavengers perform a valuable ecosystem service, but the rapid removal of these carcasses by scavengers could lead researchers to underestimate the impact of roads on wildlife.

In order to evaluate the scale and context of urban roadkill scavenging, researchers here examined which species scavenge on roadkill in urban areas, the likelihood of roadkill being removed by scavengers, and whether spatial and temporal factors (such as location and time of day) influenced the rate of removal.

Researchers deployed camera traps baited with chicken heads to simulate roadkill corpses in six residential and six parkland sites in the city of Cardiff. Seven species were observed removing the roadkill, with corvids (members of the crow family) being the most common scavengers, responsible for 42% of removals. Of the 120 corpses, 90 (76%) were removed within 12 hours. Time of day had a significant effect on the rate of removal, with the number of carcass removals peaking in the first few hours of daylight. Of roadkill placed at 9 AM, 62% of carcasses had been removed after only two hours.

Removal of corpses by scavengers could mean that the actual number of road deaths is six times more than that observed during surveys.

Seven species were observed removing the roadkill; two species of gull, carrion crow, Eurasian magpie, red fox, domestic dog, and domestic cat. Corvids were the most common scavengers, responsible for 42% of roadkill removals. In addition to the observed removals, mice, likely wood mice, and a brown rat were observed scavenging on the bait, but did not remove it.

Of the observed scavengers, birds scavenged most frequently, with 51 incidences of roadkill removal, compared to 28 by mammals. There was a significant difference between residential and parkland habitats in the relative frequencies of the different taxa scavenging the baits, showing that the likelihood of a particular animal scavenging the bait was dependent on the type of habitat. For example, gulls fed predominantly in residential areas (12 incidents compared to only once in parkland), whereas corvids mostly fed in parkland areas (28 incidents compared to 10 in residential areas).

"Removal of animals by scavengers is believed to be the most important factor causing underestimations of roadkill numbers, particularly of small animals such as garden birds and rodents," said the paper's lead author, Amy Williams Schwartz. "Our study demonstrates the frequency and speed at which scavengers can remove roadkill, and the extent to which we could underestimate the true number of casualties, but also suggests that many urban scavengers such as crows, gulls, and foxes could be providing an under-appreciated and largely unnoticed carcass removal service in our cities."

A new study has found that there is an average of 239,000 excess deaths per year of girls under the age of five in India, or 2.4 million in a decade, and excess female child mortality is found in 90% of districts in the country.

The average level of excess mortality in girls aged 0-4 in the study period of 2000-2005 was 18.5 per 1000 live births, compared to the expected mortality of girl children aged under five in areas of the world without known gender discrimination. Around 22% of the overall mortality burden of females under five is therefore due to gender bias.

IIASA postdoctoral research scholar Nandita Saikia says that the new research shows that the burden of excess female deaths in India is huge. It is the first time that the number of excess deaths amongst girls under five in India has been studied at the district level, showing specific geographic patterns of excess female mortality across India's 640 districts.

In all, 29 out of 35 states in India had overall excess mortality in girls under five, and all states and territories bar two had at least one district with excess mortality. However, the level varies.

The problem is most pronounced in northern India, where the four largest states in the region, Uttar Pradesh, Bihar, Rajasthan, and Madhya Pradesh, account for two thirds of the total excess deaths of females under five. In Uttar Pradesh excess female mortality was calculated at 30.5. In Bihar, the rate is 28.5, in Rajasthan it was 25.4, and in Madhya Pradesh, it was 22.1. In parts of western Rajasthan and northern Bihar, excess mortality as a result of gender bias accounts for 30-50% of the mortality rate of females under five.

The worst affected areas are all rural, agricultural areas with lower levels of education, high population densities, low socioeconomic development and high levels of fertility. The researchers say that many deaths of females under five are partly down to unwanted child bearing and subsequent neglect. Higher levels of female literacy and employment in more modern industries is linked to lower levels of excess mortality in females under five.

"As the regional estimates of excess deaths of girls demonstrate, any intervention to reduce the discrimination against girls in food and health care allocation should therefore target in priority regions of Bihar and Uttar Pradesh where poverty, low social development, and patriarchal institutions persist and investments on girls are limited," says Saikia. "The sustained fertility decline currently observed in North India is likely to lead to a reduction in postnatal discrimination. Unless son preference diminishes, lower fertility, however, might bring about a rise in gender-biased sex selection as was observed 20 years ago in Western India. This reinforces the need to address directly the issue of gender discrimination in addition to encouraging social and economic development for its benefits on Indian women."

Interestingly, the results do not coincide with areas with known skewed sex ratios at birth, such as Punjab, Gujarat, and Mahrashtra. Co-researcher Christophe Guilmoto from the Université Paris Descartes, France, says that for too long, the focus has been on prenatal sex selection.

"Gender-based discrimination towards girls doesn't simply prevent them from being born, it may also precipitate the death of those who are born," he says. "Gender equity is not only about rights to education, employment or political representation. It is also about care, vaccination, and nutrition of girls, and ultimately survival."

Saikia notes that if there were no excess female deaths in India, the country could have achieved its Millennium Development Goal target on child mortality, of 42 deaths per 1,000 births, very easily.

"Discrimination towards the girl child is not justified. There is a need to change mentality. Rather than discriminating against them it is necessary to raise their value through education and self-dependence," says Saikia.

JUPITER, FL - May 14, 2018 - Cancer is a disease often driven by mutations in genes. As researchers learn more about these genes, and the proteins they code for, they are seeking smarter drugs to target them. The ultimate goal is to find ways to stop cancer cells from multiplying out of control, thereby blocking the growth and spread of tumors.

Now researchers from The Scripps Research Institute are reporting an innovative new method to screen for potential cancer drugs. The technique makes use of tiny, three-dimensional ball-like aggregates of cells called spheroids. These structures can be used to interrogate hundreds or even thousands of compounds rapidly using a technique called high throughput screening. In fact, by using this approach, the team has already identified one potential drug for an important cancer gene. The results were reported in the journal Oncogene.

"What's important about this research is that we're able to do studies using a form of cancer cells that is more physiologically relevant and better recapitulates how these cells appear in the body," says Timothy Spicer, director of Lead Identification Discovery Biology and High Throughput Screening on Scripps Research's Florida campus and one of the study's corresponding authors.

"Until now, most of the research to screen for cancer drugs has used cells that are growing flat on a plate," adds Louis Scampavia, director of HTS Chemistry and Technologies at Scripps Research and one of the study's co-authors. "With these 3-D spheroids, we emulate much more closely what's found in living tissues."

The spheroids are 100 to 600 microns in diameter-equivalent to the thickness of a few sheets of paper. In contrast to single layers of cells normally used to screen for drugs, which tend to all grow at the same rate because they get the same exposure to oxygen and nutrients, the spheroids mimic what might happen in a tumor: Some cells are on the outside and some are on the inside.

In the new paper, the researchers focused on a cancer-driving protein called KRAS. The KRAS gene and other members of the related RAS gene family are found to be mutated in nearly one-third of all cancers. They are common in lung cancer, colorectal cancer, and especially pancreatic cancer. In fact, up to 90 percent of pancreatic cancers are driven by KRAS mutations, and the investigators used pancreatic cancer cell lines for the current study.

"In the past, KRAS has been a very tricky protein to target. People have spent several decades trying, but so far there has been little success," says Joseph Kissil, PhD, professor at Scripps Research Medicine and the other co-corresponding author. "The KRAS protein is relatively small, and that's made it hard to attack it directly. But the method of screening that we used in this study allowed us to come at the question in a different way."

The investigators performed what is called a phenotypic screen, which means they were looking for drugs that had an effect on cell growth, but didn't have a preconceived idea about how they might work. "We came at this in an unbiased way," Kissil explains. "We were not trying to design something to attack a specific part of the KRAS protein. We were just looking for something that acted on some part of the pathway that's driving cell growth."

The investigators report in the new paper that they have already identified one compound that was previously not know to affect KRAS, called Proscillaridin A. The compound is similar to a class of drugs used to treat some heart conditions. Although the team says this particular drug is unlikely to be developed as a cancer treatment, it validates the approach of conducting drug screenings using spheroids. "It's unlikely we would have discovered this connection using standard 2-D methods," Scampavia says.

"From our perspective, this is a proof-of-principle study," Kissel adds. "It shows you can look at libraries of drugs that have already been approved for other diseases, and find drugs that may also work for cancer. In theory, you could use this screening method for any line of cancer cells, and any mutation you want."

"We would love to use this research to create a pipeline for new oncology drugs," Spicer concludes. "Many of the most promising compounds may be overlooked with 2-D screening. This study provides direct evidence that screening for drugs using 3-D structures of cancer cells may be more appropriate."

A new Canadian guideline for impaired vision in older adults recommends against primary care screening of older adults not reporting concerns about their vision. The guideline, published in English and French in CMAJ (Canadian Medical Association Journal) by the Canadian Task Force on Preventive Health Care (CTFPHC), is aimed at primary care practitioners.

Visual impairment describes less than 20/40 vision, which usually cannot be corrected with glasses, contact lenses or vision-related procedures. This level of difficulty with vision can affect quality of life, as well as participation in work, social and leisure activities, and increases the likelihood of injuries from falls and other accidents.

The task force considered the benefits of screening for visual impairment in primary health care and referring patients to optometrists for formal vision testing.

"We found no evidence of benefit to patients aged 65 years or older from being screened for impaired vision as a way to prevent limitations on daily living or other consequences," said Dr. Brenda Wilson, Task Force Impaired Vision Working Group Chair. "The task force therefore recommends against screening for impaired vision in primary care settings for people living independently in the community."

Currently, people must make their own appointments for regular vision screening or if they suspect visual problems. Most provinces in Canada cover comprehensive eye examinations for adults aged 65 years and older by eye care professionals.

The new guideline updates a previous guideline from 1995, which recommended screening for visual impairment in elderly patients with diabetes of at least 5 years' duration. The 2018 guideline is based on the latest and highest-quality evidence on screening, which includes 15 randomized controlled trials involving participants aged 65 years or older. It is consistent with the recommendation on vision screening for older adults from the United States Preventive Services Task Force.

"Although screening does not appear to be effective, we need to look for ways to effectively support older Canadians who do experience visual impairment so that they get the services they need from optometrists or other eye care professionals" said Dr. Brett Thombs, chair of the CTFPHC .

The research team at the Visual Perception and Cognition Laboratory of the Toyohashi University of Technology has revealed that face-likeness is judged by early visual processing at around 100ms after viewing an object. The present study focuses on the relation between face-likeness recognition and brain activity to suggest for the first time that face-likeness recognition is influenced by early visual processing. The results of the present study were published in the open access journal Frontiers in Human Neuroscience.

Face-likeness recognition is the act of recognizing a non-face object as a human face. This phenomenon is called "pareidolia," and refers to "perceiving an inherently meaningless object such as a pattern, landscape or object as another object with meaning." Many spirit photographs rely on this phenomenon. While pareidolia has been argued to occur in relatively low-level visual processing, at what level of visual processing pareidolia actually occurs was never previously discerned.

Therefore, the research team of the Visual Perception and Cognition Laboratory at the Toyohashi University of Technology decided to study the relation between behavior when a face-like object is viewed and brain activity to reveal the level of visual processing at which face-likeness is recognized.

PhD student and lead author of the study Yuji Nihei explains that, "Visual processing of the human face is divided into three different stages. The first stage is early visual processing of roughly identifying the object. Then, if the object is a face, distinguishing the parts of the face (eyes, nose, mouth) from one another and processing the outline and parts of the face. Lastly, expression and individual differences are distinguished. We studied the relation between activity at these three stages of processing and the results of actual recognition and determined that face-likeness recognition occurs in the first stage of visual processing. This processing occurs at a speed of approximately 100ms after viewing an object, and so we believe that face-likeness processing occurs before we are aware of the object."

Associate Professor Minami Testuto, who leads the research team, says that, "While seeing face-likeness in various objects could be considered incorrect in terms of object recognition, we believe this is not just a mistake and actually makes us reconsider an important cognitive function. We would like to continue our study of face-likeness recognition from an objective approach."

The results of this study are believed to serve as a key to uncovering the mechanism of how humans recognize and distinguish between two types of information - "face-likeness" and objects. The results of the present study also suggest that "face-likeness" recognition occurs in early visual processing and that face-like objects are processed in the same manner as a human face in later stages. Due to this, we believe that face-likeness can be caused by an effect that gathers attention to the face, or some other like stimulus.

Cancer researchers at the University of Bath have measured systematically how efficient molecules are at suppressing the activity of a protein associated with prostate and other cancers. The molecules could eventually be developed into new anti-cancer drugs.

The research team from the Departments of Pharmacy & Pharmacology and Chemistry are studying a protein called α-methylacyl-CoA racemase (AMACR) as a potential target for cancer treatments. Levels of AMACR protein and activity are increased by ~10-fold in all prostate cancers. Reducing these levels using genetic techniques makes the cancer cells less aggressive, and their behaviour becomes more like normal cells.

Until relatively recently finding molecules that could target and inhibit AMACR has been challenging because it's been difficult to accurately measure activity levels of the protein. However, after designing a simple colour-change test which can do precisely that, the University of Bath team were able to start analysing how the structure of promising molecules affects the activity of AMACR.

The team systematically varied the design of drug molecules in order to identify which parts of the molecule are important for effectiveness against AMACR.

In particular they confirmed that the 'oiliness' of a molecule is directly related to its potency - oily regions of the drug molecule, which exclude water, can stick to their targets more easily - although this had been predicted, the University of Bath experiments confirm it for the first time.

The information from the tests will help the team move towards more promising anti-cancer drugs. Their next steps will be to use the information to design rationally even more potent molecules for testing against AMACR.

The research is published in the journal Bioorganic Chemistry.

Lead author Dr Matthew Lloyd said: "This is a small but important step in the development of new treatments for prostate cancer based on AMACR inhibition. It's important because it provides a framework with which to predict and measure drug effectiveness. This will facilitate the development of new treatments for prostate cancer and other cancers in which AMACR levels are increased.

"The test that we've developed at Bath makes this sort of work possible and will now allow us to continue to work towards new anti-cancer drugs."

The study was funded by Prostate Cancer UK with support from the Movember Foundation as part of their initiative to develop new treatments for prostate cancer.

Dr Matthew Hobbs, Deputy Director of Research at Prostate Cancer UK, said: "Over 11,000 men die from prostate cancer every year in the UK, making it the third biggest cancer killer. In these men prostate cancer cells grow and evolve and eventually become resistant to the treatments currently available to combat the disease. However, important research like this which seeks to find new, innovative ways to treat prostate cancer has the potential to stop this trend.

"It's thanks to the funds raised by supporters of Prostate Cancer UK and the Movember Foundation that this research is possible."

In the United Kingdom, prostate cancer is the most common male-specific cancer with 47,151 new diagnoses reported in 2015 and 11,287 deaths in 2014. It accounts for 26% of all cancers diagnosed in men, with one in eight men being diagnosed with prostate cancer in their lifetime. Although 84% of men will survive for at least 10 years with the disease, new treatments are urgently needed especially for those men diagnosed with more advanced disease.

The paper "Structure-activity relationships of rationally designed AMACR 1A inhibitors" is available online.

The group led by ICREA Research Professor Cayetano Gonzalez at the Institute for Research in Biomedicine (IRB Barcelona), in collaboration with Giuliano Callaini's team at the University of Siena in Italy, has published a study in The Journal of Cell Biology that identifies the critical role played by a protein called CENTROBIN in sperm tail development.

In flies, as in humans, the sperm cell (spermatozoon) is made up of the cell body proper, also referred to as the sperm "head", and the flagellum. The flagellum, also called the sperm "tail", is a slender lash-like appendage that protrudes from the cell body. By beating their tails, sperm cells swim to the female reproductive cell (oocyte) and fertilise it. A bundle of microtubules that span the entire length of the tail is critical for flagellar beating. These microtubules are arranged in a characteristic radial symmetry that has been conserved throughout evolution and is templated by a small organelle called the basal body, which sits at the base of the flagellum.

Using the vinegar fly Drosophila melanogaster as a model to study how the sperm tail develops, Gonzalez's Cell Division Lab has found that CENTROBIN plays a critical role in the assembly of a subset of microtubules within basal bodies. In the absence of CENTROBIN, basal bodies lack these microtubules, as do the non-motile tails that they template. Consequently, CENTROBIN mutant males are sterile.

A human condition: "easily decapitated spermatozoa defect'

In addition to the faulty microtubule array within the tail, the head-to-tail link is often severed in CENTROBIN mutant sperm. This effect is reminiscent of a human male sterility condition known as the "easily decapitated spermatozoa defect'. Semen from individuals affected by this condition appears normal, but minimal micro-manipulation, such as that required for in vitro fertilisation, results in sperm heads that are separated from their tails and thus that cannot swim.

In summary, the recent article demonstrates that CENTROBIN, which is well conserved between humans and flies, is a positive regulator of normal flagellum development. Remarkably, a previous study by the same group showed that CENTROBIN exerts a negative effect in the development of primary cilia. Primary cilia are a shorter version of flagella that are present in certain neurons in the fly and in many cell types in humans, where they function as sensors of external stimuli. Like flagella, primary cilia contain a microtubule array that is templated by the basal body.

Taken together, these results reveal the multifunctional nature of CENTROBIN, a protein that plays opposing roles in distinct cell types in the same organism.

A new review published online today in the journal Addiction has compiled the best, most up-to-date source of information on alcohol, tobacco, and illicit drug use and the burden of death and disease. It shows that in 2015 alcohol and tobacco use between them cost the human population more than a quarter of a billion disability-adjusted life years, with illicit drugs costing a further tens of millions.

The largest health burden from substance use was attributable to tobacco smoking and the smallest was attributable to illicit drugs. Global estimates suggest that nearly one in seven adults (15.2%) smoke tobacco and one in five adults report at least one occasion of heavy alcohol use in the past month.

Compared with the rest of the world, Central, Eastern, and Western Europe recorded consistently higher alcohol consumption per capita (11.61, 11.98 and 11.09 litres, respectively) and a higher percentage of heavy consumption amongst drinkers (50.5%, 48.2%, and 40.2%, respectively). The same European regions also recorded the highest prevalence of tobacco smoking (Eastern Europe 24.2%, Central Europe 23.7%, and Western Europe 20.9%).

In contrast, use of illicit drugs was far less common. Fewer than one in twenty people were estimated to use cannabis in the past year, and much lower estimates were observed for amphetamines, opioids and cocaine. Hotspots included the US, Canada, and Australasia. The US and Canada had one of the highest rates of cannabis, opioid, and cocaine dependence (748.7 [694.8, 812.3], 650.0 [574.5, 727.3], and 301.2 [269.3, 333.7] per 100,000 people, respectively). Australasia (Australia and New Zealand) had the highest prevalence of amphetamine dependence (491.5 per 100,000 people [441.4, 545.5]), as well as high rates of cannabis, opioid and cocaine use dependence (693.7 [648.1, 744.4], 509.9 [453.7, 577.8], and 160.5 [136.4, 187.1] per 100,000 people, respectively).

Some countries and regions (e.g., Africa, Caribbean and Latin America, Asia regions) have little or no data on substance use and associated health burden. These are typically low or middle income countries that frequently have punitive drug policies, and may experience serious political and social unrest. These countries need enhanced monitoring because they are at risk of rapid escalation in substance use and related health burden.

The report, 'Global Statistics on Alcohol, Tobacco, and Illicit Drug Use: 2017 Status Report', uses data mainly obtained from the World Health Organization, United Nations Office on Drugs and Crime, and Institute for Health Metrics and Evaluation. The authors note that there are important limitations to the data, especially for illicit drugs, but believe that putting all this information in one place will make it easier for governments and international agencies to develop policies to combat substance use.

DURHAM, N.C. -- Boy or girl? For those who want to influence their baby's sex, superstition and folk wisdom offer no shortage of advice whose effectiveness is questionable at best -- from what to eat to when to make love. But some animals have a technique backed by scientific proof: In turtles and other reptiles, whether an egg hatches male or female depends on the temperature of its nest.

The phenomenon was first discovered in reptiles more than 50 years ago, but until now the molecular details were a mystery.

In a study published May 11 in the journal Science, researchers say they have finally identified a critical part of the biological "thermometer" that turns a developing turtle male or female.

According to a team at Duke University and Zhejiang Wanli University in China, the explanation lies not in the DNA sequence itself -- the A's, T's, C's and G's -- but in a molecule that affects how genes are expressed without altering the underlying genetic code.

"Temperature-dependent sex determination has been a puzzle for a really long time," said Blanche Capel, a cell biology professor at Duke who led the research. "This is the first functional evidence of a molecular link that connects temperature with sexual development."

Unlike humans and most other mammals, the sex of many turtles, lizards and alligators isn't determined by the chromosomes they inherit, but by ambient temperatures during a sensitive stage of development.

For a common pond and pet turtle called the red-eared slider, for example, eggs incubated at 32 degrees Celsius (nearly 88 Fahrenheit) produce all female hatchlings, while those kept at 26 degrees Celsius (79 Fahrenheit) hatch as males.

In the study, the researchers show that cooler egg incubation temperatures turn up a key gene called Kdm6b in the turtle's immature sex organs, or gonads. This in turn acts as a biological "on" switch, activating other genes that allow testes to develop.

To home in on the critical Kdm6b gene, the researchers took a group of freshly laid turtle eggs, incubated them at either 26 or 32 degrees Celsius, and looked for differences in the way genes were turned on in the turtles' gonads early in development -- before their fate as ovaries or testes has been decided.

In a previous study, researchers examined all the gene readouts, or transcripts, produced in the turtles' gonads over this critical time window.

They found several genes that were turned up or down at one temperature but not the other. But one of the first genes to shift was one called Kdm6b, which became much more active at the cooler incubation temperatures that produce males, and was almost silent at warmer, female-producing temperatures.

In the new study, the team used a technique developed by collaborators at Zhejiang Wanli University to suppress the Kdm6b gene in turtle gonads and see how it affects their sexual development.

Silencing the Kdm6b gene, they found, transforms a growing turtle embryo kept at temperatures that would otherwise produce a male with testes into a baby female with ovaries instead.

Further experiments showed that the protein encoded by the Kdm6b gene in turn interacts with a region of the genome called Dmrt1, which acts as a master switch to turn on testis development.

They found that Kdm6b activates the Dmrt1 master switch by modifying histones, the ball-like proteins that DNA is wrapped around inside the cell nucleus, like thread wound around a spool.

In many species, the tail of histone proteins is decorated with special chemical markers, or methyl tags, that keep genes along the DNA molecule inactive.

Kdm6b gene activity turns on the Dmrt1 master switch by removing these repressive tags and "loosening" the histone tails, which makes the DNA wound around the histones easier to access and read.

"It's like removing the brakes off the male pathway," said co-author Ceri Weber, a PhD candidate in the Capel lab at Duke.

Researchers have found temperature-related shifts in Kdm6b gene activity in other species whose sex depends on incubation temperature, such as alligators and bearded dragons. "This suggests that similar molecular mechanisms may be at work in other reptiles too," Capel said.

The researchers think that Kdm6b and the protein it encodes don't sense heat or changes in temperature inherently, since cooler incubation temperatures increased gene activity in the turtle's future testes but not in other developing organs such as the heart or the liver.

"The next step is to find the temperature-sensing trigger," Weber said. "We're trying to narrow down the possibilities."

Thursday, May 10, 2018, Baltimore, MD - Insilico Medicine, a Baltimore-based next-generation artificial intelligence company specializing in the application of deep learning for target identification, drug discovery and aging research announces the publication of a new research paper in Molecular Pharmaceutics journal titled "Adversarial Threshold Neural Computer for Molecular De Novo Design". The described Adversarial Threshold Neural Computer (ATNC) model based on the combination of Generative Adversarial Networks (GANs) with Reinforcement Learning (RL) is intended for the design of novel small organic molecules with the desired set of pharmacological properties.

"This is a proof of concept scratching the surface of what we have in house. Stay tuned for the cool experimental validation results to be announced this Summer. I hope that part of this work integrated into our pipeline will help make the world a better and healthier place and help make perfect molecules for specific targets and multiple targets that will have a much higher chance of becoming great drugs", said Evgeny Putin, the deep learning lead at Insilico Medicine.

The architecture of GANs was initially proposed by Ian Goodfellow in 2015, and since the inception, the GAN-based models have achieved the unprecedented accuracy in image, video and text generation. The fundamental principle of GANs is adversarial training based on the competition between the Generative and Discriminative networks that leads to joint evolution and highly accurate results with the desired properties. Insilico Medicine scientists pioneered the application of GANs and their conjunction with RL for drug discovery process and published the proof of concept.

"The GAN-RL architecture proposed by Putin in this paper demonstrated the ability to generate a substantial percentage of valid and unique molecular structures. This study is a proof of concept using string representations of molecular structure and internally we are using multiple integrated generators with reinforcement learning and the proprietary representation of molecular structure, which allows us to synthesize the exact molecules and link chemistry and biology", said Alex Zhavoronkov, the founder and CEO of Insilico Medicine.

PHILADELPHIA - Different Parkinson's-related brain disorders, called synucleionpathies, are characterized by misfolded proteins embedded in cells. Researchers in the Perelman School of Medicine at the University of Pennsylvania found that the type of brain cell afflicted dictates which pathological form of α-synuclein (α-syn) protein becomes the disease culprit. The team's results were published this week in Nature.

"These unexpected findings of the effect of cell type on the generation of different α-syn strains addresses one of the most important mysteries in neurodegenerative disease research," said first author Chao Peng, PhD, a research associate in the Center for Neurodegenerative Disease Research (CNDR).

The relationship between cell type and variety of disease protein has not been described for any other neurodegenerative brain disorder. For now, the hope is that one strain associated with multiple system atrophy (MSA) might point the way to new therapies.

What had been known before this Nature study is that in cases of Parkinson's disease without and with dementia, dementia with Lewy bodies, and in about 50 percent of Alzheimer's disease patients, α-syn aggregates in neurons as Lewy bodies (LBs) and Lewy neurites in axons and dendrites. However, in MSA, a rare neurodegenerative disease with widespread effects on the brain and body, α-syn behaves differently. It mainly accumulates as glial cytoplasmic inclusions (GCIs) outside the nucleus in the cytoplasm of oligodendrocytes, a brain structural cell important for myelin production (the insulation material of nerve cell fibers).

The Penn team found that pathological α-syn in GCIs versus LBs are distinct in shape and biology. The α-syn in GCIs forms more compact structures and is about 1,000-fold more potent in seeding and spreading α-syn aggregation in animal models, which is consistent with the highly aggressive nature of MSA.

"Years ago we found that α-syn fibrils act as 'seeds' that induce normal α-syn protein to aggregate into clumps," said senior author Virginia M.-Y. Lee, PhD, CNDR director and a professor of Pathology and Laboratory Medicine. "We showed that α-syn fibrils were taken up by healthy neurons, which leads to the formation of Lewy bodies and neurites that impair neuron function, leading to nerve cell death."

Surprisingly, say the researchers, pathological α-syn in GCIs and LBs did not show a preference for a specific cell type in starting pathology when human brain-derived α-syn of each type was used to induce aggregates in cell culture and mouse models.

"This raises the question of why α-syn pathology in Parkinson's disease versus multiple system atrophy shows different potencies, properties, and distributions in neurons versus glial cells," Lee said.

The researchers also found that oligodendrocytes, but not neurons, transform misfolded α-syn into the cytoplasmic strain, which explains the distribution of the two forms by cell type. On the other hand, cytoplasmic α-syn maintains its active seeding function when propagated from neuron to neuron. From this, the researchers concluded that α-syn strains are determined by both misfolded α-syn seeds and cell type.

The team's next steps will be to uncover the underlying molecular mechanism for the differences between the strains. The molecules in oligodendrocytes responsible for the highly potent cytoplasmic strain might suggest viable drug targets for MSA and explain why therapies used to treat other synucleinopathies may not work for MSA patients.

(Geneva, 10 May, 2018) Targeted probiotic supplementation in breastfed infants can significantly reduce the potential for antibiotic resistance, new research presented today at the 51st ESPGHAN Annual Meeting shows [i].

Breastfed infants fed a specific probiotic strain of B. infantis had, on average, 87.5% less antibiotic resistance genes in their gut microbiome when compared with breastfed infants who had received lactation support alone. Thirty-eight antibiotic resistant genes were reduced in the supplemented infants, including genes associated with resistance to a wide range of drugs prescribed to treat respiratory, intestinal and urinary infections, chlamydia and acne.

Antibiotic resistance has been identified by the World Health Organisation as one of the biggest threats to global health [ii] and the increasing prevalence of antibiotic resistance gene carriage is a growing public health concern. Misuse of antibiotics in humans and animals is accelerating this threat and a growing number of infections are becoming more difficult to treat as antibiotics become less effective. Members of the public frequently take antibiotics when they are not required to, with estimates suggesting that more than half of all the antibiotics taken by humans are not actually needed [iii]. They are often fed to livestock to boost food production and resistance can spread 'vertically' when new generations inherit antibiotic resistance genes [iv].

Dr Giorgio Casaburi, lead author of the research, comments, "These results demonstrate that targeted bacterial supplementation is capable of remodelling the ecology of the infant gut microbiome and therefore reduce antibiotic gene reservoirs in children. We found that supplementation with the infant gut symbiont significantly diminished both the abundance and diversity of antibiotic resistance genes".

Dr Casaburi and his team assessed infants who, along with exclusive breastfeeding, received a supplementation of the probiotic for 21 days. After two weeks of supplementation, faecal samples were collected and compared with infants who had exclusively received breastmilk to evaluate the presence of antibiotic resistance genes.

The probiotic utilised in the research is uniquely adapted to thrive in the infant gut and is often missing from the microbiome of infants born in Europe and the US today. In the absence of this protective bacterium, other bacteria colonise the gut microbiome and enable the evolution, persistence and dissemination of antibiotic resistance genes.

"The supplementation offers a novel approach towards providing an alternative, safe and non-invasive method to decrease the number of genes that resist antibiotics in infants" added Dr Casaburi. "This is the first demonstration of significant remodelling of the infant gut microbiome. This modulation could help to reduce the burden and diversity of antibiotic resistance genes in current and future generations".

A new study has discovered that horses were first domesticated by descendants of hunter-gatherer groups in Kazakhstan who left little direct trace in the ancestry of modern populations. The research sheds new light on the long-standing "steppe theory" on the origin and movement of Indo-European languages made possible by the domestication of the horse.

The domestication of the horse was a milestone in human history that allowed people, their languages, and their ideas to move further and faster than before, leading both to widespread farming and to horse-powered warfare.

Scholars from around the world have collaborated on a new inter-disciplinary research project, which was published in the journal Science 9 May 2018. The researchers analysed ancient and modern DNA samples from humans and compared the results - the 74 ancient whole-genome sequences studied by the group were up to 11,000 years old and were from inner Asia and Turkey.

Professor Eske Willerslev, who holds positions both at St John's College, University of Cambridge, and the University of Copenhagen, jointly led the study which looked at archaeological findings, history, and linguistics.

Much of the study builds on questions raised by scholars of Indo-European studies at the Institute of Nordic Studies and Linguistics at University of Copenhagen. A number of conflicting theories have been presented about who first domesticated the horse, with previous studies pointing to people of the pastoralist Yamnaya culture, a dominant herding group who lived in Eastern Europe and Western Asia.

Dr. Guus Kroonen, historical linguist at University of Copenhagen, explains:

"The successful spread of the Indo-European languages across Eurasia has puzzled researchers for a century. It was thought that speakers of this language family played a key role in the domestication of the horse, and that this, in combination with the development of wheeled vehicles, allowed them to spread across Eurasia from the Yamnaya culture."

However, as this study shows, domesticated horses were used by the Botai people already 5,500 years ago, and much further East in Central Asia, completely independent of the Yamnaya pastoralists. A further twist to the story is that the descendants of these Botai were later pushed out from the central steppe by migrations coming from the west. Their horses were replaced too, indicating that horses were domesticated separately in other regions as well.

No link between Botai and Yamnaya cultures

The study does not find a genetic link between the people associated with the Yamnaya and Botai archaeological cultures, which is critical to understanding the eastward movement of the Yamnaya. Apparently, their eastward expansion bypassed the Botai completely, moving 3000 kilometres across the steppe to the Altai Mountains in Central and East Asia.

Professor Alan Outram from the Department of Archaeology at the University of Exeter and one of the paper's authors, states:

"We now know that the people who first domesticated the horse in Central Asia were the descendants of ice age hunters, who went on to become the earliest pastoralists in the region. Despite their local innovations, these peoples were overrun and replaced by European steppe pastoralists in the middle and later Bronze Age, and their horses were replaced too."

Languages spread through exchanges between several cultures

The authors also demonstrate the oldest known Indo-European language, Hittite, did not result from a massive population migration from the Eurasian Steppe as previously claimed.

In contrast to a series of recent studies on population movement in Europe during the Bronze Age, the new results from Asia suggest that population and language spread across the region is better understood by groups of people mixing together.

Gojko Barjamovic, Senior Lecturer on Assyriology at Harvard University, explains:

"In Anatolia, and parts of Central Asia, which held densely settled complex urban societies, the history of language spread and genetic ancestry is better described in terms of contact and absorption than by simply a movement of population."

He adds:

"The Indo-European languages are usually said to emerge in Anatolia in the 2nd millennium BCE. However, we use evidence from the palatial archives of the ancient city of Ebla in Syria to argue that Indo-European was already spoken in modern-day Turkey in the 25th century BCE. This means that the speakers of these language must have arrived there prior to any Yamnaya expansions."

The study also shows that the spread of the Indo-Iranian languages to South Asia, with Hindi, Urdu and Persian as major modern offshoots, cannot result from the Yamnaya expansions. Rather, the Indo-Iranian languages spread with a later push of pastoralist groups from the South Ural Mountains during the Middle to Late Bronze Age.

Prior to entering South Asia, these groups, thought to have spoken an Indo-Iranian language, were impacted by groups with an ancestry typical of more western Eurasian populations. This suggests that the Indo-Iranian speakers did not split off from the Yamnaya population directly, but were more closely related to the Indo-European speakers that lived in Eastern Europe.

Unique collaboration between the humanities and the natural sciences

In this study, geneticists, historians, archaeologists and linguists find common ground - pointing to increased interaction between the steppe and the Indus Valley during the Late Bronze Age as the most plausible time of entry of Indo-European languages in South Asia. Several authors of the paper had radically conflicting views before the final interpretation was achieved.

Lead author on the article, Peter de Barros Damgaard, who is a geneticist working at the University of Copenhagen comments:

"The project has been an extremely enriching and exciting process. We were able to direct many very different academic fields towards a single coherent approach. By asking the right questions, and keeping limitations of the data in mind, contextualizing, nuancing, and keeping dialogues open between scholars of radically different backgrounds and approaches, we have carved out a path for a new field of research. We have already seen too many papers come out in which models produced by geneticists working on their own have been are accepted without vital input from other fields, and, at the other extreme, seen archaeologists opposing new studies built on archaeogenetic data, due to a lack of transparency between the fields."

"Data on ancient DNA is astonishing for its ability to provide a fine-grained image of early human mobility, but it does stand on the shoulders of decades of work by scholars in other fields, from the time of excavation of human skeletons to interpreting the cultural, linguistic origins of the samples. This is how cold statistics are turned into history."

Guus Kroonen adds:

"The recent breakthrough in ancient genomics poses challenges for archaeologists, linguists and historians because old hypotheses on the spread of languages and cultures can now be tested against a whole new line of evidence on prehistoric mobility. As a result, we now see that geneticists are driven by key questions from the humanities, and that research within the humanities is energized by the influx of new data from the sciences. In the future, we hope to see more cross-disciplinary co-operations, such as the one leading to this study."