Earth

CAMBRIDGE, Mass. - The utterances of Old World monkeys, some of our primate cousins, may be more sophisticated than previously realized -- but even so, they display constraints that reinforce the singularity of human language, according to a new study co-authored by an MIT linguist.

The study reinterprets evidence about primate language and concludes that Old World monkeys can combine two items in a language sequence. And yet, their ability to combine items together seems to stop at two. The monkeys are not able to recombine language items in the same open-ended manner as humans, whose languages generate an infinite variety of sequences.

"We are saying the two systems are fundamentally different," says Shigeru Miyagawa, an MIT linguist and co-author of a new paper detailing the study's findings.

That might seem apparent. But the study's precise claim -- that even if other primates can combine terms, they cannot do so in the way humans do -- emphasizes the profound gulf in cognitive ability between humans and some of our closest relatives.

"If what we're saying in this paper is right, there's a big break between two [items in a sentence], and [the potential for] infinity," Miyagawa adds. "There is no three, there is no four, there is no five. Two and infinity. And that is the break between a nonhuman primate and human primates."

The paper, "Systems underlying human and Old World monkey communications: One, two, or infinite," is published today in the journal Frontiers in Psychology. The authors are Miyagawa, who is a professor of linguistics at MIT; and Esther Clarke, an expert in primate vocalization who is a member of the Behavior, Ecology, and Evolution Research (BEER) Center at Durham University in the U.K.

To conduct the study, Miyagawa and Clarke re-evaluated recordings of Old World monkeys, a family of primates with over 100 species, including baboons, macaques, and the probiscis monkey.

The language of some of these species has been studied fairly extensively. Research starting in the 1960s, for example, established that vervet monkeys have specific calls when they see leopards, eagles, and snakes, all of which requires different kinds of evasive action. Similarly, tamarin monkeys have one alarm call to warn of aerial predators and one to warn of ground-based predators.

In other cases, though, Old World monkeys seem capable of combining calls to create new messages. The putty-nosed monkey of West Africa, for example, has a general alarm call, which scientists call "pyow," and a specific alarm call warning of eagles, which is "hack." Sometimes these monkeys combine them in "pyow-hack" sequences of varying length, a third message that is used to spur group movement.

However, even these latter "pyow-hack" sequences start with "pyow" and end with "hack"; the terms are never alternated. Although these sequences vary in length and consequently can sound a bit different from each other, Miyagawa and Clarke break with some other analysts and think there is no "combinatorial operation" at work with putty-nosed monkey language, unlike the process through which humans rearrange terms. It is only the length of the "pyow-hack" sequence that indicates how far the monkeys will relocate.

"The putty-nose monkey's expression is complex, but the important thing is the overall length, which predicts behavior and predicts how far they travel," Miyagawa says. "They start with 'pyow' and end up with 'hack.' They never go back to 'pyow.' Never."

As a result, Miyagawa adds, "Yes, those calls are made up of two items. Looking at the data very carefully it is apparent. The other thing that is apparent is that they cannot combine more than two things. We decided there is a whole different system here," compared to human language.

Similarly, Campbell's monkey, also of West Africa, deploys calls that might be interpreted as evidence of human-style combination of language items, but which Miyagawa and Clarke believe are actually a simpler system. The monkeys make sounds rendered as "hok," for an eagle alarm, and "krak," for a leopard alarm. To each, they add an "-oo" suffix to turn those utterances into generalized aerial alarms and land alarms.

However, that does not mean the Campbell's monkey has developed a suffix as a kind of linguistic building block that could be part of a more open-ended, larger system of speech, the researchers conclude. Instead, its use is restricted to a small set of fixed utterances, none of which have more than two basic items in them.

"It's not the human system," Miyagawa says. In the paper, Miyagawa and Clarke contend that the monkeys' ability to combine these terms means they are merely deploying a "dual-compartment frame" which lacks the capacity for greater complexity.

Miyagawa also notes that when the Old World monkeys speak, they seem to use a part of the brain known as the frontal operculum. Human language is heavily associated with Broca's area, a part of the brain that seems to support more complex operations.

If the interpretation of Old World monkey language that Miyagawa and Clarke put forward here holds up, then humans' ability to harness Broca's area for language may specifically have enabled them to recombine language elements as other primates cannot -- by enabling us to link more than two items together in speech.

"It seems like a huge leap," Miyagawa says. "But it may have been a tiny [physiological] change that turned into this huge leap."

As Miyagawa acknowledges, the new findings are interpretative, and the evolutionary history of human language acquisition is necessarily uncertain in many regards. His own operating conception of how humans combine language elements follows strongly from Noam Chomsky's idea that we use a system called "Merge," which contains principles that not all linguists accept.

Still, Miyagawa suggests, further analysis of the differences between human language and the language of other primates can help us better grasp how our unique language skills evolved, perhaps 100,000 years ago.

"There's been all this effort to teach monkeys human language that didn't succeed," Miyagawa notes. "But that doesn't mean we can't learn from them."

Researchers have shed new light on how some geese can fly high for long periods of time, according to a study published today in eLife.

The team collected the first ever cardiorespiratory measurements of bar-headed geese flying in a wind tunnel at a simulated altitude of 9,000m. They discovered that the animals are able to maintain flight in these low-oxygen conditions via a reduction in their metabolism.

Bar-headed geese are famed for migratory flight at extreme altitudes, having been directly tracked flying as high as 7,290m, and anecdotally reported reaching 9,000m. Previous research suggests these birds have several adaptations that allow them to maximise their oxygen usage at high altitudes, such as the ability to deliver oxygen efficiently to individual cells. But until now, no studies have comprehensively measured the physiology of bar-headed geese during flight in low-oxygen conditions, partly because there are few wind tunnels in the world suitable to carry out such experiments.

To address this gap in our knowledge, a research team from the University of British Columbia (UBC), Vancouver, Canada, imprinted a flock of bar-headed geese born and raised at sea-level, and trained them to fly in a wind tunnel. The group was led by Jessica Meir, a postdoctoral researcher in Bill Milsom's lab at UBC at the time the study was carried out, along with Julia York, an undergraduate researcher, currently a PhD candidate at the University of Texas at Austin, US.

They found that six of the seven birds that could fly in the tunnel were capable of flight in moderately low-oxygen levels equal to around 5,500m - the altitudes at which their wild counterparts typically fly. Three of the birds were also willing to fly in severely low-oxygen conditions, equal to altitudes of roughly 9,000m, for at least the short duration of the flights carried out in the study.

"We were surprised to find their heart rate during flights in reduced oxygen was no higher than that during flights in normal oxygen levels," York says. "We also saw that the temperature in their veins decreased during our simulated flights, which is hypothesised to significantly increase the amount of oxygen they can carry in their blood. Our data suggest the animals are able to reduce their metabolism in line with the reduced amount of oxygen available, without evidence of an oxygen limitation."

Milsom adds that determining how these results relate to the longer migratory flights of bar-headed geese at high altitudes will require further work to measure the physiological variables in the wild, or during longer flights in both normal and low-oxygen conditions.

"These initial measurements pave the way for future experiments that we believe will significantly move the field of high-altitude physiology forward," Meir explains. "Additionally, our findings have relevance to all physiological and biomedical fields involving animals and humans in low-oxygen environments, such as medical conditions including heart attacks and strokes, or procedures like organ transplants."

This study is one of a number of experiments carried out by Meir during her research career to see how animals cope in extreme conditions. Her previous work has involved travelling to Antarctica to study the adaptations of emperor penguins to long underwater dives.

Meir is currently a NASA astronaut, scheduled to launch to the International Space Station for a six-month mission on September 25, 2019, where she will support research into a diversity of space sciences including how long-duration spaceflight affects human physiology.

The following papers will be presented at the ESC Congress 2019, organised by the European Society of Cardiology in Paris and published simultaneously in either The Lancet or The Lancet Global Health journals. All papers are under embargo until the stated time. Contact details for corresponding authors are provided in the Articles and linked Comments. Funding information is listed on the first page of each Article.

Embargo: 13.30hrs [UK time] / 14.30hrs [Paris time] / 8.30 am [New York time] on Sunday 1st September 2019
The Lancet: Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31887-2/fulltext

Embargo: 7.30hrs [UK time] / 8.30hrs [Paris time] / 2.30 am [New York time] on Monday 2nd September 2019
The Lancet: Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31996-8/fulltext

Embargo: 7.30hrs [UK time] / 8.30hrs [Paris time] / 2.30 am [New York time] on Monday 2nd September 2019
The Lancet: Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31877-X/fulltext

Embargo: 10.00hrs [UK time] / 11.00hrs [Paris time] / 5.00am [New York time] on Monday 2nd September 2019 -
The Lancet: A community-based comprehensive intervention to reduce cardiovascular risk in hypertension (HOPE 4): a cluster-randomised controlled trial
**Full press release to be distributed around midday New York time on Thursday 29th August**

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31949-X/fulltext

Embargo: 14.30hrs [UK time] / 15.30hrs [Paris time] / 9.30am [New York time] on Monday 2nd September 2019
The Lancet Global Health: World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/langlo/article/PIIS2214-109X(19)30318-3/fulltext

Embargo: 15.40hrs [UK time] / 16.40hrs [Paris time] / 10.40am [New York time] on Monday 2nd September 2019
The Lancet: Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease:

10-year follow-up of the multicentre randomised controlled SYNTAX trial

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31997-X/fulltext

Embargo: 10.00hrs [UK time] / 11.00hrs [Paris time] / 5.00am [New York time] on Tuesday 3rd September 2019
The Lancet: Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study
**Full press release and finalised papers to be distributed around midday New York time on Friday 30th August**

Embargo: 10.00hrs [UK time] / 11.00hrs [Paris time] / 5.00am [New York time] on Tuesday 3rd September 2019
The Lancet: Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study
**Full press release and finalised papers to be distributed around midday New York time on Friday 30th August**

Embargo: 15.40hrs [UK time] / 16.40hrs [Paris time] / 10.40am [New York time] on Tuesday 3rd September 2019
The Lancet: Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial

Once the embargo lifts, please use this link as the one above will be deactivated: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31872-0/fulltext

Mothers who are dissatisfied with their male partners spend more time talking to their infants - but only if the child is a boy, according to a new study from researchers at the University of Cambridge.

It is well known that having a child can put a strain on the parents' relationship, but whether this then has an impact on the child's own development in its first few years is not known. The quality of a couple's relationship is known to be related to developmental outcomes such as their behaviour and educational attainment in school-aged children, but has been little studied in relation to parent-infant talk, despite parent-infant talk being important for the child's development.

To examine the relationship between the quality of a couple's relationship and parent-infant talk, researchers from the Centre for Family Research at the University of Cambridge studied 93 first-time, heterosexual parents and their interactions with their infants. The team asked parents about the quality of their couple relationship and how satisfied they were and then gave the infants at age seven months a wearable 'talk pedometer' that recorded naturalistic parent-infant talk for a full day in which both parents were at home.

The researchers used software to provide an automated analysis of the frequency of adult spoken words to their infant and of parent-infant 'conversations'.

The findings of the research, which was supported by Wellcome and the Economic and Social Research Council, are published in the Journal of Family Psychology.

After taking depression into account (because of its links with both couple relationship quality and parent-infant talk), the researchers found that the more dissatisfied a couple reported their relationship to be, the more the mother spoke to her infant. Mothers who reported the quality of their relationship to be 'low' used around 35% more words than a mother whose relationship was 'average' and started around 20% more conversations. However, these effects were only found with infant sons, not daughters.

The researchers did not analyse the content of the mother-infant talk, so it is not possible to say whether the mother was complaining to her infant or talking positively.

"It's possible that the mum is trying to compensate for the poor relationship she has with her partner by putting more time and effort into her relationship with her other close male social partner, her son," says Dr Elian Fink from the Centre for Family Research and the Faculty of Education.

"What is particularly interesting is that mums only seem to compensate when they have infant sons, not daughters. It could be that mothers view their daughters as mini versions of themselves rather than of their partners."

Regardless of infant gender, fathers showed significantly less overall talk and initiated fewer conversations than did mothers, even though the fathers are increasingly becoming involved in parenting and the recordings were taken specifically on a day when both parents were at home. However, the amount that they spoke to their infants was unrelated to the quality of the couple's relationship.

"Even when dads spend more time around their infants, this doesn't necessarily mean they are interacting with them more," adds Dr Fink. "One possible reason may be that there's still an imbalance in who responds to the basic care needs of their infant. So, for example, if it's the mother who still shoulders the burden of changing the nappy, this at least offers an opportune time to engage in direct communication with her infant."

Dr Fink hopes the findings will encourage parents to make a conscious effort to talk more to their infants, whether they are boys or girls.

"Parent-child interaction is important for a child's development, with conversation playing a particular role for the child's language development," she says. "Finding time to talk to children is very important. Using opportunities within the daily routine, such as mealtimes and bedtime, to have conversations with your child may help foster later child talk."

A previously unknown type of light wave has been discovered by researchers, based on the pioneering work of a 19th century Scottish scientist.

Equations developed by renowned mathematician and physicist James Clerk Maxwell have helped to reveal how crystals can be manipulated to produce a distinctive form of light wave.

The phenomena - recently named Dyakonov-Voigt waves - could have a range of useful applications, such as improving biosensors used to screen blood samples or developing fibre optic circuits that transfer data more efficiently.

Scientists and engineers from the University of Edinburgh and Pennsylvania State University made the discovery by analysing how light - which travels in the form of waves - interacts with certain naturally occurring or man-made crystals.

They found that Dyakonov-Voigt waves are produced at a specific region - known as an interface - where the crystals meet another material, such as oil or water. These waves can be produced only using certain types of crystal whose optical properties depend on the direction in which light passes through them, researchers say.

The team identified the waves' unique properties using mathematical models that incorporated equations developed by James Clerk Maxwell. Since the mid-1800s, research on how light interacts with crystals has built on the work of Maxwell, who studied at the University of Edinburgh from the age of 16.

Dyakonov-Voigt waves, named after two leading scientists, diminish as they move away from the interface - a process called decay - and travel only in a single direction, the team found. Other types of so-called surface waves decay more quickly and travel in multiple directions.

Dr Tom Mackay, of the University of Edinburgh's School of Mathematics, who jointly led the study, said: "Dyakonov-Voigt waves represent a step forward in our understanding of how light interacts with complex materials, and offer opportunities for a range of technological advancements."

University of Cambridge researchers have shown that an algorithm can predict the outcomes of complex chemical reactions with over 90% accuracy, outperforming trained chemists. The algorithm also shows chemists how to make target compounds, providing the chemical 'map' to the desired destination. The results are reported in two studies in the journals ACS Central Science and Chemical Communications.

A central challenge in drug discovery and materials science is finding ways to make complicated organic molecules by chemically joining together simpler building blocks. The problem is that those building blocks often react in unexpected ways.

"Making molecules is often described as an art realised with trial-and-error experimentation because our understanding of chemical reactivity is far from complete," said Dr Alpha Lee from Cambridge's Cavendish Laboratory, who led the studies. "Machine learning algorithms can have a better understanding of chemistry because they distil patterns of reactivity from millions of published chemical reactions, something that a chemist cannot do."

The algorithm developed by Lee and his group uses tools in pattern recognition to recognise how chemical groups in molecules react, by training the model on millions of reactions published in patents.

The researchers looked at chemical reaction prediction as a machine translation problem. The reacting molecules are considered as one 'language,' while the product is considered as a different language. The model then uses the patterns in the text to learn how to 'translate' between the two languages.

Using this approach, the model achieves 90% accuracy in predicting the correct product of unseen chemical reactions, whereas the accuracy of trained human chemists is around 80%. The researchers say that the model is accurate enough to detect errors in the data and correctly predict a plethora of difficult reactions.

The model also knows what it doesn't know. It produces an uncertainty score, which eliminates incorrect predictions with 89% accuracy. As experiments are time-consuming, accurate prediction is crucial to avoid pursuing expensive experimental pathways that eventually end in failure.

In the second study, Lee and his group, collaborating with the biopharmaceutical company Pfizer, demonstrated the practical potential of the method in drug discovery.

The researchers showed that when trained on published chemistry research, the model can make accurate predictions of reactions based on lab notebooks, showing that the model has learned the rules of chemistry and can apply it to drug discovery settings.

The team also showed that the model can predict sequences of reactions that would lead to a desired product. They applied this methodology to diverse drug-like molecules, showing that the steps that it predicts are chemically reasonable. This technology can significantly reduce the time of preclinical drug discovery because it provides medicinal chemists with a blueprint of where to begin.

"Our platform is like a GPS for chemistry," said Lee, who is also a Research Fellow at St Catharine's College. "It informs chemists whether a reaction is a go or a no-go, and how to navigate reaction routes to make a new molecule."

The Cambridge researchers are currently using this reaction prediction technology to develop a complete platform that bridges the design-make-test cycle in drug discovery and materials discovery: predicting promising bioactive molecules, ways to make those complex organic molecules, and selecting the experiments that are the most informative. The researchers are now working on extracting chemical insights from the model, attempting to understand what it has learned that humans have not.

"We can potentially make a lot of progress in chemistry if we learn what kinds of patterns the model is looking at to make a prediction," said Peter Bolgar, a PhD student in synthetic organic chemistry involved in both studies. "The model and human chemists together would become extremely powerful in designing experiments, more than each would be without the other."

Paris, France - 3 Sept 2019: Nearly one-third of patients with an implantable cardioverter defibrillator (ICD) resume driving despite it being medically contraindicated - a practice that is dangerous for themselves and others, and is illegal in some countries. The Danish research is presented today at ESC Congress 2019 together with the World Congress of Cardiology.(1)

ICDs are implanted to correct potentially lethal ventricular arrhythmias (heart rhythm disorders) and reduce the risk of sudden death. Some patients receive an ICD for primary prevention: they have not had a cardiac arrest or ventricular arrhythmia before but are at increased risk - typically those with heart failure. Others receive an ICD for secondary prevention: they have already experienced and survived either a cardiac arrest or ventricular arrhythmia, are at even higher risk of further arrhythmias, and are subject to a longer driving ban.

The length of driving bans varies by country. The ESC recommends a permanent ban on all professional driving (e.g. heavy trucks, buses). (2) Driving for personal use is banned for four weeks after ICD implantation for primary prevention, and three months for secondary prevention. If the ICD delivers a shock to correct an arrhythmia, there is also a three-month driving ban. Danish guidelines differ in one respect: primary prevention ICD patients can drive after one week, granted they are on home-monitoring for their ICD.

"It is the underlying heart condition and not the presence of the ICD device itself that is cause for concern, since it might cause an arrhythmia and loss of consciousness, and thus potentially great harm to the patient or bystanders if occurring while the patient is behind the wheel," said study author Dr Jenny Bjerre of Gentofte University Hospital, Denmark. "That is why patients refusing to have an ICD implanted for secondary prevention are subject to driving restrictions as well."

It is unclear how many patients are aware of, and adhere to, these restrictions. This study investigated these issues in a Danish nationwide cohort of ICD patients. A questionnaire was sent to the 3,913 adults who received a first-time ICD between 2013 and 2016. Additional data was obtained from national registries.

Of 2,741 respondents, 2,513 (92%) had a valid driving licence at the time of ICD implantation and 175 drivers (7%) also had a licence for professional driving. More than 30% of ICD patients, including professional drivers, resumed driving during the banned period. Up to 60% could not recall being informed of any restriction.

Patients who said they were unaware of the restrictions were three times more likely to drive when banned than those who reported being informed. "Not surprisingly, this was the largest predictor of nonadherence to the restrictions," said Dr Bjerre. "However, we also found that some ICD patients who recalled being informed chose not to adhere to the restrictions and drove anyway."

Dr Bjerre noted that in Denmark, physicians are responsible for informing patients if a medical condition leads to any driving restrictions. "Information is the key word here," she said. "These driving restrictions are worthless if we do not tell patients about them. On the other hand, patients do not remember everything they are told, and if you have recently survived a cardiac arrest, driving restrictions might not be your biggest concern. Better communication is required - for example by repeating the information, also in writing, explaining the rationale behind the restrictions and including family members in the discussions. We also need more studies on the absolute risk of traffic accidents in this patient population."

Men were 50% more likely to drive while banned than women. Patients 60 years and older were 20% more likely to drive while banned than younger patients. And being the only driver in the household was linked with a 30% greater likelihood of driving while banned than those who lived with other people who could drive.

Dr Bjerre said: "We can only speculate on why these groups were more likely to be nonadherent. Overall, we believe the necessity of a car in daily life is the most important factor. It is not hard to imagine an ICD patient might feel isolated, have trouble running errands, etc., during a period with driving restrictions, especially if they are older and living alone."

The penalty for driving while banned depends on national legislation. In Denmark, there is a risk of legal prosecution and/or insurance-related consequences if an ICD patient is involved in a traffic accident during a period with a documented medical driving restriction.

But Dr Bjerre said: "The Danish police are not automatically informed about driving restrictions for medical reasons. In another qualitative study we performed on the topic, some ICD patients stated this lack of consequence as one of the main reasons for nonadherence."

Protein aggregates have been observed in the nerve tissue of patients with Parkinson's disease which consist of individual components (monomers) of the protein α-synuclein which assemble into what are referred to as amyloid fibrils. Similar deposits are also found in the case of other neurodegenerative diseases such as Alzheimer's. Researchers are looking for approaches to prevent fibril formation and potentially cure the diseases.

In 2014, Düsseldorf-based researchers led by Prof. Dr. Wolfgang Hoyer described how a class of engineered binding-proteins, β-wrapins, are able to prevent α-synuclein aggregation. Hoyer says: "We subsequently investigated with research partners precisely how the β-wrapins function and where they disrupt the α-synuclein aggregation process."

The collaborative group including first author of the study Emil D. Agerschou and Prof. Hoyer from the Chair of Physical Biology at HHU and the FZJ, Prof. Dr. Alexander Büll (Technical University of Denmark) and Prof. Dr. Björn Falkenburger (Technical University of Dresden) as well as other partners at the University of Cambridge and the German Center for Neurodegenerative Diseases in Bonn has now presented its findings in the journal eLife.

Firstly, the researchers found out that the β-wrapins prevent new α-synuclein monomers from elongating the amyloid fibrils. To do this, the β-wrapins capture the monomers and form chemical complexes with them.

But there is a further property that makes the β-wrapins particularly effective, as explained by Emil Agerschou: "The β-wrapins prevent seed fibrils from forming in the first place. It is especially relevant that very small amounts of the wrapins are sufficient for this to happen, so you don't need a binding-protein for every monomer." This is referred to as a 'sub-stoichiometric effect' that makes the process especially effective. It is the aforementioned complexes comprising binding-proteins and monomers that are responsible for inhibiting seed formation.

"We discovered a few years ago that α-synuclein fibrils can proliferate quickly under certain conditions in a kind of chain reaction. We were really astonished to see that the β-wrapins suppress the chain reactions very efficiently", adds Prof. Büll: "We think we now understand how this is achieved."

In addition, the researchers have examined the effect of the β-wrapins not only in test tubes but also in cell culture and in animal models. Diseased fruit flies (Drosophila) treated with β-wrapins displayed notably improved motor skills in a climbing assay.

Prof. Hoyer is still cautious about potential therapeutic use: "The positive results in living creatures give us hope that we have possibly found a path to an active ingredient through the β-wrapins. However, it will still be a long time before this could potentially be used for humans."

New, lower-cost help may soon be on the way to help manage one of the biggest threats facing the Great Barrier Reef.

That threat is pollution from land making its way downstream by way of the many rivers and streams that flow into coastal waters along the reef.

The size of the reef - which stretches for 2,300 kilometres along the Queensland coast - makes it extremely hard to get an idea of what's happening in real-time.

Now, in collaboration with scientists at the Queensland Department of Environment and Science, researchers at the ARC Centre of Excellence for Mathematical and Statistical Frontiers (ACEMS) have developed statistical predictive tools that could lead to the deployment of many more low-cost sensors in those rivers and streams.

"At present, there are less than 50 long-term river monitoring stations providing information that informs programs related to the protection of the Great Barrier Reef. That means there are thousands of kilometres of coastal lands and waterways where we have limited information," said Dr Catherine Leigh, an ACEMS Associate Investigator with QUT's School of Mathematical Sciences.

There is an opportunity to infill at a finer scale with lower cost sensors. However, at this stage, low cost sensors aren't yet able to show the two things that are most important in determining water quality. Those are direct measures of sediments and nutrients. Sediments can smother plants and animals. Nutrients are important for life, but an imbalance can lead to a variety of problems. What the low cost sensors do measure are turbidity and conductivity. Turbidity is a measure of water clarity, and conductivity reflects the levels of ions like salt in the water.

In research just published in PLOS ONE, the ACEMS team developed statistical tools to take that turbidity and conductivity data and predict levels of sediments and nutrients in the water.

"They're really the key things water agencies are looking for, both in what their values are and how they are changing over time," said Dr Leigh.

The sensor data were provided by the Water Quality and Investigations (WQI) Team with the Queensland Department of Environment and Science. By being able to predict levels of sediment and nutrients, managers can look toward automating the sensor process.

"Right now, someone has to physically go to where the monitoring station is, get a sample, take it back to a lab and test it. If we can automate this process with the sensors, we can get a lot more frequent predictions of what's happening," said Dr Sevvandi Kandanaarachchi, an ACEMS Associate Investigator in the Department of Econometrics and Business Statistics at Monash University.

"Predicting these quantities is important because if they suddenly change, then that's an indication that something with the system needs to be looked into."

Dr Leigh hopes the project will lead to the deployment of many more low-cost sensors. She also says they're looking into developing an app that farmers and other landowners can use.

"They're keen to make sure they're not wasting nutrients, that what they use is taken up by the plants on the land and not end up in a stream," said Dr Leigh. "They're also keen to reduce land erosion."

In work published earlier this year, the ACEMS and WQI teams showed how to detect anomalies in the sensor data. In other words, they needed ways to show if a sensor wasn't working properly.

"You want to know that the data you're collecting is good before you go and predict something else," said Dr Leigh.

This new research will also help answer questions like where to place the sensors, how many are needed in certain places, and whether they need to be moved around.

"The big picture is making sure certain things that could hurt the reef and our rivers don't end up in a stream. If they do, that we can act in a timely fashion to figure what's happening and why," said Dr Leigh.

A simple and sensitive urine test developed by Imperial and MIT engineers has produced a colour change in urine to signal growing tumours in mice.

Tools that detect cancer in its early stages can increase patient survival and quality of life. However, cancer screening approaches often call for expensive equipment and trips to the clinic, which may not be feasible in rural or developing areas with little medical infrastructure. The emerging field of point-of-care diagnostics is therefore working on cheaper, faster, and easier-to-use tests.

An international pair of engineering labs have now developed a tool that changes the colour of mouse urine when colon cancer is present. The findings from testing the fast, non-invasive cancer test are published today in Nature Nanotechnology.

The early stage technology, developed by teams led by Imperial's Professor Molly Stevens and MIT professor and Howard Hughes Medical Institute investigator Sangeeta Bhatia, works by injecting nanosensors into mice, which are cut up by enzymes released by the tumour, known as proteases.

When the nanosensors are broken up by proteases, they pass through the kidney, and can be seen with the naked eye after a urine test that produces a blue colour change.

The researchers applied this technology to mice with colon cancer, and found that urine from tumour-bearing mice becomes bright blue, relative to test samples taken from healthy mice.

Professor Stevens, of Imperial's Departments of Materials and Bioengineering, said: "By taking advantage of a chemical reaction that produces a colour change, this test can be administered without the need for expensive and hard-to-use lab instruments.

"The simple readout could potentially be captured by a smartphone picture and transmitted to remote caregivers to connect patients to treatment."

Sensing signals

When tumours grow and spread, they often produce biological signals known as biomarkers that clinicians use to both detect and track disease. However, not all biomarkers play an active role in tumour growth, and most are present in such small quantities that they can be challenging to find.

One family of tumour proteins known as matrix metalloproteinases (MMPs) have attracted attention as potential biomarkers, since these enzymes help promote the growth and spread of tumours by chewing up the tissue scaffolds that normally keep cells in place.

Many cancer types, including colon tumours, produce high levels of several MMP enzymes, including one called MMP9.

In this study, the Imperial-MIT team developed nanosensors where ultra-small gold nanoclusters (AuNCs) were connected to a protein carrier through linkages that are broken by MMP9s

To develop the colour-changing urine test, the researchers used two AuNC properties - their very small (The researchers designed the AuNC-protein complexes to disassemble after being cut by MMPs in the tumour microenvironment or blood. When broken apart, the released AuNCs travel via the blood and are small enough to be filtered through the kidneys into the urine.

In healthy mice without high MMP levels, the complexes remain intact, and are too large to pass into the urine. If AuNCs have been concentrated in the urine, a chemical test will produce a blue colour change that is visible with the naked eye.

For this study, the researchers developed sensors that are cut apart by particular MMPs and tested them in mice. The researchers demonstrated that their colour change test could accurately detect which urine samples came from mice with colon tumours in a study of 28 mice injected with the sensors, where 14 mice were healthy and 14 had tumours.

Within half an hour of the chemical treatment, only the urine from mice with colon tumours had a strong blue colour. By contrast, urine from the healthy control mice exhibited no colour change.

The team also designed the AuNC surfaces to go 'unseen' by the immune system to prevent immune reactions or toxic side effects, and to prevent abundant serum proteins from sticking to them, which would make the nanosensors too large to be filtered by the kidneys.

During a four-week follow up after nanosensor administration, the mice showed no signs of side effects, and there was no evidence that the protein-sensor complex or free AuNCs lingered in the bodies of the mice.

Co-first author Dr Colleen Loynachan, of Imperial's Department of Materials, said: "The AuNCs are similar to materials already used in the clinic for imaging tumours, but here we are taking advantage of their unique properties to give us additional information about disease. However, there's still a lot of optimisation and testing needed before the technology can move beyond the lab."

Accessible diagnostics

Next, the team will work to increase the specificity and sensitivity of the sensors by testing them in additional animal models to investigate diagnostic accuracy and safety.

"Proteases play functional roles in a number of diseases such as cancer, infectious diseases, inflammation, and thrombosis," said co-first author Ava Soleimany, of Harvard and MIT. "By designing versions of our sensors that can be cut by different proteases, we could apply this colour-based test to detect a diversity of conditions."

The researchers are now working on a formulation that is easier to administer, and identifying ways to make the sensors responsive to multiple biomarkers in order to distinguish between cancers and other diseases.

Due to their function, the lungs are constantly exposed to various compounds carried in the air, sometimes harmful, sometimes harmless. The lung immune system plays a pivotal role in deciding or not deciding to mount an immune response in order to sustain respiratory function. In some cases, there is a dysfunction of the immune system that responds against harmless compounds, as is the case in the development of asthma. In this regard, researchers from the University of Liège, under the direction of the Professors Fabrice Bureau and Thomas Marichal, previously discovered that specific cells in the lung, called "interstitial macrophages", could prevent the development of asthma. However, these cells were only rudimentarily characterized. In an article published in Nature Communications, the Immunophysiology Laboratory of the GIGA Institute, headed by Prof. Thomas Marichal, reports that two very distinct sub-populations of interstitial macrophages exist, and identifies their local precursors. This new knowledge is a further step towards understanding the regulation of the lung immune system and developing targeted approaches to prevent respiratory diseases, such as asthma.

A study conducted by the Immunophysiology Laboratory led by Prof. Thomas Marichal (Research Associate, Fund for Scientific Research - FNRS, ERC and Welbio Investigator - Walloon Excellence in Life Sciences and Biotechnology, GIGA-ULiège) and published in Nature Communications, reveals new insights regarding a population of cells of the pulmonary immune system: the interstitial macrophages. These poorly studied cells are involved in preventing the development of asthma and are therefore a potential target for the development of therapies against immune-mediated respiratory diseases such as asthma. In this context, a deeper knowledge of these cells is an important prerequisite, which has recently been clarified by the research team.

First, Joey Schyns, the first author of the study, discovered that interstitial macrophages in mice are a heterogeneous population composed of two very distinct subpopulations. These subpopulations exhibit different function, origin and morphology, and are located in different pulmonary zones. The involvement of each of these sub-populations in the development of chronic respiratory diseases is potentially very different, so it is important, from now on, to consider them as separate entities in future research.

In addition, the researchers also found that a subpopulation of these interstitial macrophages comes directly from specific blood monocytes called "patrolling monocytes" that can exit the bloodstream and reach the lung.

This discovery is the first step in an ambitious research project funded by an ERC Starting Grant, deployed by the European Research Council, and obtained by Thomas Marichal last year. Ultimately, this project should allow a better understanding of the mechanisms underlying the fine regulation of these sub-populations of macrophages, and will provide essential elements for the development of targeted approaches for the prevention of respiratory diseases in which the (dys)functions of these macrophages are involved.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information.

1. Poor diet causes blindness in a young "fussy eater"

Abstract: http://annals.org/aim/article/doi/10.7326/L19-0361
URLs go live when the embargo lifts

A poor diet caused a young patient's blindness, according to a case report published in Annals of Internal Medicine. According to the authors, nutritional optic neuropathy should be considered in any patient with unexplained vision symptoms and poor diet, regardless of BMI.

The risks for poor cardiovascular health, obesity, and cancer associated with junk food consumption are well known, but poor nutrition can also permanently damage the nervous system, particularly vision. Nutritional optic neuropathy is a dysfunction of the optic nerve usually caused by malabsorption, drugs, or poor diet combined with alcoholism and/or smoking. It is rare in developed countries. The condition is potentially reversible if caught early. But if left untreated, it leads to permanent blindness.

Researchers from Bristol Eye Hospital, Bristol, United Kingdom report the case of a 14-year-old patient who first visited his family physician complaining of tiredness. Aside from being labeled a "fussy eater," the boy had a normal BMI and took no medications. Tests showed macrocytic anemia and low vitamin B12 levels, which were treated with vitamin B12 injections and dietary advice. By age 15 years, the patient had developed sensorineural hearing loss and vision symptoms, but no cause was found. By age 17, the patient's vision had become progressively worse, to the point of blindness. The physicians investigated the patient's nutrition and found vitamin B12 deficiency, low copper and selenium levels, a high zinc level, and markedly reduced vitamin D level and bone mineral density. The patient confessed that since elementary school, he had avoided foods with certain textures and only ate French fries, Pringles, white bread, processed ham slices, and sausage. By the time his condition was diagnosed, the patient had permanently impaired vision.

Notes and media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the corresponding author, Dr. Denize Atan, please contact Caroline Clancy at caroline.clancy@bristol.ac.uk or + 44 (0)117 428 2407.

2. Haloperidol shows no clear benefit for preventing or treating delirium in hospitalized patients
Second generation antipsychotics may offer some delirium prevention benefits in postoperative settings

Abstract: http://annals.org/aim/article/doi/10.7326/M19-1859
Abstract: http://annals.org/aim/article/doi/10.7326/M19-1860
URLs go live when the embargo lifts

Compared to placebo, first-generation antipsychotic, haloperidol, shows no clear benefit for treating or preventing delirium in hospitalized patients. Second-generation antipsychotics may offer some prevention benefits in postoperative settings. Findings from two systematic reviews are published in Annals of Internal Medicine.

Delirium is an acute disorder marked by impairments in attention and cognition, caused by an underlying medical problem. It often occurs after an acute illness or surgery and may affect up to 50 percent of hospitalized older adults. Antipsychotics are used to prevent and treat delirium, but their benefits and harms are unclear.

Researchers from Johns Hopkins University School of Medicine reviewed 14 randomized controlled trials (RCTs) to examine the benefits and harms of haloperidol or second-generation antipsychotics for preventing delirium in adults, and 16 RCTs and 10 observational studies to examine the benefits and harms of haloperidol or second-generation antipsychotics for treating delirium in adults. With regard to prevention, the researchers found little or no evidence to determine the effects of antipsychotics on cognitive function, delirium severity, caregiver burden, or sedation. Haloperidol did not appear to prevent delirium, although the research suggests that there may be some benefit with second-generation antipsychotics in postoperative settings. With regard to treating delirium, both haloperidol and second-generation antipsychotics did not demonstrate any clear benefit compared to placebo. Using haloperidol or second-generation antipsychotics to prevent or treat delirium did not decrease length of hospital stay and made little or no difference in sedation or neurologic side effects but potentially harmful cardiac side effects did occur more frequently. According to the study authors, future trials should use standardized outcome measures, as more research is needed to assess the effects of antipsychotics on patient agitation and distress, subsequent memories of delirium, caregiver burden and distress, inappropriate continuation of antipsychotic therapy, and long-term cognitive functional outcomes.

Notes and media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with author Karin Neufeld, MD, MPH, please contact Vanessa McMains vmcmain1@jhmi.edu.

3. People inadvertently ingest thousands of tiny plastic particles every year
Bottled water may be one of the strongest contributors to microplastics ingestion

Abstract: http://annals.org/aim/article/doi/10.7326/M19-0618
Editorial: http://annals.org/aim/article/doi/10.7326/M19-2474
URLs go live when the embargo lifts

A study of human stool samples reveals that people inadvertently eat thousands of tiny plastic particles every year. Various types of microplastics were detected in fecal matter, suggesting that plastic particles are present in many different sources. Findings from a prospective case series, which were presented last year at the United European Gastroenterology Week, are now published in Annals of Internal Medicine.

More than 350 million tons of plastic are produced each year and some of it pollutes the environment. Microplastics, or plastic particles smaller than 5 mm, may be ingested by marine organisms where they can then enter the food chain.

Researchers from the Medical University of Vienna and the Environment Agency Austria studied human feces samples from 8 adults living in Europe and Asia to look for the presence of microplastics and to determine whether humans involuntarily ingest them. All 8 stool samples tested positive for microplastics, with a median of 20 microplastics per 10 g of human stool (daily stool excretion of an average adult is approximately 100 g). Polyethylene and polyethylene terephthalate accounted for the largest share of plastics found in human stool. The researchers also detected 7 other plastic types, suggesting that there are many different sources of ingestion. According to the literature, the estimated annual intake of microplastics is 123 to 11,000 particles from shellfish; 37 to 1,000 particles from salt; and 4,400 to 5,800 particles from tap water. Airborne fallout accounts for 13,731 to 68,415 swallowed particles per year and, bottled water may also be a strong contributor to microplastic ingestion, with an average of 118 to 325 particles per liter, for a total of 90,000 microplastics annually if the recommended water intake comes entirely from bottled sources.

The scientists emphasize that further research is needed to determine the effects of plastic ingestion on human health.

Notes and media contacts:

The abstract presented at the United European Gastroenterology Week led to many international reports on this research. For the first time, this research is published as a peer-reviewed paper and accessible in Annals of Internal Medicine. For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the lead author, Philipp Schwabl, MD, please contact thorsten.medwedeff@meduniwien.ac.at.

4. Patients with LMNA mutations likely to face life-threatening neurologic or cardiologic conditions

Abstract: http://annals.org/aim/article/doi/10.7326/M18-2768
URLs go live when the embargo lifts

Patients with the LMNA (lamin A/C) gene will likely face life-threatening cardiac and neuromuscular conditions in their lifetime, with neuromuscular conditions starting at a much earlier age. The clinical care team for these patients should include at least a cardiologist and neurologist. Findings from an observational study are published in Annals of Internal Medicine.

Mutations in the LMNA gene have been associated with neuromuscular and cardiac manifestations. Although skeletal myopathy may occur apart from heart disease, life-threatening arrhythmias, and dilated cardiomyopathy have been described in patients with skeletal muscle disease, and sudden cardiac death accounts for up to 30 percent of all deaths. However, because LMNA-related disease is so rare, not enough is known about its natural history.

Researchers from Vita-Salute University and San Raffaele Hospital (Milan, Italy) presented results of a national study on 164 patients with LMNA mutations enrolled at 13 referral centers, to learn more about the natural history of LMNA-related disease. They found neuromuscular manifestations preceded cardiac signs by a median of 11 years. However, by the end of the 10-year follow-up, 90 percent of the patients had relevant cardiac arrhythmias followed by structural heart disease. According to the researchers, these findings show for the first time that the link between neuromuscular and cardiac features can be used to predict risk of sudden arrhythmic death and heart failure in LMNA patients. Based on their findings, the researchers believe that clinicians who care for patients with LMNA mutations should always consider including cardiologists and neurologists on the clinical team. An advantage to this approach might be earlier identification of high-risk patients who might benefit from protective strategies, such as implantable cardioverter-defibrillator therapy and referral to heart transplant centers.

Notes and media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the lead author, Giovanni Peretto, MD, please contact him directly at peretto.giovanni@hsr.it.

Dog brain structure varies across breeds and is correlated with specific behaviors, according to new research published in JNeurosci. These findings show how, by selectively breeding for certain behaviors, humans have shaped the brains of their best friends.

Over several hundred years, humans have selectively bred dogs to express specific physical and behavioral characteristics. Erin Hecht and colleagues investigated the effects of this selective pressure on brain structure by analyzing magnetic resonance imaging scans of 33 dog breeds. The research team observed wide variation in brain structure that was not simply related to body size or head shape.

The team then examined the areas of the brain with the most variation across breeds. This generated maps of six brain networks, with proposed functions varying from social bonding to movement, that were each associated with at least one behavioral characteristic. The variation in behaviors across breeds was correlated with anatomical variation in the six brain networks.

Studying the neuroanatomical variation in dogs offers a unique opportunity to study the evolutionary relationship between brain structure and behavior.

Chronic cocaine use changes gene expression in the hippocampus, according to research in mice recently published in JNeurosci.

Chronic drug users learn to associate the drug-taking environment with the drug itself, reinforcing memories that contribute to addiction. These memories are thought to be created by changes in gene expression in the hippocampus and potentially involve the gene FosB, but the exact mechanism is unknown.

A.J. Robison and colleagues at Michigan State University examined how cocaine exposure affected expression of the FosB gene in the hippocampus. Mice that were administered cocaine daily showed increased expression of FosB compared to mice that received saline. Chronic cocaine use caused epigenetic modification of the gene, leading it to becoming more active. Additionally, when the scientists blocked the changes made to FosB, the mice were unable to form associations between cocaine and the environment where they received it, implicating epigenetic regulation of the gene in drug memory formation.

These results offer new insights in the molecular changes that take place in the hippocampus during chronic cocaine use. Further research in this area could lead to the development of addiction therapies.

New research from the University of Maryland and the National Institutes of Health reveals a new role for the enzyme telomerase. Telomerase's only known role in normal tissue was to protect certain cells that divide regularly, such as embryonic cells, sperm cells, adult stem cells and immune cells. Scientists thought telomerase was turned off in all other cells, except in cancerous tumors where it promotes unlimited cell division.

The new study found that telomerase reactivates in normal adult cells at a critical point in the aging process. Just before cell death, a burst of telomerase buffers cells from the stresses of aging, slowing the process and reducing DNA damage that could lead to cancer. The study was published in the Proceedings of the National Academy of Sciences on September 2, 2019.

"This study reshapes the current understanding of telomerase's function in normal cells,"said Kan Cao, senior author of the study and an associate professor of cell biology and molecular genetics at UMD. "Our work shows, for the first time, that there is a role for telomerase in adult cells beyond promoting tumor formation. We can now say that regulated activation of telomerase at a critical point in a cell's life cycle serves an important function."

Telomerase prevents the shortening of telomeres--a specialized DNA-protein structure at the end of a cell's chromosomes that protect the chromosomes from damage. Telomerase plays a critical role during embryonic development and stem cell differentiation, when cells divide profusely. In normal adult cells, telomerase is turned off and telomeres shorten with every cell division until they reach a critical length. At critical telomere length, cells stop dividing and either die or experience DNA damage that could cause malignancies.

Before this new work, scientists thought that telomerase expression in most adult cells could only lead to unlimited cell division like that seen in cancerous tumors.

Cao and her colleagues suspected telomerase may have a function in adult cells when they observed dramatic differences in the laboratory among sibling mice with shortened telomeres. The mice were the progeny of wild-type mice and genetically modified mice that had been bred for many generations without the ability to produce telomerase. All the siblings had abnormally short telomeres, but the researchers found that mice that had not inherited the gene to produce telomerase from their wild-type parent exhibited shorter lifespans, progressive tissue atrophy and spontaneous cancers.

To understand what was going on, Cao and her colleagues compared the skin cells of the sibling mice and found that while both cell lines had comparably short telomeres, cells from telomerase-deficient mice stopped dividing sooner and had more malignant transformations than cells from siblings that produced telomerase.

What's more, the researchers found that as skin cells from non-telomerase-deficient mice approached critical telomere length, they naturally produced a burst of telomerase, which slowed the process of telomere shortening and reduced the amount of DNA damage that could lead to cancer. According to Cao, these results suggest that telomerase expressed near the end of a cell's lifespan softened the blow of aging and led to a more gradual cell death.

The researchers also found that reactivating the gene for expressing telomerase in the telomerase-deficient cells rescued them, prolonging their ability to divide and reducing DNA damage.

To see if what they observed in mice held true for humans, the team conducted laboratory studies on human skin cells. The researchers found that human cells also expressed telomerase as they approached critical telomere length. In addition, human skin cells that were unable to express telomerase reached critical telomere length more quickly and displayed significantly more DNA damage than those that did express telomerase.

Cao said that the next step for researchers is to find out how telomerase expression is turned on as cells approach critical telomere length and to explore the underlying mechanisms by which telomerase acts as a buffer against the stresses of shortening telomeres.