Culture

PITTSBURGH, Aug. 23, 2019 - Critically ill children brought to hospital emergency departments that are ill-prepared to care for pediatric emergencies have more than three times the odds of dying compared to those brought to hospitals well-equipped to care for them, according to an analysis led by University of Pittsburgh and University of California-Los Angeles physician-scientists.

The findings, published today in the journal Pediatrics, are the first to provide evidence from multiple states linking the readiness of hospital emergency departments to care for critically ill or injured children with outcomes, and could guide a variety of policy responses.

"Pediatric care requires specialized equipment, training and protocols to provide the best care to children. Obtaining that kind of preparedness is costly and time-consuming," said senior author Jeremy Kahn, M.D., M.S., professor in the Department of Critical Care Medicine at Pitt's School of Medicine and the Department of Health Policy and Management at Pitt's Graduate School of Public Health. "Our study suggests that efforts to better prepare hospitals to care for pediatric emergencies save lives."

Kahn and his colleagues obtained data from 426 hospitals in Florida, Iowa, Massachusetts, Nebraska and New York, on 20,483 critically ill patients age 18 or younger who were brought to the hospital emergency department. They cross-referenced the patient outcomes with the "pediatric readiness" of the hospital's emergency department.

Pediatric readiness is indicated by a score assigned following assessment by the National Pediatric Readiness Project, a quality improvement effort of several federal government and non-profit advocacy organizations. Hospitals receive higher scores based on several factors, including whether they have equipment designed for use on children, pediatric-specific protocols for medical procedures and care, and educational programming to keep clinicians up-to-date on the latest guidelines in pediatric care. The standardized readiness score ranges from 0 to 100.

The team divided the hospitals into four groups based on their pediatric readiness score, with the lowest quartile's scores ranging from 29.6 to 59.3, and the highest from 88.2 to 99.9. Hospitals in the lowest quartile had a pediatric mortality rate for critically ill children of 11.1%, compared to 3.4% for the highest quartile.

"Our findings indicate that it matters which hospital a critically ill or injured child is brought to in an emergency," said co-author Jennifer Marin, M.D., M.Sc., an emergency physician at UPMC Children's Hospital of Pittsburgh and associate professor of pediatrics and emergency medicine in Pitt's School of Medicine. "A hospital's pediatric readiness should be a factor in determining to which hospital a critically ill child should be transported."

There likely isn't one perfect solution to the disparity in outcomes, noted lead author Stefanie Ames, M.D., M.S., a pediatrician specializing in critical care medicine at UCLA Mattel Children's Hospital and assistant professor in the Division of Pediatric Critical Care at UCLA David Geffen School of Medicine.

"Should we focus only on improving the pediatric readiness of all hospitals, potentially investing money and resources in hospitals that rarely see children? Or should we do more to direct pediatric emergencies to hospitals well-equipped to care for them, potentially increasing transport times?" she asked. "Some combination will likely be needed and potential solutions also could incorporate telemedicine and processes to promote quick recognition and transfer of pediatric emergencies to more prepared hospitals."

ROCHESTER, Minn. -- Owning a pet may help maintain a healthy heart, especially if that pet is a dog, according to the first analysis of data from the Kardiozive Brno 2030 study. The study examines the association of pet ownership -- specifically dog ownership -- with cardiovascular disease risk factors and cardiovascular health. The results are published in Mayo Clinic Proceedings: Innovations, Quality & Outcomes.

The study first established baseline health and socio-economic information on more than 2,000 subjects in the city of Brno, Czech Republic, from January 2013 through Dec. 2014. Follow-up evaluations are scheduled for five-year intervals until 2030.

In the 2019 evaluation, the study looked at 1,769 subjects with no history of heart disease and scored them based on Life's Simple 7 ideal health behaviors and factors, as outlined by the American Heart Association: body mass index, diet, physical activity, smoking status, blood pressure, blood glucose and total cholesterol.

The study compared the cardiovascular health scores of pet owners overall to those who did not own pets. Then it compared dog owners to other pet owners and those who did not own pets.

"In general, people who owned any pet were more likely to report more physical activity, better diet and blood sugar at ideal level," says Andrea Maugeri, Ph.D., a researcher with the International Clinical Research Center at St. Anne's University Hospital in Brno and the University of Catania in Catania, Italy. "The greatest benefits from having a pet were for those who owned a dog, independent of their age, sex and education level."

The study demonstrates an association between dog ownership and heart health, which is in line with the American Heart Association's scientific statement on the benefits of owning a dog in terms of physical activity, engagement and reduction of cardiovascular disease risk.

Dr. Maugeri says that the study findings support the idea that people could adopt, rescue or purchase a pet as a potential strategy to improve their cardiovascular health as long as pet ownership led them to a more physically active lifestyle.

Francisco Lopez-Jimenez, M.D., chair of the Division of Preventive Cardiology at Mayo Clinic in Rochester, says that having a dog may prompt owners to go out, move around and play with their dog regularly. Owning a dog also has been linked to better mental health in other studies and less perception of social isolation -- both risk factors for heart attacks. Dr. Lopez-Jimenez is a senior investigator of this study.

Big brains can help an animal mount quick, flexible behavioral responses to frequent or unexpected environmental changes. But some birds just don't need 'em.

A global study comparing 2,062 birds finds that, in highly variable environments, birds tend to have either larger or smaller brains relative to their body size. Birds with smaller brains tend to use ecological strategies that are not available to big-brained counterparts. Instead of relying on grey matter to survive, these birds tend to have large bodies, eat readily available food and make lots of babies.

The new research from biologists at Washington University in St. Louis appears Aug. 23 in the journal Nature Communications.

"The fact is that there are a great many species that do quite well with small brains," said Trevor Fristoe, formerly a postdoctoral researcher at Washington University, now at the University of Konstanz in Germany.

"What's really interesting is that we don't see any middle ground here," Fristoe said. "The resident species with intermediate brain size are almost completely absent from high latitude (colder and more climatically variable) environments. The species that don't go all in on either of the extreme strategies are forced to migrate to more benign climates during the winter."

"Having a large brain is typically associated with strong energetic demands and a slower life-history," said Carlos Botero, assistant professor of biology in Arts & Sciences and co-author of the paper. "Free from these constraints, species with small brains can exhibit traits and lifestyles that are never seen in larger-brained ones.

"What we found is that alternative ecological strategies that either increase or decrease investments in brain tissue are equally capable of coping with the challenges of living in high-latitude environments," he said.

Because the brain is such a costly organ to develop and maintain, biologists have long been interested in understanding how large brain size -- in all species -- could have evolved.

One hypothesis is based around the idea that one of the main advantages of possessing a big brain is that it allows for a high degree of behavioral flexibility. With flexibility comes the ability to respond to different conditions -- such as wide swings in temperature, or changes in food availability.

The so-called cognitive buffer hypothesis is not the only possible explanation for the evolution of brain size -- but it is an important and influential one.

Relative brain size is a measure of the size of the brain as compared to the body -- think: an ostrich's brain might be much bigger than a chickadee's brain, but so is the ostrich's body. Predictably, the global distribution of relative brain size of birds follows a bell curve, with most species landing squarely in the middle, and only a handful of outliers with relatively large or relatively small brains.

Previous studies had found general trends towards larger relative brain sizes in higher latitudes, where conditions are more variable -- consistent with the cognitive buffer hypothesis. Fristoe and Botero's new study is different because it looks at the full distribution of brain sizes across environments, allowing them to test whether different sizes are over- or under-represented.

Excluding contributions from migrants -- the birds that live in polar or temperate environments only during more favorable times of the year -- the researchers found that at high latitudes, bird brain size appears to be bimodal. This morphological pattern means that bird brains are significantly more likely to be relatively large, or relatively small, compared to body size.

What was going on here? Fristoe, born in Alaska, had a few ideas.

In fact, Fristoe suggests that the Alaska state bird, the ptarmigan, might be a good poster child for the small-brained species. Endearing though she is -- with her plushy bosom, feathered feet and unusual chuckling call -- she's not exactly known for her smarts. The ptarmigan can, however, chow down on twigs and willow leaves with the best of them.

"In our paper, we find that small-brained species in these environments employ strategies that are unachievable with a large brain," Fristoe said. "First, these species are able to persist by foraging on readily available but difficult to digest resources such as dormant plant buds, the needles of conifers, or even twigs.

"These foods can be found even during harsh winter conditions, but they are fibrous and require a large gut to digest," he said. "Gut tissue, like brain tissue, is energetically demanding, and limited budgets mean that it is challenging to maintain a lot of both.

"We also found that these species have high reproductive rates, producing many offspring every year," Fristoe said. "This would allow their populations to recover from high mortality during particularly challenging conditions. Because big-brained species tend to invest more time in raising fewer offspring, this is a strategy that is not available to them."

In other words, maybe big brains are not all that.

"Brains are not evolving in isolation -- they are part of a broader suite of adaptations that help organisms be successful in their lives," Botero said. "Because of trade-offs between different aspects of that total phenotype, we find that two different lineages may respond to selection from environmental oscillations in completely different ways.

"Given that our own species uses its brain to cope with these changes, it is not really surprising that biologists, ourselves included, have historically exhibited a bias toward thinking about environmental variability as a force that drives the expansion of brain size," Botero said. "But the interesting thing that we find here is that when we take a broader view, we realize that other strategies also work -- and remarkably, the alternative here involves making a brain actually smaller!"

Elite athletes have high rates of oral disease despite brushing their teeth more frequently than most people, finds a new UCL study.

The findings, published in the British Dental Journal, highlight potential for improvement as most of the athletes expressed an interest in changing their oral hygiene behaviour to improve their oral health.

The UCL Eastman Dental Institute research team surveyed 352 Olympic and professional athletes across 11 sports, including cycling, swimming, rugby, football, rowing, hockey, sailing and athletics, when they provided dental check-ups for male and female athletes measuring tooth decay, gum health and acid erosion.

The researchers also asked athletes what they did to keep their mouth, teeth and gums healthy.

The dental check-ups revealed substantial amounts of oral disease as reported in a 2018 paper, finding that nearly half (49.1%) had untreated tooth decay, the large majority showed early signs of gum inflammation, and almost a third (32%) reported that their oral health had a negative impact on their training and performance.*

Elite athletes have poor oral health despite their efforts to care for their teeth: this new study found that 94% reported brushing their teeth at least twice a day, and 44% reported regularly cleaning between their teeth (flossing) - substantially higher figures than for the general population (75% for twice-daily brushing and 21% for flossing**).

The researchers found that the athletes regularly use sports drinks (87%), energy bars (59%) and energy gels (70%), which are known to damage teeth.

"We found that a majority of the athletes in our survey already have good oral health related habits in as much as they brush their teeth twice a day, visit the dentist regularly, don't smoke and have a healthy general diet," said researcher Dr Julie Gallagher (UCL Eastman Dental Institute Centre for Oral Health and Performance).

"However, they use sports drinks, energy gels and bars frequently during training and competition; the sugar in these products increases the risk of tooth decay and the acidity of them increases the risk of erosion. This could be contributing to the high levels of tooth decay and acid erosion we saw during the dental check-ups."

The study builds on research carried out by the Centre since the London 2012 Olympics, led by Professor Ian Needleman. Previous findings have suggested that elite athletes may also face an elevated risk of oral disease from a dry mouth during intensive training.

Encouragingly, the surveyed athletes said they would consider adopting even better oral hygiene habits to tackle this and an intervention study has already been piloted.***

Dr Gallagher said: "Athletes were willing to consider behaviour changes such as additional fluoride use from mouthwash, more frequent dental visits, and reducing their intake of sports drinks, to improve oral health."

"We subsequently asked some of them and support team members to help us design an oral health intervention study, based on contemporary behaviour change theory and we will publish the results soon."

BLOCKCHAIN. Researchers at the University of Copenhagen have developed a prototype of an app that may potentially prescribe the optimal dose of medicine for the individual patient, as well as prevent counterfeit products.

Big data. Machine Learning. Internet of Things. Blockchain. Futuristic concepts from the world of technology will likely soon find their way into your medicine cabinet - and onto your mobile phone.

Using a prototype app for smartphones, researchers from the University of Copenhagen have taken the next step in the dosing, production and distribution of the pharmaceutical products of the future. And the time for innovation is more than ripe, says Professor Jukka Rantanen of the Department of Pharmacy:

'200 years ago, the first patent on making tablets was filed and the products have not changed much since. We are still having the same tablets. What we are doing now is suggesting a totally new type of product', he says.

'By rethinking the product design principles, related manufacturing solutions and distribution models for the pharmaceutical products, it is possible to dramatically reduce the overall price of medicine while also improving the safety and efficacy of the medication'.

App-othecary

The core of Jukka Rantanen and his research group's wager for a future solution for pharmaceutical products is the new concept of cryptopharmaceuticals, embodying the mentioned prototype of an app for smartphones.

The app is called 'MedBlockChain' and has been developed by the group's former MSc-student Lasse Nørfeldt. It is, among other things, based on the research group's earlier work on digitalisation of pharmaceutical products, for example in the form of printing medications as edible QR codes.

With the app, patients will be able to scan a medication and receive confirmation that it is a genuine product and not a fake item. A problem that, according to Jukka Rantanen, is particularly serious in countries with less structured medicines regulatory agencies.

At the same time, patients can choose to provide access to a range of personal data - everything from heart rate monitor watches, pedometers and internet-connected bath scales to genetic profiles, screen time and social media usage - all contributing with knowledge that can enable computer systems based on artificial intelligence to gradually pin down the optimal dose for each patient.

'This type of data already exist in our information-rich society. It would be logical to employ this big data for something useful. Not just for sharing on Facebook, your exercise app or something like that, but also for defining your optimal dose of given medicine', says Jukka Rantanen.

Builds on Blockchain

With the growing mass of personal data, data security is also gaining importance, Jukka Rantanen points out.

To guarantee data security, the app uses the so-called blockchain technology, which is probably best known in connection with the cryptocurrency Bitcoin.

With blockchain, information - or data blocks - are linked in a chain that cannot be changed without simultaneously altering all other links of information in the chain. Thus, all changes will be detected and may be traced. If something looks suspicious, the system can also generate an alarm.

As an example, a patient who scans a QR code on his medication may be alerted by an alarm if the code does not match the one that the pharmaceutical company has entered into the system, or if the medication does not match with the prescription. Conversely, the pharmaceutical company may be alerted if an otherwise unique medication code is registered more than once.

Likewise, an absence of registrations may form the basis for alarms as it may reveal that the patient is not taking his or her medication as planned. This information may for example be shared with the patient's doctor or relatives.

Cryptopharmaceuticals

The blockchain concept may still seem distant to most people, but in fact, the technology is already being used in similar ways for everything from insurance and finance to shipping and food, explains Jukka Rantanen.

As an example, Chinese consumers have already become accustomed to scanning items in the supermarket to confirm that the product they are buying is, for example, indeed bacon produced in Denmark, and not a counterfeit product.

'All of this is technologically possible. Now, the big question is how we should handle all of this data and who should get access to it. That is the discussion we hope to start with this new concept of cryptopharmaceuticals', says Jukka Rantanen.

He emphasises Denmark as an obvious candidate as a pioneer country for the technology. Among other things based on the country's existing tradition of storing citizens' health data and prominent pharmaceutical industry.

'I think it has huge potential for Denmark to be among the first movers on this type of product. It is not limited to only one clinical condition. There could be a completely new type of product family coming out of this', says Jukka Rantanen.

For the research team at the University of Copenhagen, the next step is to test the app on a test group of patients. This could for example be diabetes, where patients are most often accustomed to taking medication and measuring their personal blood sugar on a regular basis.

The 'MedBlockChain' app may be downloaded from the App Store and Google PLAY. Note that this product is not final, but an illustrative prototype.

* What is Blockchain? *

A blockchain is a growing chain of data where each link - or block - is connected by means of a special, encrypted code.

Each block has its own timestamp and contains information on previous blocks. Therefore, you can always go back and trace what has happened along the way.

A network of computers, often in a huge number, shares the chain of data blocks. When new blocks are added, it will be confirmed by all the computers in the network, using a consensus mechanism.

The design makes blockchains almost impossible to manipulate. It is thus a very secure way to process and store data.

Despite the fact that people in sub-Saharan Africa are now living longer than they did two decades ago, their average life expectancy remains below that of the rest of the world population. A new study looked into the importance of various causes of death in Zambia and how eliminating the most prominent of these would impact life expectancy in the country.

In 2018, the average life expectancy in Africa was 61 years for men and 64 years for women, while the average global life expectancy was 70 years for men and 74 years for women. Life expectancy is commonly used as an indicator of a population's general health and wellbeing, where populations with low life expectancies generally have problems maintaining health and longevity, while the opposite is true for populations with higher life expectancies. Improvements in terms of health and welfare are credited as one of the main reasons why life expectancy on the continent has been on the rise over the last two decades. Governments however need information on the most prominent causes of death in their countries for health policy formulation, planning, targeting, allocation of resources, monitoring, and the evaluation of existing population health programs and interventions. Unfortunately, in most African countries, this information is not readily available as death registration is incomplete due to inefficient and rudimentary civil registration systems and the fact that most deaths occur at home and are therefore seldom attended by medical professionals.

In their study published in the journal Tropical Medicine and International Health, researchers from IIASA, the University of the Witwatersrand, and the University of Zambia analyzed the World Health Organization's Zambia Sample Vital Registration with Verbal Autopsy (SAVVY) survey data to determine the main causes of death among adults in in the country. What sets this new study apart from previous work on the subject is that the researchers also endeavored to quantify the relative importance of causes of death in terms of the years of life expectancy gained if a specific cause of death were to be eliminated. The study further explored the data to determine whether there were any age-sex cause-specific mortality patterns for the five major causes of death identified within the adult age group and if there was any kind of socioeconomic or regional disparity in the causes of death among the adult population.

"There is a great demand for analyzing SAVVY data in order to understand cause of death patterns specific to Zambia. An empirical investigation based on real data gives crucial input to prioritize health investments that could help to minimize premature deaths, which could in turn have immense implications on the economic and physiological wellbeing of the country," explains Nandita Saikia, a former postdoctoral researcher at IIASA and one of the authors of the study.

One of the biggest health issues that Africa has been plagued with is the HIV/AIDS epidemic, which is widely cited as the main reason for the continued lower life expectancy on the continent compared to that of the rest of the world's population. The study results show that HIV/AIDS indeed also remains the leading cause of death among Zambian adults in the age group 15 to 59 years, with higher proportions among women than men. For men, injuries and accidental deaths was the second leading cause of death, while for women it was tuberculosis. The researchers however point out that some HIV/AIDS deaths might have been misclassified as tuberculosis deaths as the two are closely associated. Malaria and non-communicable diseases of the circulatory system each also accounted for a significant portion of deaths, although the ranking of these diseases varied by gender.

The study indicates that a notable number of additional years of life expectancy would be gained across the population by eliminating especially HIV/AIDS in the adult age group. For the male population, the number of years gained would be 5.77 years, while for the female population it would be 6.40 years in the 15 to 59 age group. Eliminating tuberculosis and malaria in the country could also increase adult life expectancy by between 1.09 and 1.71 years. In addition to the above, the analysis shows a correlation between level of education and the prevalence of HIV/AIDS, along with a strong regional variation in cause of death patterns, especially in terms of HIV/AIDS deaths, which varied between 25.5% in the northern province to 45.1% in the western province of Zambia.

"Our findings reiterate the importance of continuous health investment towards eradicating diseases like HIV/AIDS in terms of treatment, awareness, education, and prevention. At the same time, interventions should take into account age-sex or socioeconomic characteristics. For instance, while men might need more interventions to reduce injury-related deaths, women might need access to more treatment for diseases like HIV/AIDS or tuberculosis," concludes study lead author Vesper Chisumpa, a PhD student at the University of the Witwatersrand and a lecturer at the University of Zambia.

Researchers from The University of Queensland and University of Cambridge are exploring ways to help scientists better protect their work from the influence of the food industry.

With rising obesity levels, and significant public interest in diet and health, the ethics surrounding research in this area is centre-stage.

UQ School of Public Health nutrition expert Dr Katherine Cullerton said scientists have long been divided on the best way to manage industry involvement in diet and health research.

"While some scientists feel that the food industry should never be involved, many take the view that achieving healthier diets among whole populations will require actions by the food industry - and for these actions to be effective it requires new research and access to food industry data," Dr Cullerton said.

"As government funding for research is poorly available in some nations, more academics are looking to industries to contribute funding.

"This is a particular challenge in low income countries, which represent important, emerging markets for food companies."

The study sought to build consensus on this issue through seeking the views of population health researchers and research stakeholders (e.g. funders, policy officers and journals) internationally.

"The research found high levels of agreement among researchers and research stakeholders for many principles designed to prevent or manage conflicts of interest," she said.

"More contentious were principles that required values-based decision-making, such as determining which organisations in the food sector are acceptable to interact with.

"Our study, however, showed there was in fact consensus on many of the principles, although researchers are divided on what is acceptable when it comes to funding and interactions with these companies," she said.

"Companies in the food industry want to influence food and public health policy in their favour.

"They fund certain areas of research for many reasons; one reason can be to deflect attention away from products that are associated with poor health outcomes."

This research highlights the fact that greater understanding of the risks associated with accepting food industry funding or simply interacting with food companies was necessary.

"Some researchers are unaware that they are susceptible to conflicts of interest or that they might be at risk of unconscious biases adversely affecting their science," Dr Cullerton said.

"Ultimately, all of these factors represent significant reputational risks for researchers."

In the final stage of this research, Dr Cullerton and her colleagues in Cambridge will develop internationally-agreed guidance and a toolkit to help researchers better manage the risks resulting from interacting with the food industry.

In a new study, researchers at the University of Illinois and the Missouri University of Science and Technology modeled a method to manipulate nanoparticles as an alternative mode of propulsion for tiny spacecraft that require very small levels of thrust.

The team simulated a system that uses light to generate an electromagnetic field. Neutral nanoparticles made from glass or some other material that insulates rather than conducts electric charges are used. The nanoparticles become polarized. All of the positive charges are displaced in the direction of the field and negative charges shift in the opposite direction. It creates an internal electric field that produces a force to move the particles from a reservoir, funneled through an injector, then shot out of an accelerator to produce thrust.

The study, that has been about eight years in the making, analytically showed that the technique can work, and suggested parameters for success.

"The challenge is in selecting the right permittivity of the medium, the right amount of charge, in which all of this happens," said Joshua Rovey, associate professor in the Department of Aerospace Engineering in The Grainger College of Engineering at the U of I. "You have to choose the right materials for the nanoparticles themselves as well as the material surrounding the nanoparticles as they move through the structure."

The technique is based on a field of physics called plasmonics that studies how optical light or optical electromagnetic waves, interact with nanoscale structures, such as a bar or prism.

Rovey explained when the light hits the nanoscale structure, a resonant interaction occurs. It creates strong electromagnetic fields right next to that structure. And those electromagnetic fields can manipulate particles by applying forces to nanoscale particles that are near those structures. The study focused on how to feed the nanoparticles into the accelerator structure, or injector and how the angles of the plates in the injector affect the forces on these nanoparticles.

"One of the main motivating factors for the concept was the absence of or lack of a power supply in space," Rovey said. "If we can just harness the sun directly, have the sun shine directly on the nanostructures themselves, there's no need for an electrical power supply or solar panel to provide power."

Rovey said this study was a numerical simulation. The next step will be to create nanoscale structures in a lab, load then into the system, apply a light source, and observe how the nanoparticles move.

Traditional medicines mostly function as inhibitors, attacking the disease-relevant proteins that cause cancer, by binding to their accessible pockets. Following this strategy, only ~20% of all proteins are chemically addressable, leaving some of the most relevant targets inaccessible to therapeutic development.

Targeted protein degradation (TPD) is a novel approach in drug development that could overcome this limitation, and currently represents a promising therapeutic strategy towards, for example, cancer treatment. TPD is based on small-molecules, generally called "degraders", which induce the degradation of proteins by re-directing ubiquitin E3 ligases towards the protein we aim to eliminate. In other words, utilizing the cell's Ubiquitin Proteasome System (UPS), which is our body's natural way of seeking out and destroying damaged proteins.

Until now TPD had been mostly studied from a structural perspective. Georg Winter's laboratory at CeMM focused on identifying and mechanistically understanding genetic determinants of sensitivity to small-molecule degraders. "We selected a representative set of five degraders, which hijack different ubiquitin E3 ligases to degrade proteins of clinical relevance, such as BRD4, CDK9, or GSPT1. Conducting resistance screens, we were able to identify genes that determine the efficacy of targeted protein degradation", explains Cristina Mayor-Ruiz, CeMM postdoc and co-first author of the study.

The data obtained identify central UPS regulators as essential for degrader efficacy. "When those proteins are perturbed, ubiquitin E3 ligases lose their ability to flexibly assemble and disassemble in response to cellular needs. Instead, they start tagging themselves for destruction in a process called auto-degradation. As a consequence, the tested degrader drugs fail to destabilize their target proteins and are ineffective in blocking cancer cell growth", elaborates Martin Jaeger, CeMM PhD student and second co-first author of the study.

The research conducted by Cristina Mayor-Ruiz, Martin Jaeger et al. combining functional genomics and quantitative proteomics is the first study that comprehensively dissects cellular determinants of mechanistically different small-molecule degraders, bringing new light into their rational design.

"Now that degraders are entering the clinic, understanding potential resistance mechanisms may inform on ways to overcome it. The modulator gene-networks that we have identified can serve as biomarkers to support patient stratification, but also teach us a lot about fundamental aspects of the regulation and dynamics of the protein degradation machinery", says Georg Winter, CeMM Principal Investigator.

The deaths of 17 elderly people earlier this summer were the result of systemic failures in the public health system in England, according to a leading public health expert.

Writing in the Journal of the Royal Society of Medicine, Professor John Ashton describes a confused picture of what was happening when cases of listeria were first reported in June, with Public Health England apparently reluctant to divulge the full story. Five patients died with others affected across the country. Only a few weeks later it was reported that 12 people in Essex receiving community treatment for wounds had died from the spread of group 'A' streptococcus.

Professor Ashton draws comparisons with two major incidents that caused 41 deaths in the mid-1980s involving outbreaks of salmonella food poisoning and legionella. According to a 1988 enquiry, a lack of effective local environmental and communicable disease control was deemed to be central to both events.

"It is now time to digest these latest failings of a public health system that was only put in place six years ago as part of Andrew Lansley's structural changes to the NHS and for public health," he writes.

"The return of the public health function to local government in 2013 meant many directors of public health were placed in structures in which they are line managed by directors of adult social care, with restrictions placed on their scope for action and freedom of expression.

"There is a schism in which the clinical perspective in local government has been disappearing and the links between local authorities and the NHS have become ever more dysfunctional."

The lesson from history, he suggests, is that we should not embark on another re-organisational folly but rather find ways to strengthen what we now have and support its evolution into something fit for purpose.

A new study indicates that some exoplanets may have better conditions for life to thrive than Earth itself has. "This is a surprising conclusion", said lead researcher Dr Stephanie Olson, "it shows us that conditions on some exoplanets with favourable ocean circulation patterns could be better suited to support life that is more abundant or more active than life on Earth."

The discovery of exoplanets has accelerated the search for life outside our solar system. The huge distances to these exoplanets means that they are effectively impossible to reach with space probes, so scientists are working with remote sensing tool such as telescopes, to understand what conditions prevail on different exoplanets. Making sense of these remote observations requires the development of sophisticated models for planetary climate and evolution to allow scientists to recognize which of these distant planets that might host life.

Presenting a new synthesis of this work in a Keynote Lecture at the Goldschmidt Geochemistry Congress in Barcelona, Dr Stephanie Olson (University of Chicago) describes the search to identify the best environments for life on exoplanets:

"NASA's search for life in the Universe is focused on so-called Habitable Zone planets, which are worlds that have the potential for liquid water oceans. But not all oceans are equally hospitable--and some oceans will be better places to live than others due to their global circulation patterns".

Olson's team modelled likely conditions on different types of exoplanets using the ROCKE-3D software*, developed by NASA's Goddard Institute for Space Studies (GISS), to simulate the climates and ocean habitats of different types of exoplanets.

"Our work has been aimed at identifying the exoplanet oceans which have the greatest capacity to host globally abundant and active life. Life in Earth's oceans depends on upwelling (upward flow) which returns nutrients from the dark depths of the ocean to the sunlit portions of the ocean where photosynthetic life lives. More upwelling means more nutrient resupply, which means more biological activity. These are the conditions we need to look for on exoplanets".

They modelled a variety of possible exoplanets, and were able to define which exoplanet types stand the best chance of developing and sustaining thriving biospheres.

"We have used an ocean circulation model to identify which planets will have the most efficient upwelling and thus offer particularly hospitable oceans. We found that higher atmospheric density, slower rotation rates, and the presence of continents all yield higher upwelling rates. A further implication is that Earth might not be optimally habitable--and life elsewhere may enjoy a planet that is even more hospitable than our own.

There will always be limitations to our technology, so life is almost certainly more common than "detectable" life. This means that in our search for life in the Universe, we should target the subset of habitable planets that will be most favourable to large, globally active biospheres because those are the planets where life will be easiest to detect--and where non-detections will be most meaningful".

Dr Olson notes that we don't yet have telescopes which can identify appropriate exoplanets and test this hypothesis, but says that "Ideally this work this will inform telescope design to ensure that future missions, such as the proposed LUVOIR or HabEx telescope concepts, have the right capabilities; now we know what to look for, so we need to start looking".

Commenting, Professor Chris Reinhard (Georgia Institute of Technology) said:

"We expect oceans to be important in regulating some of the most compelling remotely detectable signs of life on habitable worlds, but our understanding of oceans beyond our solar system is currently very rudimentary. Dr. Olson's work represents a significant and exciting step forward in our understanding of exoplanet oceanography".

Professor Reinhard was not involved in this work, this is an independent comment.

EXOPLANETS

The first exoplanet was discovered in 1992, and currently more than 4000 exoplanets have been confirmed so far. The nearest know exoplanet is Proxima Centauri b, which is 4.25 light years away. Currently much of the search for life on exoplanets focuses on those in the habitable zone, which is the range of distances from a star where a planet's temperature allows liquid water oceans, critical for life on Earth.

*See ROCKE-3D website, https://data.giss.nasa.gov/rocke3d/maps/

Conference website: https://goldschmidt.info/2019/index

Research into the self-destruction of cells in humans and plants could lead to treatments for neurodegenerative brain diseases and the development of disease-resistant plants.

A study co-led by The University of Queensland's Professor Bostjan Kobe identified the role certain proteins play in cellular suicide.

"To sustain life, diverse organisms like humans and plants have cells that commit suicide for the benefit of the rest of the organism," Professor Kobe said.

"This is a key part of our own immune response - infected cells will often commit suicide, so the greater organism can live.

"Surprisingly though, studying proteins involved in the cell death process in human neurons has led us to discover how cell death also occurs in plants.

"We've found common ways human and plant cells bring about cell suicide."

The team used a combination of structural biology, biochemistry, neurobiology and plant science to analyse cells and proteins, laying the foundation for some potentially ground-breaking innovations.

"Neurodegenerative diseases affect millions of people worldwide, and come about for different reasons, but what connects them is the breakdown of brain cells," Professor Kobe said.

"A particular protein - SARM1 - is essential for this brain cell breakdown across different neurodegenerative diseases.

"We've provided crucial information about this protein - revealing its three-dimensional structure - that will accelerate the development of drugs that could delay or stop this breakdown."

A better understanding of cell death processes may also lead to the development of disease-resistant plants, helping boost yields, minimise waste and bolster food security.

"Food security is similarly an increasingly relevant problem worldwide," Professor Kobe said.

"Plant diseases account for more than 15 per cent of crops losses per year, before they're even harvested.

"Specific plant resistance genes can protect plants from disease, but how the products of these genes work has been poorly understood.

"Part of this resistance is that - similar to human neurons - infected cells self-destruct.

"Knowing how this process happens in neurons, we were able to find how resistance comes about in plants.

"This takes us a step closer to making effective synthetic resistance genes that can be used to provide additional protection in Australia and worldwide from crop diseases."

Researchers have uncovered a crucial link between dietary zinc intake and protection against Streptococcus pneumoniae, the primary bacterial cause of pneumonia.

Globally, it is estimated that nearly two billion people suffer from zinc deficiency, but why this increases susceptibility to bacterial infection has not been well understood - until now.

University of Melbourne Associate Professor Christopher McDevitt, a laboratory head at the Doherty Institute, led an interdisciplinary team using state-of-the-art imaging techniques to reveal how the immune system uses zinc as an antimicrobial for protection during attack by Streptococcus pneumoniae.

Published today in PLOS Pathogens, the team which included University of Adelaide Research Fellow Dr Bart Eijkelkamp, from the Research Centre for Infectious Diseases compared infections in mice fed with different levels of zinc.

They found that mice with lower zinc intake succumbed to infection up to three times faster because their immune systems had insufficient zinc to aid in killing the bacteria.

"Dietary zinc is associated with immune function and resistance to bacterial infection, but how it provides protection has remained elusive," Dr Eijkelkamp said.

"Our work shows that zinc is mobilised to sites of infection where it stresses the invading bacteria and helps specific immune cells kill Streptococcus pneumoniae."

This work also translated its findings by showing that specific human immune cells could use zinc to enhance their killing of invading Streptococcus pneumoniae.

"The findings in this paper are a direct result of application of novel elemental imaging technology to uncover relationships that have previously been hidden to analysis, and a testament to cross-disciplinary collaboration," said Professor Philip Doble, Director of the Elemental Bio-imaging Facility at the University of Technology Sydney, and a co-author of the study.

Pneumonia accounts for more than one million deaths every year, with the greatest health burden in countries where zinc deficiency frequently remains a major social challenge.

"Our findings highlight the importance of ensuring dietary zinc sufficiency as part of any population-wide strategy to control the burden of pneumococcal disease in conjunction with vaccination and other antimicrobial approaches," Associate Professor McDevitt said.'

Cells rely on protein complexes known as ATP synthases or ATPases for their energy needs - adenosine triphosphate (ATP) molecules power most of the processes sustaining life. Structural biologist Professor Leonid Sazanov and his research group from the Institute of Science and Technology Austria (IST Austria) in Klosterneuburg, Austria have now determined the first atomic structure of the representative of the V/A-ATPase family, filling in the gap in the evolutionary tree of these essential molecular machines. These results obtained using the latest cryo-electron microscopy methods revealed a turbine or water mill similar structure of the enzyme and have now been published in the journal Science.

Rotary power

ATP synthases/ATPases are large membrane protein complexes which share overall gross building plans and rotary catalysis mechanisms. This protein family includes F-type enzyme found in mitochondria (power factories of the cell), chloroplasts (organelles that conduct photosynthesis in plants) and bacteria; V (vacuolar)-type found in intracellular compartments in eukaryotes (higher organisms with a nucleus) and A (archaeal)-type found in prokaryotes - archaea (ancient microorganisms) and some bacteria.

Different flavors of ATPases

F- and A-type enzymes usually function to produce ATP, driven by proton flow across the membrane. V-type enzymes usually work in reverse, using ATP to pump protons. V- and A-ATPases are similar structurally but they differ from the F-type by having two or three peripheral stalks and additional connecting protein subunits between V1 and Vo. V-type enzymes probably evolved from the A-type and because of these similarities A-type is also termed V/A-ATPase. Some bacteria, including Thermus thermophilus, acquired an A-type enzyme. Long Zhou, postdoc in the Sazanov research group of IST Austria, has purified and studied this enzyme (ThV1Vo) by cryo-EM. In contrast to F-type, for V-type ATPases only the structures of the isolated V1 and Vo domains were determined previously. How V1 is coupled to Vo was therefore not known, and the knowledge about the full catalytic cycle was lacking.

Plasticity and competition

The scientists determined not one, but in total five structures of the entire ThV1Vo enzyme, using cryo-electron microscopy methods developed recently in the so-called "resolution revolution" of this technique. The structures represent several conformational states of the enzyme differing by the position of the rotor inside the stator. Global conformational plasticity of ThV1Vo is revealed as substantial V1 wobbling in space in transition from one state to another. It is a result of mechanical competition between rotation of the bent central rotor and stiffness of the stator. V1-Vo coupling is achieved via close structural and electrostatic match between the shaft and V-type specific subunit linking it to the c-ring. The visualization of the proton path revealed significant differences in the distribution of charged protein residues from that in F-ATPases, with a stricter "check-point" preventing "slipping" of the enzyme.

Why additional complexity?

Instead of a single peripheral stalk of F-type enzymes, A-types such as ThV1Vo have two peripheral stalks, while eukaryotic V-types have three. But what is the advantage of the additional complexity in the already very large protein assembly, along with additional subunits linking V1 and Vo? The F1/V1 domain has a three-fold symmetry and so one ATP molecule is produced (or consumed) per each 120° rotation of the stator inside F1/V1. Professor Leonid Sazanov says: "In V/A-ATPases this step is a one-off 120° rotation, in contrast to F-ATP synthase where it is divided into several sub-steps. Thus, greater plasticity may be required in ThV1Vo in order to link these 120° steps in V1 to smaller per c subunit steps in the Vo c12-ring. This additional flexibility may be afforded in V-types by the additional peripheral stalks and connecting subunits. Our new structures show how this is achieved, providing a framework for the entire V-ATPase family".

Plants, like humans and animals, have over millions of years evolved complex immune systems that fend off invading pathogens. But unlike many animals, plants lack adaptive immunity conferred by antibodies. This means each plant cell must defend itself against all potential pathogens - a daunting task.

Hiding inside each plant cell, protein complexes encoded by disease resistance genes are like sleeping armies, waking up and activating defenses when harmful pathogens such as fungi or bacteria are detected. Such genes encode traits used by agricultural biotechnologists to generate disease-resistant crops, and plant biologists are striving to illuminate every aspect of how they work - much of which remains shrouded in mystery.

In new research published in the journal Science, a team of biologists, including Colorado State University Assistant Professor of Biology Marc Nishimura, have shed new light on a crucial aspect of the plant immune response. Their discovery, revealing how plant resistance proteins trigger localized cell death, could lead to new strategies for engineering disease resistance in next-generation crops.

The research team was led by Nishimura, Jeff Dangl of the University of North Carolina at Chapel Hill, and Jeffrey Milbrandt of the Washington University School of Medicine. Nishimura started the work as a research scientist in the lab of Erin Osborne Nishimura, CSU assistant professor in the Department of Biochemistry and Molecular Biology.

Together with colleagues, Nishimura identified the mechanism of one little-understood domain of plant resistance proteins called a "toll-interleukin-1 receptor," or TIR domain. The team showed that during the plant immune response, the TIR domain is an enzyme that degrades a molecule called NAD+, which is essential for metabolism in all organisms. By cleaving NAD+, the plant self-destructs infected cells while leaving others unharmed.

Scientists had previously surmised that plant TIR domains might act like physical scaffolds, building a structure that attaches to the cell's plasma membrane and recruiting other proteins to the area to begin an immune response. This is how these domains work in animal cells, including in humans.

But in 2017, Nishimura's collaborators at Washington University School of Medicine observed an unusual animal TIR domain, found in a protein called SARM1, that doesn't work like other TIR signaling scaffolds in animal cells. Rather, it functions as an enzyme. Nishimura and colleagues set out to probe whether this domain could have a similar function in plant immunity.

Nishimura and colleagues' new work in Science shows that the role of TIR domains in the plant immune response is indeed functionally related to the role of the more unusual animal TIR domain in SARM1. They found that the plant TIR domain is itself an enzyme that cleaves NAD+, rather than acting as a structural scaffold that recruits other components. But there was an important difference. While the animal TIR domain in SARM1 kills cells by depleting NAD+ levels, plant TIR domains instead appear to cleave NAD+ to generate a signaling molecule. This molecule - not seen in animal cells - is structurally related to a classical signaling molecule called cyclic ADP-Ribose. The team is now working to understand how this new product they saw influences cell death and disease resistance.

"For 25 years, we didn't know what TIR domains did in plants," Nishimura said. "So these results were very interesting in terms of advancing our understanding of how TIR domains actually trigger immunity."

Uncovering individual biochemical pathways in the plant immune response may be crucially important to how plant systems are manipulated to protect food crops, particularly as new pathogens emerge and global food supplies become vulnerable, Nishimura said.

"Hopefully, really mechanistically understanding immune receptors will help us transfer existing receptors while retaining function, and ultimately let us rationally engineer new receptors to recognize emerging pathogens," he said.