Culture

Mycophenolic acid (MPA), discovered in 1893, was the first natural antibiotic to be isolated and crystallized in human history. Today, this fungal metabolite has been developed into multiple first-line immunosuppressive drugs to control immunologic rejection during organ transplantation and treat various autoimmune diseases.

However, the biogenesis of such an old and important molecule was an unsolved mystery for more than a century.

Recently, scientists from the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences cracked this intriguing black box by fully elucidating the biosynthetic pathway of MPA. The results were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The researchers revealed that MPA biogenesis requires very unique cooperation between biosynthetic enzymes and β-oxidation catabolic machinery.

Interestingly, the involved enzymes were observed to be compartmentalized in different organelles including cytoplasm, the endoplasmic reticulum, the Golgi apparatus, and peroxisomes.

In this pathway, the oxygenase MpaB', which is intriguingly homologous to a latex-clearing enzyme, was identified as the long-sought key enzyme responsible for oxidative cleavage of the farnesyl side chain that is structurally similar to rubber.

The resultant carboxylic acid intermediate allows it to be recognized by the fungal β-oxidation machinery located in the peroxisomes. The following successive β-oxidation chain-shortening process is elegantly gated by the peroxisomal acyl-CoA hydrolase MpaH', thus leading to efficient and specific production of MPA.

The scientists concluded that compartmentalized biosynthesis is likely a very important characteristic of natural product biosynthesis in higher organisms such as fungi and plants.

They hope their work will prompt more research on this phenomenon since there is only very limited knowledge about the subcellular localization of fungal biosynthetic enzymes and their involvement in product formation and intermediate trafficking.

The researchers also hope the insights gained from this study will encourage industrial strain improvements that would lower the cost of this popular immunosuppressive drug as well as novel drug development based on MPA structural derivatization. "Ultimately, we wish that millions of patients will benefit from this basic research," said LI Shengying, corresponding author of the study.

The cumulative stresses caused by historic earthquakes could provide some explanation as to why and where they occur, according to new research.

Scientists have previously struggled to identify patterns for earthquakes happening in hazardous areas around the world, with the suggestion that they appear to strike largely at random.

However, a study published in Nature Communications suggests that Coulomb pre-stress - the static stress present on a fault plane prior to rupture - can go some way to explaining both historical and modern series of earthquakes.

The study was led by Dr Zoë Mildon, Lecturer in Earth Sciences at the University of Plymouth, and features research conducted during her PhD at University College London (UCL). It also involved researchers from UCL, Birkbeck, University of London and Tohoku University in Japan, and was funded by the Natural Environment Research Council and the Japan Society for the Promotion of Science.

It combines centuries of written evidence of earthquake damage to towns and villages with state-of-the-art modelling, through which scientists demonstrate that positive stresses - a legacy of previous earthquakes in the region - are present on faults before the majority of earthquakes occur.

Dr Mildon recently presented some of her findings at the 2019 General Assembly of the European Geophysics Union, and said: "Earthquakes are caused by rock sliding past each other along fault lines which causes the forces and stress in the surrounding rocks to change after a big earthquake. It is often assumed that the nearest fault to a particular earthquake will be the next to rupture. However, our study shows this is never the case so typical approaches to modelling Coulomb stress transfer (CST) have limited potential to improve seismic hazard assessment.

"Our model adds the stresses of lots of earthquakes together and shows that in the majority of cases fault lines are positively stressed when they rupture. It is a step change in modelling CST and shows this is an ignored yet vital factor when trying to explain earthquake triggering."

The research focuses on the central Apennines region of Italy, which has regularly been struck by earthquakes over the past 700 years.

These historical earthquakes are known about from written records started in 1349 that detail the amount of damage and lives lost in individual towns and villages throughout the region. By looking at the locations and amount of damage, scientists can work out where, when and how large historical earthquakes occurred.

Looking at the locations of earthquakes over the last 700 years, it would be easy to assume these incidents occurred at random as they jump around the region.

But using their new method, they were able to demonstrate that 97 per cent (28 out of 29) of the earthquakes between 1703 and 2016 occurred on faults that were either wholly or partially positively stressed.

This includes the series of earthquakes that destroyed the town of Amatrice and Norcia in 2016, leaving almost 300 people dead and whole towns reduced to rubble.

Dr Mildon added: "Earthquakes are hugely destructive to both people and property, and the Holy Grail of earthquake science would be to predict where they are going to happen and when. We are a very long way from that, and indeed it may never be possible to accurately predict the location, time and size of future earthquakes. Our research, however, could be a starting point in helping us develop better forecasts of which fault lines might be more susceptible based on previous tremors."

CAMBRIDGE, MA -- MIT chemical engineers have devised a new way to create very tiny droplets of one liquid suspended within another liquid, known as nanoemulsions. Such emulsions are similar to the mixture that forms when you shake an oil-and-vinegar salad dressing, but with much smaller droplets. Their tiny size allows them to remain stable for relatively long periods of time.

The researchers also found a way to easily convert the liquid nanoemulsions to a gel when they reach body temperature (37 degrees Celsius), which could be useful for developing materials that can deliver medication when rubbed on the skin or injected into the body.

"The pharmaceutical industry is hugely interested in nanoemulsions as a way of delivering small molecule therapeutics. That could be topically, through ingestion, or by spraying into the nose, because once you start getting into the size range of hundreds of nanometers you can permeate much more effectively into the skin," says Patrick Doyle, the Robert T. Haslam Professor of Chemical Engineering and the senior author of the study.

In their new study, which appears in the June 21 issue of Nature Communications, the researchers created nanoemulsions that were stable for more than a year. To demonstrate the emulsions' potential usefulness for delivering drugs, the researchers showed that they could incorporate ibuprofen into the droplets.

Seyed Meysam Hashemnejad, a former MIT postdoc, is the first author of the study. Other authors include former postdoc Abu Zayed Badruddoza, L'Oréal senior scientist Brady Zarket, and former MIT summer research intern Carlos Ricardo Castaneda.

Energy reduction

One of the easiest ways to create an emulsion is to add energy -- by shaking your salad dressing, for example, or using a homogenizer to break down fat globules in milk. The more energy that goes in, the smaller the droplets, and the more stable they are.

Nanoemulsions, which contain droplets with a diameter 200 nanometers or smaller, are desirable not only because they are more stable, but they also have a higher ratio of surface area to volume, which allows them to carry larger payloads of active ingredients such as drugs or sunscreens.

Over the past few years, Doyle's lab has been working on lower-energy strategies for making nanoemulsions, which could make the process easier to adapt for large-scale industrial manufacturing.

Detergent-like chemicals called surfactants can speed up the formation of emulsions, but many of the surfactants that have previously been used for creating nanoemulsions are not FDA-approved for use in humans. Doyle and his students chose two surfactants that are uncharged, which makes them less likely to irritate the skin, and are already FDA-approved as food or cosmetic additives. They also added a small amount of polyethylene glycol (PEG), a biocompatible polymer used for drug delivery that helps the solution to form even smaller droplets, down to about 50 nanometers in diameter.

"With this approach, you don't have to put in much energy at all," Doyle says. "In fact, a slow stirring bar almost spontaneously creates these super small emulsions."

Active ingredients can be mixed into the oil phase before the emulsion is formed, so they end up loaded into the droplets of the emulsion.

Once they had developed a low-energy way to create nanoemulsions, using nontoxic ingredients, the researchers added a step that would allow the emulsions to be easily converted to gels when they reach body temperature. They achieved this by incorporating heat-sensitive polymers called poloxamers, or Pluronics, which are already FDA-approved and used in some drugs and cosmetics.

Pluronics contain three "blocks" of polymers: The outer two regions are hydrophilic, while the middle region is slightly hydrophobic. At room temperature, these molecules dissolve in water but do not interact much with the droplets that form the emulsion. However, when heated, the hydrophobic regions attach to the droplets, forcing them to pack together more tightly and creating a jelly-like solid. This process happens within seconds of heating the emulsion to the necessary temperature.

Tunable properties

The researchers found that they could tune the properties of the gels, including the temperature at which the material becomes a gel, by changing the size of the emulsion droplets and the concentration and structure of the Pluronics that they added to the emulsion. They can also alter traits such as elasticity and yield stress, which is a measure of how much force is needed to spread the gel.

Doyle is now exploring ways to incorporate a variety of active pharmaceutical ingredients into this type of gel. Such products could be useful for delivering topical medications to help heal burns or other types of injuries, or could be injected to form a "drug depot" that would solidify inside the body and release drugs over an extended period of time. These droplets could also be made small enough that they could be used in nasal sprays for delivering inhalable drugs, Doyle says.

For cosmetic applications, this approach could be used to create moisturizers or other products that are more shelf-stable and feel smoother on the skin.

Bacteria living on the skin of frogs could save them from a deadly virus, new research suggests.

Ranavirus kills large numbers of European common frogs - the species most often seen in UK ponds - and is one of many threats facing amphibians worldwide.

Scientists from the University of Exeter and ZSL's Institute of Zoology compared the bacteria living on frogs - known as their "microbiome" - from groups with varying history of ranavirus.

They found that populations with a history of outbreaks had a "distinct" skin microbiome when compared to those where no outbreaks had occurred.

"Whether a population of frogs becomes diseased might depend on the species of bacteria living on their skin," said Dr Lewis Campbell.

"Ranavirus is widespread, but its presence in the environment doesn't necessarily mean frogs become diseased - there appears to be some other factor that determines this.

"The skin is often the first infection point in ranavirus, and the first stage of the disease can be skin sores.

"It's possible that the structure of a frog's microbiome - the mix of bacteria on its skin - can inhibit the growth and spread of the virus so it can't reach a level that causes disease.

"While the results of our study demonstrate a clear link between the frog skin microbiome and disease, further research will be need to understand the exact mechanisms which cause this relationship to form."

Laboratory trials will help establish whether a history of ranavirus infection causes the microbiome differences, or whether these are pre-existing differences that predispose some populations to infection.

The scientists tested the skin bacteria of more than 200 wild adult European common frogs (Rana temporaria) from ten populations.

They found that the microbiome of individual frogs is usually most similar to that of others in the same population (those living in the same geographical area), but that populations with the same disease history were more similar to each other than to populations of the opposite disease history.

Even though amphibians can partially "curate" their microbiome by producing proteins that benefit specific bacteria, they are limited to those bacteria which are available in their environment.

Ranavirus can wipe out entire common frog populations and, though the new findings need further investigation, the researchers hope their work could help the species.

Dr Xavier Harrison said: "There's growing evidence that skin bacteria may protect amphibians from lethal pathogens such as chytrid fungus, and that we can develop cocktails of probiotic bacteria to prevent vulnerable individuals from contracting disease.

"Our work suggests that given enough effort and research, similar probiotic therapies may be effective against ranavirus."

Washington, DC - When it comes to getting a date, there's any number of ways people can present themselves and their interests. One of the newer phenomena is a "foodie call" where a person sets up a date with someone they are not romantically interested in, for the purpose of getting a free meal. New research finds that 23 - 33% of women in an online study say they've engaged in a "foodie call."

Upon further analysis, the social and personality psychology researchers found that women who scored high on the "dark triad" of personality traits (i.e., psychopathy, Machiavellianism, narcissism), as well as expressed traditional gender role beliefs, were most likely to engage in a foodie call and find it acceptable.

The research, by Brian Collisson, Jennifer Howell, and Trista Harig of Azusa Pacific University and UC Merced, appears in the journal Social Psychological and Personality Science.

In the first study, 820 women were recruited, with 40% reporting they were single, 33% married, and 27% saying they were in a committed relationship but not married. Out of them, 85% said they were heterosexual, and they were the focus for this study.

The women answered a series of questions that measured their personality traits, beliefs about gender roles, and their foodie call history. They were also asked if they thought a foodie call was socially acceptable.

23% of women in this first group revealed they'd engaged in a foodie call. Most did so occasionally or rarely. Although women who had engaged in a foodie call believed it was more acceptable, most women believed foodie calls were extremely to moderately unacceptable.

The second study analyzed a similar set of questions of 357 heterosexual women and found 33% had engaged in a foodie call. It is important to note, however, that neither of these studies recruited representative samples of women, so we cannot know if these percentages are accurate for women in general.

For both groups, those that engaged in foodie calls scored higher in the "dark triad" personality traits.

"Several dark traits have been linked to deceptive and exploitative behavior in romantic relationships, such as one-night stands, faking an orgasm, or sending unsolicited sexual pictures," says Collisson.

Collisson and Harig said they became interested in the subject of foodie calls after reading about the phenomenon in the news.

As for how many foodies calls might be occurring in the United States, Collisson says that can't be inferred from the current research.

"They could be more prevalent, for instance, if women lied or misremembered their foodie calls to maintain a positive view of their dating history," says Collisson.

The researchers also note that foodie calls could occur in many types of relationships, and could be perpetrated by all genders.

Chameleon prawns change colour to camouflage themselves as the seaweed around them changes seasonally, new research shows.

Unlike chameleons and cuttlefish, chameleon prawns (Hippolyte varians) take weeks to change colour, so the study - by the University of Exeter and the Federal University of ABC (Brazil) - shows that their abilities are suited to seasonal changes to their surroundings rather than rapidly adapting to new backgrounds.

However, rock pools are highly diverse environments, and the research also shows that in the short term the prawns can use behaviour - selecting seaweed that best matches their existing colouration.

Chameleon prawns are remarkably colourful, ranging from bright block colours to varying degrees of transparency, and are common in UK rock pools.

"Our study shows that these prawns exhibit impressive levels of camouflage on the seaweeds in which they live," said PhD student Sam Green, of the University of Exeter.

"We measured the camouflage of prawns to the vision of their predators and recorded colour change in the lab, and found the prawns can improve camouflage against their new backgrounds over a number of weeks.

"Seaweeds vary seasonally in UK rockpools and this ability probably enables prawns to maintain camouflage throughout the year.

"However, as the rock pool environment consists of a variety of different coloured seaweed patches, our behavioural experiments show that the prawns also select backgrounds that match their existing appearance.

"This helps maintain camouflage in the short term, helping prawns to deal with the challenges of rock pool life. For example, a wave could dislodge a prawn from its chosen perch.

"This demonstrates how colour change and behaviour combine to facilitate camouflage in varying environments over different timescales."

Professor Martin Stevens added: "The rock pool environment is an incredibly challenging place to live and is constantly changing every day and over the seasons.

"The combination of colour change and behaviour enables prawns to cope with this and reduce the chance of them becoming a meal for a hungry predator."

Dr Rafael Duarte, a post-doctoral researcher from the Federal University of ABC (Brazil), concluded: "Similar outcomes are expected to be observed in different coloured species from a range of taxonomic groups and living both in terrestrial and aquatic habitats that vary spatially and seasonally in terms of background composition."

The researchers studied chameleon prawns of varied sex and size, and two seaweed species - green sea lettuce (Ulva lactuca) and red dulse (Palmaria palmata) - from rock pools at Gyllyngvase beach in Cornwall.

All living things - from the simplest animal and plant organisms to the human body - live closely together with an enormous abundance of microbial symbionts, which colonise the insides and outsides of their tissues. The functional collaboration of host and microorganisms, which scientists refer to as a metaorganism, has only recently come into the focus of life science research. Today we know that we can only understand many of life's processes in connection with the interactions between organism and symbionts. The Collaborative Research Centre (CRC) 1182 "Origin and Function of Metaorganisms" at Kiel University (CAU) aims to understand the communication and the functional consequences of host-microbe relationships.

A key issue for the researchers at the CRC 1182 is how the composition of an organism's microbiome forms during its individual development. It is still unclear as to whether the microbial community composition is more governed by a functional selection process or if random processes dominate. In order to examine the microbiome composition, a research team from the CAU's CRC 1182 and the Max Planck Institute for Evolutionary Biology in Plön (MPI-EB) has now applied the theory of the so-called "neutral metaorganism" to an entire spectrum of model organisms, from very simple creatures to complex vertebrates. The scientists from Kiel and Plön published their findings yesterday in the journal PLOS Biology.

The null model of evolutionary theory

Theoretical models offer one way to make the highly complex, individual microbiome composition manageable. A fundamental model in evolutionary research is the so-called neutral null model. This is used to predict how populations would develop without any selection pressure whatsoever. The research team at the CRC 1182 has now applied this model to several model organisms from threadworms to house mice and compared the predictions with experimentally collected data. "Theory and experimental data match surprisingly well for many organisms. The predicted composition in the house mouse, for example, is found in the actual microbial species community," summarised Dr Michael Sieber, research associate at the MPI-EB and member of the CRC 1182. "t is possible that selection plays a lesser role in the microbiome's composition than we previously assumed, while this does not mean that the microbiome has no important functions for the organism, it could be an indication that many different compositions of the microbiome can perform these functions equally well. And which specific composition actually forms in a single organism is then driven by chance."

A map for further exploration of the microbiome

The researchers did notice some significant deviations between the neutral model and the real compositions of the microbiome, however. For example, individual bacterial species in the mouse microbiome did not match the neutral prediction. And the microbial species composition of the Caenorhabditis elegans thread worm did not match the neutral model at all.

"We assume that these deviations between model and reality could indicate specific functions of certain microorganisms," Sieber emphasised. Investigating the systematic deviations from the neutral model therefore holds the potential to discover key functions of certain bacterial species within the microbiome.

First explanations for the deviations from the neutral model are already being discussed. Some non-neutral bacteria in the mouse microbiome, for example, are involved in digestion and their presence may therefore be the result of a targeted selection process. On the other hand, Caenorhabditis elegans, with its very fast generational change, might not live long enough to develop a stable, mainly neutral composition of its microbiome. "The model of the neutral metaorganism therefore provides an important theoretical basis for further functional analyses of microbiome compositions across the entire spectrum of the model organisms investigated in our Collaborative Research Centre," said CRC 1182 spokesperson Prof. Thomas Bosch.

A team of University of Copenhagen researchers has compiled the first and only evidence that narwhals and beluga whales can breed successfully. DNA and stable isotope analysis of an anomalous skull from the Natural History Museum of Denmark has allowed researchers to confirm the existence of a narwhal-beluga hybrid.

For nearly thirty years, a strange-looking whale skull has gathered dust in the collections of the Natural History Museum of Denmark. Now, a team of researchers has determined the reason for the skull's unique characteristics: it belongs to a narwhal-beluga hybrid.

A Greenlandic hunter shot the whale in the 1980's and was puzzled by its odd appearance. He therefore kept the skull and placed it on the roof of his toolshed. Several years later, Professor Mads Peter Heide-Jørgensen of the Greenland Institute of Natural Resources visited the settlement and also immediately recognized the skull's strange characteristics. He interviewed the hunter about the anomalous whale he had shot, and sent the skull to Copenhagen. Since then, it has been stored at the Zoological Museum, a part of the Natural History Museum of Denmark.

"As far as we know, this is the first and only evidence in the world that these two Arctic whale species can interbreed. Based on the intermediate shape of the skull and teeth, it was suggested that the specimen might be a narwhal-beluga hybrid, but this could not be confirmed. Now we provide the data that confirm that yes - it is indeed a hybrid," says Eline Lorenzen, evolutionary biologist and curator at the University of Copenhagen's Natural History Museum of Denmark. Lorenzen led the study, which was published today in Scientific Reports.

Using DNA and stable isotope analysis, the scientists determined that the skull belonged to a male, first-generation hybrid between a female narwhal and male beluga.

Bizarre set of chops

The hybrid's skull was considerably larger than that of a typical narwhal or beluga. But the teeth were markedly different. Whereas narwhals have only one or rarely two long spiraling tusks, belugas have a set of uniform conical teeth that are aligned in straight rows. The hybrid skull has a set of long, spiraling and pointed teeth, that are angled horizontally.

"This whale has a bizarre set of teeth. The isotope analysis allowed us to determine that the animal's diet was entirely different than that of a narwhal or beluga - and it is possible that its teeth influenced its foraging strategy. Whereas the other two species fed in the water column, the hybrid was a bottom dweller," according to Mikkel Skovrind, a PhD student at the Natural History Museum and first author of the paper.

The researchers do not know what prompted the two species to mate, but it suggests a new phenomenon:

"We have analyzed the nuclear genomes of a narwhal and a beluga, but see no evidence of interbreeding for at least the past 1.25 million years of their evolutionary histories. So, interbreeding between the species appears to be either a very rare or a new occurrence. To my knowledge, it has not been observed or recorded before," says Eline Lorenzen.

Gems among the museum collections

Lorenzen points out that she and her colleagues used novel analytical methods that have only recently been developed.

"There are some true gems in the world's natural history collections that can provide us with key insights into the evolution and diversity of life on Earth. It is incredible when material - such as this skull, which has been stored in our collection for decades - can be revisited with new methodologies to gain novel biological insights" says Eline Lorenzen.

Mikkel Skovrind adds: "It would be interesting to find out if similar hybrid whales have been spotted elsewhere."

FACTS:

By extracting DNA from the anomalous whale skull and comparing it to a genetic reference panel of narwhal and beluga, researchers established the whale's genomic affiliation.

Researchers analyzed reference stocks of narwhal and beluga for stable isotopes and compared these with isotope values from the hybrid skull. By measuring bone carbon and nitrogen concentrations, researchers were able to discern whether the whale's diet consisted of food from the water column or from the sea floor. The isotopes demonstrated that the hybrid whale's dietary choices were very different than those of either narwhal or beluga.

Narwhals and belugas are the only toothed whales endemic to the Arctic region. While they are each other's closest relatives and roughly equal in size, the two species differ in their morphology and behaviour. The narwhal is characterized by its long, spiraled tusk and has a greyish-brown, mottled pigmentation, whereas belugas have two rows of uniform teeth, and adults are completely white. Narwhals are specialists when it comes to dietary choice, and belugas are generalists.

The research is a collaboration between the Natural History Museum of Denmark at the University of Copenhagen, the Greenland Institute of Natural Resources and the Department of Anthropology, Trent University (CA).

The research is supported by the Carlsberg Foundation, the Villum Fonden Young Investigator programme and the Canada Research Chair programme.

Access the research article in Scientific Reports here

New insights into how people first arrived in Australia have been revealed by a group of experts brought together to investigate the continent's deep history.

They used sophisticated modelling to determine not only the likely routes travelled by Aboriginal people tens of thousands of years ago, but also the sizes of groups required for the population to survive in harsh conditions.

The research, published today in two companion papers (one in Scientific Reports and the other in Nature Ecology and Evolution), confirms the theory that people arrived in several large and deliberate migrations by island-hopping to reach New Guinea more than 50,000 years ago.

While many Aboriginal cultures believe people have always been here, others have strong oral histories of ancestral beings arriving from the north.

"We know that Aboriginal people have lived here for more than 50,000 years. This research offers a greater understanding of how migration events took place and further evidence of the marine and navigation capabilities used to make these deliberate journeys," said Professor Michael Bird, from the Australian Research Council Centre of Excellence for Australian Biodiversity and Heritage (CABAH) and James Cook University.

The team of multidisciplinary researchers from CABAH and the CSRIO set out to establish the most likely route travelled to reach the ancient mega-continent, known as Sahul (New Guinea, Australia and Tasmania joined at times of low sea level).

"We developed demographic models to determine which island-hopping route ancient people most likely took," said CABAH's Professor Corey Bradshaw, from Flinders University.

"A northern route connecting the islands of Mangoli, Buru, and Seram into West Papua New Guinea would probably have been easiest to navigate and survive. This route was easiest when compared to the southern route from Timor that leads to the now-drowned Sahul Shelf in the modern-day Kimberley region."

The researchers also used complex mathematical modelling -- considering factors including fertility, longevity, past climate conditions, and other ecological principles -- to calculate the numbers of people required for the population as a whole to survive.

The simulations indicate that at least 1300 people arrived in either a single migration event or smaller, successive waves averaging at least 130 people every 70 years or so, over the course of about 700 years.

"This suggests planned and well-organised maritime migration, rather than accidental arrival" Professor Bradshaw added.

The studies confirm the ancestors of Aboriginal and Torres Strait Islander people possessed sophisticated technology and knowledge to build watercraft. This research also showcases the remarkable ability at that time to plan, navigate, and make multiple complicated, open-ocean voyages to directly transport large numbers of people.

"Both studies are unique because they relied on past environmental information and did not use any genetic data. We are very excited to see how further archaeological and genetics studies in CABAH can contribute to this story," says Dr Laura Weyrich, a CABAH investigator at the University of Adelaide.

The papers Early human settlement of Sahul was not an accident and Minimum founding populations for the first peopling of Sahul, were co-authored by scientists from around Australia, including Flinders University, James Cook University, University of Wollongong, University of New South Wales, University of Adelaide, Australian National University, and the CSIRO.

CABAH brings together expertise from diverse academic disciplines to answer fundamental questions about the natural and human history of our region, including how and when people first came to Australia.

Certain cancer cells depend on exporting the metabolite lactate, which accumulates during the generation on energy. Lactate plays an important role in many biochemical and cellular processes. In healthy cells it is produced if our body is not supplied with enough oxygen during intensive exercise. During this anaerobic energy production, lactate accumulates in cells and acidifies them. In certain cancer cells, metabolic processes are disturbed and large amounts of lactate are produced even if the supply with oxygen is sufficient to cover the energy demand. This phenomenon is known as the "Warburg Effect", which was observed for the first time by Otto Warburg, for whose discovery he was awarded the Nobel Prize for Physiology or Medicine in 1913.

Inhibiting transport pathways

Cancer cells use a transport protein, monocarboxylate transporter 4 (MCT4), to export lactate and thus to reduce cellular acidification. The transporter increases the lactate concentration outside the cell and acidifies the cell surrounding. This supports tumor growth and metastasis as the exported lactate is taken up into other cancer cells by another transport protein (MCT1), where it serves as fuel. Therefore, inhibiting MCT1 and MCT4 is a promising approach to fight certain types of cancer. However, so far no approved inhibitors for these transporters are on the market. "In order to develop such potent and highly selective inhibitors detailed knowledge of the structures of MCT1 and MCT4 is important", says Dimitrios Fotiadis from the Institute of Biochemistry and Molecular Medicine (IBMM) of the University of Bern and the National Centre of Competence in Research (NCCR) TransCure.

Both transporters belong to the so-called "Solute carrier 16"-family (SLC16), which is responsible for the delivery of essential substances in the body and which also plays an important role in the uptake, action and excretion of drugs. Therefore, MCT1 and MCT4 are particularly suited as therapeutic targets. No structure of an SLC16 lactate-transporter has been determined and published until now. The research group of Dimitrios Fotiadis succeeded in this now. The results of the study have been recently published in the journal "Nature Communications".

Discovery of promising binding site

Fotiadis' team published the first structure of a lactate-transporter of the SLC16-family (SfMCT) at high-resolution that is related to MCT1 and MCT4. "Based on this long sought-after structure of a protein of the SLC16-family we obtained insights into the molecular working mechanism of these proteins", says Patrick Bosshart from the IBMM and the NCCR TransCure, who is first author of the study. The researchers also investigated the transport properties of SfMCT and possible binding sites for inhibitors. "The solved structure of SfMCT together with our detailed transport study can contribute to the structure-based design of drugs that target MCT1 and MCT4 using homology models", says Dimitrios Fotiadis, who is last author of the study. The fact that the binding site in the solved structure of SfMCT is accessible from the outside of the cell (so called "outward-open" conformation) is an important observation. This conformation is essential from a pharmacological perspective in order to generate models of MCT1 and MCT4 based on the structure of SfMCT and to test inhibitors using these models.

The study was financially supported by the Swiss National Science Foundation (SNSF) and the National Centre of Competence in Research (NCCR) TransCure, located at the University of Bern.

NCCR TransCure: Membrane transport and human diseases

Many major human diseases such as diabetes, hypertension, cardiovascular diseases, cancer, osteoporosis, neurodegenerative and psychiatric disorders are related to or are based on the dysfunction of membrane transporters and channels.

Transporters are integral membrane proteins that move important substances such as nutrients, drugs and other substrates across cellular membranes. Because of their importance as cellular gatekeepers, a deep understanding of their structure, functioning and role in diseases is of fundamental significance for advances in basic research and for the development of novel therapeutic drugs.

A team of researchers from McMaster University has mapped at atomic resolution a toxic protein linked to Alzheimer's disease, allowing them to better understand what is happening deep within the brain during the earliest stages of the disease.

The findings, published on the front cover of the current edition of the Royal Society of Chemistry flagship journal Chemical Science, provide new insights into the behavior of one of the prime suspects of Alzheimer's disease: a protein fragment known as amyloid beta, which clumps together into oligomers during the early stages of the disease.

Researchers liken amyloid beta oligomers to a neurotoxic 'bomb', causing the irreversible death of neurons.

"To defuse the bomb, we need to know with a high degree of precision which wires to cut and which to avoid," explains Giuseppe Melacini, senior author and a professor in the Departments of Chemistry and Chemical Biology as well as Biochemistry and Biomedical Sciences at McMaster University.

"This is why it is critical to map the structural features that differentiate what is toxic and what is not. However, this is a challenging task due to the transient and elusive nature of these oligomers," he says.

Melacini, who has studied the underlying mechanisms of Alzheimer's for nearly two decades, is working with a team of physicists, chemists, biologists and dementia specialists at McMaster, including Maikel Rheinstädter, Richard Epand, Ryan Wylie and Chris Verschoor. Each team member brings a unique perspective and specialty to an investigation which requires highly specialized equipment, including wide-angle X-ray diffraction and nuclear magnetic resonance (NMR) to conduct the analysis at the atomic level.

For the study, the team used a library of natural products extracted from green tea that are believed to interfere with the formation of the toxic protein oligomers to varying degrees. Using this toolkit they were able to build oligomers with different toxicities, allowing the team to gain unprecedented insights into how they interact with neurons and cause cell death.

They hope this research can help them determine how to defuse the neurotoxic bomb.

"Alzheimer's disease is a major medical, social and economic problem," says Rashik Ahmed, the lead author on the paper and PhD candidate in the Department of Biochemistry and Biomedical Sciences. "This research is the first step towards identifying how we can stop the progression of Alzheimer's disease before it becomes irreparable."

By some estimates, there are more than half a million Canadians living with dementia and the number is expected to reach more than a million by the year 2031. Once symptoms emerge, there is no known cure for Alzheimer's and treatment options are limited.

A total of 174 chicken breeds are described in a publicly accessible database which scientists from the University of Göttingen and the Friedrich Loeffler Institute in Neustadt-Mariensee have built up in recent years with numerous international partners. This database, the Synbreed Chicken Diversity Panel (SCDP), includes information about a large proportion of the available chicken species and their diversity. In the accompanying scientific study, the researchers genotyped 3,235 animals for nearly 600,000 single nucleotide polymorphisms (SNPs). SNPs are variations in separate genetic building blocks at specific regions of the genome that vary between individual animals. The researchers created a family tree of exceptional completeness and detail. The results have been published in the journal BMC Genomics.

The variety of breeds in the database ranges from wild birds to commercial broilers and egg-layers. In addition, it includes a range of local breeds from almost every continent as well as strains bred by hobbyists in Germany. In the study, the research team analysed genetic diversity within and between populations. The study showed that genetic diversity is reduced both within the hobby breeds and in high-performing commercial breeds, especially in those bred for egg-laying. In contrast, in African, South American and some Asian and European breeds, there is still considerable genetic diversity. "It is important for the sustainability and flexibility of breeding that these very different breeds are preserved," said Professor Henner Simianer and Professor Steffen Weigend from the Center for Integrated Breeding Research at the University of Göttingen.

Researchers at the University of Tokyo conducted a census of the Japanese population around 2,500 years ago using the Y chromosomes of men living on the main islands of modern-day Japan. This is the first time analysis of modern genomes has estimated the size of an ancient human population before they were met by a separate ancient population.

"Evidence at archaeological dig sites has been used to estimate the size of ancient human populations, but the difficulty and unpredictability of finding those sites is a big limitation. Now we have a method that uses a large amount of modern data," said Associate Professor Jun Ohashi, an expert in human evolutionary genetics and leader of the research team that performed the analysis.

Archaeological mystery

The current theory on human migrations into Japan is that the original inhabitants, the Jomon people, were met about 2,500 years ago by a separate group coming mainly from the Korean Peninsula, the Yayoi people.

Archaeologists have identified fewer Jomon sites from the Late Jomon Period, the era immediately before the Yayoi arrival. Global temperatures and sea levels dropped during that period, which could have made life more difficult for the hunter-gatherer Jomon people.

When the Yayoi people arrived, they brought wet rice farming to Japan, which would have led to a more stable food supply for the remaining Jomon people living with the new Yayoi migrants.

The lesser amount of archaeological remains from the Late Jomon Period could be evidence of an actual population decline, or just that the archaeological dig sites have not yet been found.

Genetic evidence

Ohashi's research team decided to start digging through the human genome to address this archaeological mystery. They began by comparing the Y-chromosome sequences of modern Japanese men to those of Korean and other East Asian men. Y chromosomes are passed on from father to son with very little change over generations, so modern Y-chromosome sequences can reliably estimate the Y chromosomes of men thousands of years ago.

Researchers used DNA samples collected before 1990 from 345 men whose families were from the three main islands of Honshu, Shikoku, and Kyushu in Japan.

The research team identified one group of DNA sequences that only Japanese men had. That unique sequence group likely came from the Jomon people. The researchers identified six sequence groups common to both Japanese men and men with other East Asian heritage (Korean, Vietnamese, Chinese), which likely came from the Yayoi people or other ancestors common to Japanese and East Asian people.

DNA confirms archaeology

Researchers built evolutionary family trees using the Y-chromosome sequences and saw a pattern indicative of a population decrease and sudden increase: a remarkable decrease in the number of ancestral Y-chromosome sequences around 2,500 years ago.

Interestingly, modern Japanese men seem to have a greater percentage of Jomon ancestral DNA in their Y chromosomes than the rest of their genomes.

Previous genetic analyses concluded that modern ethnically Japanese people get about 12 percent of their entire genomes from Jomon ancestors and the rest from Yayoi ancestors. Ohashi's research team calculated that the one group of Jomon sequences they identified accounted for 35.4 percent of the entire Y chromosome, indicating that the specific sequence would have been extremely common in Jomon men.

Since it is easier for a sequence to become common in a small population, this is another indication that the size of the Jomon population decreased during the Late Jomon Period before the arrival of the Yayoi people.

"We hope this method might be useful to confirm other ancient human dynamics not fully explained by archaeology," said Ohashi.

When it comes to keeping track of prescribed medications between clinic visits, many patients rely on printed medication lists automatically generated from electronic health records (EHRs).

An examination of the EHRs of a cohort of ophthalmology patients revealed that one-third had at least one discrepancy between the medications discussed in the clinician's notes and those on the medication list.

These findings raise concerns about patient safety and continuity of care.

The study, published in JAMA Ophthalmology, was conducted by investigators at the University of Michigan Kellogg Eye Center. The team examined medication-related information contained in the EHRs of patients treated for microbial keratitis between July 2015 and August.

"Corneal infection is an important disease condition to study ophthalmic medication lists because the medications change rapidly," says cornea specialist Maria Woodward, M.S., M.D., assistant professor of ophthalmology and the study's lead author.

Often, many medications are used, some requiring compounding, making telephone orders to specialty pharmacies common.

"Because of the multiple clinic visits and frequent medication changes," Woodward says, "it is imperative to have strong verbal and written communication between providers and patients who are battling corneal infections."

In a typical appointment, a provider verbally communicates medication instructions to the patient. At the same time, notes from that discussion are typed into an unstructured or "free text" section of the patient's EHR by either the doctor, a technician or a medical scribe.

The patient then receives a medication list generated from the EHR as part of a printed after-visit summary.

"That summary should confirm how the provider intends medications to be used," says Woodward, also a health services researcher at the U-M Institute for Healthcare Policy and Innovation.

The team found that one-third of patients had at least one medication mismatch in their records.

While this is the first study focused on ophthalmic medications, the results are consistent with studies of medications used in other medical specialties.

"This level of inconsistency is a red flag," Woodward says. "Patients who rely on the after-visit summary may be at risk for avoidable medication errors that may affect their healing or experience medication toxicity."

Identifying the root cause

The switch to the EHR has led to many improvements in patient care. But as this study shows, it's not a perfect tool for the provider or the patient.

In a typical clinic visit, a prescription entered into the EHR triggers both an order to the patient's pharmacy and an update to the medication list.

But several scenarios can result in mismatches between the clinical notes and the medication list.

"Issues arise when a medication is started by an outside provider and continued at the new hospital and when patients require compounded medications that must be telephoned in to a pharmacist in the evening," Woodward says.

These scenarios expose a shortcoming of the EHR: Data about medications (and other information) is captured in multiple formats in multiple locations.

"The only way to ensure that the medication list is completely accurate is to double-document. The same information must be entered into the clinician's note and the formal medication list -- two separate places," Woodward says.

"In a busy clinical setting, our top priority is communicating directly with the patient and answering their questions," she says. "We're focused on clarifying the treatment plan and addressing concerns, so duplicating note taking does not rise to our primary mission."

To improve both the reliability of medication information patients depend on and the accuracy of data used for research, Woodward's study team recommends that EHR developers create software solutions to ease the burden of clinical documentation and make it easier to reconcile medication names and dosages.

New UC Riverside-led research settles a longstanding debate about whether the most ancient animal communities were deliberately mobile. It turns out they were, because they were hungry.

"This is the first time in the fossil record we see an animal moving to get food," said study lead Scott Evans, a UCR paleontology doctoral candidate.

Evans' team demonstrated that the 550-million-year-old ocean-dwelling creatures moved on their own rather than being pushed around by waves or weather. The research answers questions about when, why and how animals first developed mobility.

The team searched for evidence of movement in more than 1,300 fossils of Dickinsonia, dinner-plate-shaped creatures up to a meter long that lived and fed on a layer of ocean slime.

Details of the team's analysis were published this month in the journal Geobiology. It found that Dickinsonia move like worms, constricting and relaxing their muscles to go after their next meal of microorganisms.

Dickinsonia were first discovered in the 1940s and since then, scientists have debated whether the fossils showed evidence of self-directed movement. To test this, it was crucial that Evans be able to analyze how multiple creatures living in the same area behaved relative to one another.

Evans and study co-author Mary Droser, a UCR professor of paleontology, reasoned that if Dickinsonia were riding waves or caught in storms, then all the individuals in the same area would have been moved in the same direction. However, that isn't what the evidence shows.

"Multiple fossils within the same community showed random movement not at all consistent with water currents," Evans said.

Critically, Evans was able to use fossil communities in the Australian outback unearthed by Droser and paper co-author James Gehling of the South Australian Museum. The duo systematically excavated large bed surfaces containing as many as 200 Dickinsonia fossils, allowing Evans to test whether the groups of the animals moved in the same or different directions, Evans said.

The team also analyzed the directions traveled by individual Dickinsonia.

"Something being transported by current should flip over or be somewhat aimless," Evans said. "These movement patterns clearly show directionality based on the animals' biology, and that they preferred to move forward."

Future studies at UCR will try to determine what Dickinsonia bodies were made of. "The tissues of the animals are not preserved, so it's not possible to directly analyze their body composition," he said. "But we will look at other clues they left behind."

Understanding Dickinsonia's capabilities offers insight not only into the evolution of animal life on Earth, but also about the Earth itself and possibly about life on other planets.

"If we want to search for complex life on other planets, we need to know how and why complex life evolved here," Evans said. "Knowing the conditions that enabled large mobile organisms to move during the Ediacaran era, 550 million years ago, gives us a clue about the habitable zone elsewhere."

That Dickinsonia could move helps confirm a large amount of oxygen was available in Earth's oceans during that time period, since it would have been required to fuel their movement. In a related study, Evans explored a spike in ocean oxygen levels during the Ediacaran period. Later, when oxygen levels dropped, Evans said that Dickinsonia - and things like them - went extinct.