Earth

A phase I/II clinical trial by researchers at Stanford University suggests that vaccines prepared from a patient’s own tumor cells may prevent the incurable blood cancer mantle cell lymphoma (MCL) from returning after treatment. The study, which will be published June 19 in the Journal of Experimental Medicine (JEM), reveals that the vaccines are a safe and effective way to induce the body’s immune system to attack any tumor cells that could cause disease relapse.

MCL is an aggressive form of non-Hodgkin lymphoma in which white blood cells known as B cells become cancerous and form tumors in the lymph nodes and other parts of the body. The disease is generally treated with a combination of chemotherapy and immunotherapy, often accompanied by a hematopoietic stem cell transplant to restore the body’s ability to form normal, healthy blood cells. But the cancer usually returns, and the average survival time for MCL patients is 5–7 years.

Ronald Levy and colleagues at Stanford University previously developed a tumor cell–based vaccine that prevents lymphomas from recurring in mice. Tumor cells isolated from the mice are loaded with CpG oligonucleotides, short fragments of DNA that mimic bacterial DNA and can prompt an immune response against the cells when they are injected back into the mice. “Guided by these preclinical results, we designed a phase I/II clinical trial (NCT00490529) to evaluate the therapeutic potential of a similar vaccination approach as an additive to standard stem cell transplantation for patients with MCL,” Levy says.

In the trial, 47 MCL patients who had achieved remission through standard immune- and chemotherapies were vaccinated with their own, CpG-loaded, tumor cells. The patients’ immune cells were then collected and saved while the patients received a stem cell transplant. Finally, the immune cells were transferred back into the patients, who were then monitored for signs of their MCL returning.

The vaccination regimen appeared to be safe, causing no side effects beyond those normally associated with stem cell transplants. Over the following year, 89% of the patients remained free of minimal residual disease (MRD), meaning that their blood contained too few cancer cells to form any new tumors. “That surpasses previously reported MRD-free rates for MCL patients,” Levy says.

Of the patients, 40% formed immune cells capable of directly attacking and killing cancer cells. These patients appeared to be especially well protected from disease relapse, going much longer without any recurrence of MCL, even if their tumors contained genetic mutations associated with a poor prognosis.

“Overall, our data demonstrate that the addition of a CpG-activated whole cell tumor vaccination followed by adoptive transfer of vaccine-primed immune cells to the treatment of MCL is feasible, safe, and can induce immune responses that are associated with a superior clinical outcome,” Levy says. The researchers are now considering ways to improve the immune response to tumor cell vaccination still further.

Walter and Eliza Hall Institute researchers have made significant advances in understanding the inflammatory cell death regulatory protein MLKL and its role in disease.

In a trio of studies published today in the journal Nature Communications, the team used advanced imaging to visualise key steps in the activation of MLKL, revealing previously unseen details about how this protein drives an inflammatory form of cell death called necroptosis. They also showed for the first time that inherited variants of MLKL are connected to a human inflammatory disease. By examining sequence variations in human MLKL and comparing the structure of different animals' MLKL proteins, the team also provided evidence for MLKL having been subject to evolutionary pressures, potentially through its role in protecting against infections.

The multidisciplinary research was led by Dr Andre Samson, Dr Joanne Hildebrand, Dr Maria Kauppi, Ms Katherine Davies, Associate Professor Edwin Hawkins, Associate Professor Peter Czabotar, Professor Warren Alexander, Professor John Silke and Associate Professor James Murphy.

At a glance

- MLKL is a protein that is required for cells to die by an inflammatory process called necroptosis.

- In three concurrent publications, a multidisciplinary team has greatly advanced the understanding of the structure and function of MLKL.

- The team also revealed that alterations in MLKL are associated with a human inflammatory disease, and provided evidence for evolutionary pressures having led to substantial variability in MLKL between different vertebrate species.

Understanding inflammatory cell death

Cell death is a way that the body protects itself from diseases, by removing unwanted or dangerous cells. In some situations - such as viral or bacterial infections - dying cells trigger inflammation to protect neighbouring cells from the infection. This form of cell death is called 'necroptosis', and is tightly controlled by specific proteins within cells.

Associate Professor James Murphy said the protein MLKL was an important regulator of necroptosis. "While MLKL and necroptosis protect our bodies from infections, excessive necroptosis has been linked with inflammatory conditions such as inflammatory bowel diseases," he said. "Our research team has taken several complementary approaches to better understand how MLKL functions - which could improve the understanding and treatment of diseases involving excessive necroptosis."

One study, led by Dr Andre Samson, used advanced imaging technologies to watch the MLKL protein in cells as they underwent necroptosis. Dr Samson said this identified two important 'checkpoints' in necroptosis. "We could see how MLKL changed its location as necroptosis occurred, clumping and migrating to different parts of the cell as the cell progressed towards death," he said.

"Intriguingly, we could see activated MLKL gather at the junctions between neighbouring cells - potentially suggesting a way for one dying cell to trigger necroptosis in surrounding cells, which could be a form of protection against infections."

Role of MLKL in inflammatory diseases

Dr Joanne Hildebrand and Dr Maria Kauppi examined links between alterations in the MLKL protein and inflammatory conditions. Dr Hildebrand said Institute researchers isolated a variant of MLKL that caused a lethal inflammatory condition in laboratory models. "We discovered this form of MLKL contained a single mutation in a particular region of the protein that made MLKL hyperactive, triggering necroptosis and inflammation," she said.

"By searching genome databases, we discovered similar variants in the human MLKL gene are surprisingly common - around ten per cent of human genomes from around the world carry altered forms of the MLKL gene that result in a more-easily activated, more inflammatory version of the protein.

The team speculated that the pro-inflammatory variant of MLKL might be associated with inflammatory diseases. "We looked more closely at databases of genomes of people with inflammatory diseases to understand the prevalence of MLKL variants. Indeed, people with an autoinflammatory condition chronic recurrent multifocal osteomyelitis (CRMO) were much more likely to carry two copies of a pro-inflammatory variant of the MLKL gene than people without an inflammatory disease. This is the first time changes in MLKL have been associated with a human inflammatory disease," Dr Hildebrand said.

Evolutionary pressure on MLKL

Dr Hildebrand said the high frequency of MLKL variants in humans around the world suggested that the more inflammatory variants of the protein might have offered an evolutionary benefit at some point of human history. "Perhaps having a more inflammatory form of MLKL meant some people could survive infectious diseases better than those people who only had the less-easily activated form of the protein," she said.

In a separate paper, Ms Katherine Davies led research investigating the three-dimensional structure of MLKL in different vertebrate species, using the Australian Synchrotron and CSIRO Collaborative Crystallisation Centre.

Dr Davies said usually when one protein is found in different vertebrate species, the proteins in the different species have a similar structure that has been conserved during evolution. "To our surprise, the structures of MLKL were quite different between different vertebrate species - even between closely related species such as rats and mice. In fact, rat MLKL is so different from mouse MLKL that the rat protein cannot function in mouse cells - which is surprising as many proteins are interchangeable between these two species," Dr Davies said.

"We think that evolutionary pressures such as infections may have driven substantial changes in MLKL as vertebrates evolved. Animals with variant forms of MLKL may have been able to survive some pressures better than other animals, driving changes in MLKL to accumulate, much faster than for many other proteins.

"Together with the data for human variations in MLKL, this suggests MLKL is critical for cells to balance beneficial inflammation, which protects against infections, with harmful inflammation that causes inflammatory diseases," Dr Davies said.

Long-term research yields rewards

Associate Professor James Murphy said the team's research started through studying the inflammatory variant of MLKL more than 13 years ago - at a time when MLKL's role in necroptosis was not known.

"Our most recent discoveries, made by a multidisciplinary research team, have provided a massive advance to the field of necroptosis, adding substantial detail to our understanding of MLKL. This will provide an enormous boost to a range of research into inflammatory diseases. Our team and others are already working to develop new medicines that could temper MLKL-driven inflammation, which we hope could be a new approach to treating a range of inflammatory diseases," Associate Professor Murphy said.

A high-resolution paramagnetic resonance detection method based on the diamond nitrogen-vacancy (NV) color center quantum sensor was proposed and experimentally implemented in a study led by academician DU Jiangfeng from CAS Key Laboratory of Microscale Magnetic Resonance of University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS).

The researchers obtained the single-spin paramagnetic resonance spectrum with kilohertz (kHz) spectral resolution. The study was published in Science Advances.

A major development trend of electron paramagnetic resonance spectroscopy is to get as accurate information as possible from as few samples as possible, which requires enhancing both spatial resolution and spectral resolution. In recent decades, the spatial resolution has been improved considerably, and the detection of single-spin paramagnetic resonance even reached to the nanoscale due to the emergence of new detection technology. However, the spectral resolution remains in the megahertz (MHz) scale because of uncontrollable external noise. Therefore, a new method has to be found in order to break through the current limitation of spectral resolution caused by noise.

One more direct and effective way is to make the measured spin naturally insensitive to external noise. A certain kind of spin states can resist the disturbance of external magnetic field noise, and the spectral lines generated by electron when transiting between these spin states will be narrowed. It has been reported that this phenomenon also exists for a kind of paramagnetic material under zero magnetic field in previous research. However, the detection sensitivity of traditional paramagnetic resonance technology is related to the magnitude of magnetic field, and the detection efficiency in zero field is extremely low, which limits the practical application.

Therefore, the researchers used NV color center quantum sensor in diamond to detect paramagnetic resonance. Previous work has proved that the NV color center still has single-spin level detection sensitivity even at zero field.

In order to observe the narrowing of the spectral lines and realize high-resolution spectroscopy detection, it is also necessary to eliminate the broadening of the spectral line caused by the NV sensor itself. Inspired by the correlation detection in nuclear magnetic resonance (NMR), DU's team designed a paramagnetic resonance correlation sequence suitable for zero field, which greatly suppressed the intrinsic broadening of NV sensors.

Using this new method, they successfully detected the narrowing transition of the electron spin of a single nitrogen atom in diamond in their experiment. Compared with the traditional method, the spectral resolution has been improved considerably by 27 times, reaching 8.6 kHz.

This experimental results showed that the paramagnetic resonance technology based on NV quantum sensor can achieve both high spatial and high spectral resolution. At the same time, this method is not limited by harsh environmental conditions (such as vacuum or low temperature), which is very competitive in biological applications. More detailed information of structural, dynamic changes and local environmental characteristics of a single molecule can be analyzed.

Kanazawa, Japan - Neuroblastoma is one of the most common cancers in children and has limited treatment options. In a new study, researchers from Kanazawa University retrospectively analyzed children with refractory or relapsed high-risk neuroblastoma who were treated with 131I-metaiodobenzylguanidine (131I-MIBG) and discovered a favorable prognosis in these patients.

Neuroblastoma forms in organs that embryologically originate from nerve tissue, such as the adrenal glands or the nervous system, and is the most common solid tumor that occurs in children in areas outside the head. Neuroblastoma patients can be divided into three distinct risk groups based on the child's age, cancer stage, and the morphology of the cancer. While children in the low- and intermediate-risk groups can often be cured by surgery or chemotherapy and thus have favorable outcomes, children in the high-risk group have to undergo more aggressive chemotherapy, stem cell transplantation or radiation with limited success and overall poor prognosis.

"Up to 50% of the children in the high-risk group do not respond to available treatment options. Even if they do, many of the affected children have a relapse following treatment," says corresponding author of the study Seigo Kinuya. "Given that fewer than 50% of children survive five years following diagnosis, our goal was to investigate new treatment avenues for children with high-risk neuroblastoma."

To achieve their goal, the researchers turned to 131I-MIBG, which is a radiation-emitting form of MIBG. MIBG is structurally similar to norepinephrine, a hormone produced by nerve tissues, and thus enriches in those tissues. Although it has been available since 1986, it was not until recently that a high-dose of 131I-MIBG has found regular use in clinical settings. The researchers therefore retrospectively investigated 20 patients with refractory or relapsed high-risk neuroblastoma who were treated with high-dose 131I-MIBG at Kanazawa University Hospital to analyze the efficacy of the drug as well as the outcome of the patients within a 5-year period.

The researchers found that in the 19 patients with complete follow-up data, the so-called event-free survival rate, which describes the time after treatment that the patient remained free of complications, was 42% at 1 year and 16% at 5 years. The overall survival, which describes the time that patients diagnosed with the disease are still alive, was 58% at 1 year and 42% at 5 years. Intriguingly, the researchers found that patients had a significantly higher likelihood of survival if they underwent 131I-MIBG therapy in less than 3 years following diagnosis, had no pain, had a tumor that did not increase hormone synthesis upon 131I-MIBG treatment, or had a Curie score 131I-MIBG therapy, which is a diagnostic scoring system used to measure the extent of neuroblastoma. Although all patients showed signs of hematological side effects, such as decreases in blood cell counts requiring transfusions or stem cell transplantation, non-hematological side effects were present in only one patient, who complained of anorexia and nausea.

"These are striking results that show that high-dose 131I-MIBG therapy could provide favorable prognosis in certain high-risk neuroblastoma patients," says Kinuya. "Our findings could provide the foundation for a new treatment option for neuroblastoma."

What The Study Did: State guidelines for ventilator allocation decision-making during the COVID-19 pandemic are examined in this review.

Authors: Gina M. Piscitello, M.D., of Rush University in Chicago, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.12606)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

#  #  #

Media advisory: The full study and commentary are linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.12606?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=061920

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

A new study of albatrosses has found that wind plays a bigger role in their decision to take flight than previously thought, and due to their differences in body size, males and females differ in their response to wind.

With a wingspan of over three meters --the largest of any bird alive today-- the wandering albatross can fly thousands of miles, even around the world, gliding for long periods in search of fish or squid. Birds search for prey in flight and capture it after landing on the sea surface. Due to their long wings, taking off from the sea surface is by far their most energetically demanding activity, requiring four times more energy than gliding flight.

Now, research by University of Liverpool scientists published in the Journal of Animal Ecology, sheds new light on the previously neglected role of wind in the flight decisions of seabirds.

Using GPS loggers, researchers tracked the flight patterns of over 300 albatrosses from two major populations in the Southern Ocean, one of the windiest areas on the planet.

By combining tracking data with computer modelling, they found that the seabirds wait on the sea surface for winds to pick up before attempting to fly again. They also found that males, which are 20% bigger than females, wait for stronger winds to help them take off from the ocean surface and sustain their flight.

University of Liverpool seabird ecologist and lead author of the study, Dr Tommy Clay, said: "Albatrosses are the oceans' great voyagers and are well-known for their ability to glide on winds with barely a flap of their wings.

"Our study reveals that albatross behaviour is fine-tuned to the winds they encounter. In order to save energy, birds rely on strong winds for take-off, males more so than females.

"Ongoing changes to wind patterns as a result of climate change may pose different risks to males and females. In recent years, increases in wind speeds have led to higher breeding success, but as winds become less predictable, birds may be unable to adapt."

Changing wind patterns around Antarctica have seen reductions in wind speeds in more northerly areas, where females are more likely to feed, and increases in southerly areas, where males are more common, which could affect how far they can travel to find food and their body condition.

These changes are more likely to benefit males. However, more research is needed to determine the long-term effects on populations.

The fieldwork was conducted over a seven year period in the remote sub-Antarctic islands of South Georgia in the south-west Atlantic Ocean and Crozet in the south-west Indian Ocean.

The analysis was led by researchers at the University of Liverpool in collaboration with an international and highly interdisciplinary team.

During a person's life, the experience of a stressful life event can lead to the development of depressive symptoms, even in a non-clinical population. For example, a relationship breakup is a fairly common event and is a powerful risk factor for quality of life, in addition to increasing the risk of a major depressive disorder.

Resting-state neuroimaging studies have increasingly identified abnormal whole-brain communication in patients with depression, but it is currently unclear whether depressive symptoms in individuals without a clinical diagnosis have reliable neural underpinnings. Therefore, not enough attention has been paid to and not enough reliable neurological data are available concerning the symptoms of depression that some individuals may present at some time in their life without a clinical diagnosis, having been exposed to a stressful situation.

Research published in the advanced online edition of the journal NeuroImage: Clinical on 26 May studies whether individual differences in the severity of depressive symptoms following the breakdown of a relationship are associated to changes in resting-state whole-brain dynamics.

A study by Sonsoles Alonso Martínez, conducted under the supervision of Gustavo Deco, an ICREA research professor with the Department of Information and Communication Technologies (DTIC) and director of the Center for Brain and Cognition (CBC) at UPF, and co-author of the work, along with members of research centres at the European universities of Groningen (Netherlands), Oxford (UK), Aarhus (Denmark) and Minho (Braga, Portugal). Deco has contributed especially to the study methodology.

"In this study, we set out to investigate the dynamical complexity of the brain at rest by applying the intrinsic ignition framework to a dataset of 69 participants with varying degrees of depressive symptoms following a relationship breakup. We hypothesized that greater levels of self-reported depressive symptoms are associated with reduced global integration and reduced spatiotemporal variability in the functional organization of the brain", upholds Gustavo Deco, co-author of the study.

Intrinsic ignition analysis, proposed by Deco and Kringelbach (2017), both co-authors of the study, allows characterizing the degree of integration in the brain that results from spontaneous events arising over time. These events reveal the ability of a given region to start the propagation of neural activity (i.e., ignition) to other regions eliciting varying degrees of integration in the brain. In turn, integration reflects the capacity of the brain to become interconnected and exchange information.

"We investigated whether the severity of depressive symptoms in non-clinical individuals was associated with changes in the dynamical complexity of the brain at rest", the authors state. At the global level, ignition and ignition variability can be averaged across all brain regions to produce a global measure of integration and temporal variability, respectively. Temporal variability indicates the degree of dynamic flexibility, also referred to as metastability.

The results of the study revealed that the severity of depressive symptoms was associated with deficits in the brain's ability to integrate and process information globally over time. In addition, the researchers found that the majority of depressive symptoms were associated with reduced spatial diversity (i.e., hierarchy) and reduced temporal variability (i.e., metastability) in the functional organization of the brain.

Given the growing evidence that demonstrates altered resting-state dynamics across neuropsychiatric disorders, "our results in a nonclinical (yet vulnerable) population sample suggest the merit of investigating brain rigidity, understood as less complex brain dynamics, as a potential risk marker for mental health problems", the study authors conclude.

Sophia Antipolis - 19 June 2020: Voice analysis by a smartphone app identifies lung congestion in heart failure patients, allowing early intervention before their condition deteriorates. The small study is presented today on HFA Discoveries, a scientific platform of the European Society of Cardiology (ESC).1

"Speech is personal and as such, very small changes (related to the same person) can be detected - for example, the ability of parents to notice health issues by listening to their kids," said study author Professor Offer Amir, director of the Heart Institute, Hadassah Medical Centre, Jerusalem, Israel. "Today we report results of the first easy to use, non-invasive, personalised heart failure monitoring device. It requires a simple 30-second recording each day, in any language."

Heart failure is one of the leading causes of morbidity and mortality, affecting more than 26 million people worldwide, and is the leading cause of hospitalisation in the US and Europe. Tight surveillance of patients could reduce related hospitalisations and deaths.

In patients with heart failure, the pumping function of the heart is not working as it should. The most common symptom is shortness of breath, which is caused by water congestion in the lungs. Congestion can be life-threatening and early identification is crucial.

Lung congestion causes subtle changes in speech patterns, which may be a tool for assessing clinical status. Speech processing is currently used in a number of ways, for example converting text to speech and automatic voice recognition. This study examined the ability of a novel mobile application to distinguish between congested and non-congested states.2

The study included 40 patients admitted to hospital with acute heart failure and lung congestion. Patients were asked to record five sentences into a standard smartphone upon admission and then again just prior to discharge when they were no longer congested. The duration of each recording was 2-5 seconds. The researchers found that the technology successfully distinguished between the congested state at admission and the non-congested state at discharge.

Professor Amir said the system could be used to monitor heart failure patients at home. Physicians prescribe the app, patients download it to their smartphone and submit voice recordings when they feel well so the app can create a personalised "healthy" model. Each day patients add a recording, which the app compares to the healthy model. Small deviations denoting the start of fluid accumulation generate an alert, which physicians pick up from a designated web portal.

"Those with early signs of lung congestion could receive adjustments to their treatment, thereby preventing the need for hospitalisation," said Professor Amir. "As more speech samples are obtained, the model becomes increasingly sensitive to changes."

He added: "During the current COVID-19 pandemic healthcare professionals are transitioning many outpatient visits for heart failure patients to telemedicine platforms, highlighting the importance of remote monitoring to reduce the risk of exposure to coronavirus."

DURHAM, N.C. - The neighborhood a child grows up in may influence their health for years to come in previously invisible ways.

A long-term study of 2,000 children born in England and Wales and followed to age 18 found that young adults raised in communities marked by more economic deprivation, physical dilapidation, social disconnection and danger display differences in the epigenome -- the proteins and chemical compounds that regulate the activity of their genes.

The researchers say the study lends support to the hypothesis that gene regulation may be one biological pathway through which neighborhood disadvantage "gets under the skin" to engender long-term health disparities.

The differences were identified in genes previously linked to chronic inflammation, exposure to tobacco smoke, outdoor air pollution, and lung cancer and may put these people at risk for poorer health later in life. Epigenetic differences remained even after taking into account the socioeconomic conditions of children's families, and were seen in young adults who did not smoke or display evidence of high inflammation.

"These findings may help explain how long-term health disparities among communities emerge," said Aaron Reuben, a Ph.D. candidate at Duke who was the study's lead author. "They also tell us that children who look the same physically and are otherwise healthy may enter adulthood wired at the cellular level for different outcomes in the future."

It's not possible to know yet whether these differences are lasting or could be modified, Reuben said. "That is something we will need to continue to evaluate."

The study, appearing this month in the journal JAMA Network Open, drew from diverse data sources to characterize the physical, social, economic, and health and safety characteristics of children's neighborhoods across their childhood and adolescence. Data were gathered from local government and criminal justice databases, systematic observation of neighborhood conditions (via Google Street View) and detailed surveys of neighborhood residents. Researchers combined this high-resolution multi-decade neighborhood data with epigenetic information derived from blood drawn from participants at at age 18.

"The research is an important reminder that geography and genes work together to shape our health," said Avshalom Caspi, the Edward M. Arnett Professor of Psychology & Neuroscience at Duke and a senior author on the study.

In a journal commentary that accompanied the study, psychiatric epidemiologist at Harvard Medical School Erin Dunn noted that neighborhood-induced gene regulation differences "are likely implicated in many adverse health outcomes, spanning from mental health disorders to cancer, obesity, and metabolic diseases." She writes, "I hope that studies like this by Reuben and colleagues will prompt researchers to explore these complex concepts and to bridge social determinants of health with epigenetic processes."

The way animals compete and choose within their struggle to reproduce could have big consequences for extinction risk, according to new research from the University of East Anglia.

A new study, published today in Global Change Biology, shows how removing sexual competition and choice through enforced monogamy creates populations that are less resilient to environmental stress, such as climate change.

The research team looked at how flour beetles (Tribolium castaneum) coped with environmental and genetic stress after they had evolved under monogamous versus polyandrous mating patterns.

They say that their findings could help with conservation management, and where species are being bred in captivity.
Lead researcher Prof Matt Gage, from UEA's School of Biological Sciences, said: "Species around the world are undergoing mass extinction due to a range of factors such as climate change, habitat loss and genetic bottlenecks.

"These different stresses can trap populations within a reinforcing feedback loop known as the extinction vortex.

"We used this extinction vortex scenario to experimentally measure the importance of sexual competition and choice for population resilience."

The research team studied flour beetle populations that had been evolved in a lab for 10 years. While some lines of beetles were allowed to engage in a polyandrous mating pattern where each female was given a choice of five males every generation, another group were forced to be monogamous with no competition or choice.

After 95 generations of these two conditions, the team looked at how well the different lines coped with 15 further generations of different environmental and genetic stresses down a simulated 'extinction vortex'.

Prof Gage said: "We mimicked 'real life' scenarios facing biodiversity today through repeated cycles of stress from food limitation, exposure to heatwaves, and being forced through a genetic bottleneck.

"We found that the beetles from the monogamous history of selection could not cope with environmental or genetic stress in the vortex. They were much more likely to decline, and all had become extinct by the end of the trial.

"So the removal of competition and choice from reproduction had created populations that were weaker when facing environmental and genetic stress.

"By contrast, the beetles with a polyandrous background, where males had been forced to compete and females had been given the opportunity to choose their mates for reproduction, declined much more slowly with 60 per cent of the population still alive at the end of the study.

"It's not clear whether the forces that operate in the struggle to reproduce are positive or negative for population resilience. Darwin famously felt sick when he looked at the tail of a peacock because he could not understand how such a flamboyant structure could evolve if it hampered survival, but our study clearly shows how important this sexual selection is for maintaining wider population health.

"Our long-term experiment suggests that sexual selection is a positive force for population resilience by purging out bad genes and fixing in good genes, improving a population's overall genetic quality and therefore resilience for facing harsh environments or genetic stress."

The researchers say that their findings should apply to any species that reproduces sexually, experiences some degree of sexual selection, and faces environmental stress.

Prof Gage added: "We propose that, if an endangered species has an evolved mating pattern where competition and choice is evident, then that opportunity should wherever possible be given to maintain genetic health."

LEBANON, NH - The development of pancreatic cancer is driven by co-existing mutations in an oncogene involved in controlling cell growth, called KRAS, and in a tumor suppressor gene, called p53. But how these mutations cooperate to promote cancer is unknown. A new study co-led by Steven Leach, MD, Director of Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC), uncovers a direct link between these mutations and the mechanism that regulates cell activity, providing insight for future development of therapeutics that could hit this newly found target in pancreatic cancer.

The study is co-led by Leach; Omar Abel-Wahab, MD, Associate Member in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center (MSKCC); and Luisa Escobar-Hoyos, PhD, MSc, Assistant Professor of Therapeutic Radiology at Yale School of Medicine and former post-doc in the Leach laboratory at MSKCC. Dr. Escobar-Hoyos conceived of and performed the work and serves as lead author, while Dr. Leach serves as co-senior author and along with Dr. Abdel-Wahab supervised the work, both while at MSKCC and while at NCCC. "The most commonly mutated tumor suppressor gene in cancer, p53, dramatically rewires RNA splicing, the fundamental cell mechanism by which RNA is processed before being translated into protein. The rewiring is done in a manner that leads to further activation of the KRAS oncogene, the major 'driver' gene in human pancreatic cancer," explains Leach.

The team analyzed every known mRNA splice variant encoded by the human genome - more than 200,000 possible sequences, in hundreds of pancreatic cancer patients. Their findings, "Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer" are newly published in Cancer Cell. "Our paper shows that a new class of drugs that alter RNA splicing have selective activity against p53-mutant pancreatic cancers," says Leach.

This study shows that there are still fundamental mechanisms to be discovered in cancer that can lead to new treatment strategies. Based on these findings, next steps will be to design clinical trials that will evaluate these new drugs in patients with pancreatic cancer.

Osaka, Japan - Oxidative stress is the result of reactive oxygen species (ROS) generation, and can be damaging to cells and tissues. In a new study, researchers from Osaka University developed a novel dietary silicon (Si)-based antioxidant agent that suppressed the development and progression of kidney failure and Parkinson's disease in rodents.

ROS are generated as a result of metabolism and the immune response, but also during certain disease processes, contributing to continued tissue damage. Chronic kidney disease and Parkinson's disease are among those diseases that have been shown to result from oxidative stress. Although ROS encompass several different molecules, not all ROS are alike. While Hydroxyl (OH) radicals are highly damaging to tissues through their effect on cells and DNA, others, like hydrogen peroxide and superoxide anions, are important components of the normal immune response.

"Eliminating only hydroxyl radicals is important to avoid disrupting normal physiological processes," says lead author of the study Yuki Kobayashi. "Previous attempts to do so, like taking in hydrogen-rich water or breathing in hydrogen-containing air, have shown limited results. We wanted to develop a new dietary agent that efficiently enables the elimination of damaging hydroxyl radicals."

To achieve their goal, the researchers produced a novel Si-based agent from Si powder. Because the agent is taken by mouth, the researchers first evaluated the efficacy of the agent in an environment similar to that in bowels, that is, a pH of 8.3 and at 36°C. 1g of the new agent was able to generate 400 ml of hydrogen in 24 hours, which is the equivalent of drinking 22 liters of hydrogen-rich water. The new agent thus enabled the continuous production of high amounts of an OH-eliminating molecule.

But was it sufficient to protect tissues from being damaged by ROS? To address this question, the researchers turned to animal models of chronic kidney disease and Parkinson's disease. When they fed rats who had 5/6 of their kidneys removed with the Si-based agent, kidney function was preserved and tissue levels of oxidative stress as well as inflammation were significantly lowered, as compared with those of control animals. Similarly, when they fed animals with Parkinson's disease with the Si-based agent, degeneration of neurons responsible for the disease was significantly attenuated.

"These are striking results that show that our Si-based agent is effective in preventing the progression of chronic kidney disease and Parkinson's disease in well-established animal models," says corresponding author Shoichi Shimada. "Our findings could provide new insights into the clinical management of patients with these diseases, for which currently no curative approach exists."

Rare metals crucial to green industries turn out to have a surprising origin. Ancient global climate change and certain kinds of undersea geology drove fish populations to specific locations. As remains of the fish fossilized, they accumulated valuable elements and these fossil beds became concentrated deposits of such metals. This discovery could aid future prospects for deposits of so-called rare-earth elements in other undersea locations.

Did you know that key components for things like wind turbines, LEDs and rechargeable batteries rely heavily on a group of metals known as rare-earth elements and yttrium (REY)? At present, the world's supply of these metals mainly comes from mines in China; however, a large deposit near the Japanese island of Minamitorishima could soon help satisfy the ever-increasing demand. But how did the REY deposit get there and why that location?

"That story begins back in time in the Eocene epoch 34.5 million years ago, about halfway between now and the time of the dinosaurs," said Assistant Professor Junichiro Ohta. "At that time, several things happened that led to the REY deposit. Firstly, vast amounts of nutrients accumulated in the deep ocean. Secondly, the planet underwent cooling which altered sea currents, stirring up these nutrient deposits. The seamounts then caused upwellings of nutrients delivering them to the fish, which thrived as a result."

Surprisingly, it's these fish, or rather their fossilized remains around Minamitorishima, that account for the REY deposits. As the fish died and underwent fossilization, REY metals in the environment, which would otherwise remain diffuse, accumulate inside the fossils. The research group had previously made this fish-to-REY deposit connection, but how and when the fossil deposits formed was an open question until now.

"I'm really pleased we made this discovery by looking at fragments of bones and teeth," said Ohta. "It was a difficult but satisfying task dating the deposits by comparing fossils we uncovered against a database of fossils with known ages. Equally so was another way we dated the deposits, by measuring the ratio of osmium isotopes in seawater trapped in REY-rich mud and comparing those to established records."

The story of fish that became a useful resource for renewable energy technology is, ironically, parallel to that of the ancient organisms that became oil, which led to the very problems renewable technologies now aim to solve. And how could this study help?

"Based on this new theory for the genesis of REY deposits in the ocean, we can improve the way we find future deposits," said Ohta. "We can target the feet of large seamounts on the seabed, many of which are distributed from the western North Pacific Ocean to the Central Pacific Ocean, so are in theory accessible to Japan."

The REY sources by Minamitorishima could sufficiently satisfy current global demand for hundreds of years. However, getting to them may be extremely difficult as the deposit is just over 5 kilometers below sea level, and at present no resource has ever been commercially mined from such a depth. Additional or alternative sources may be useful so improved ways to find them would be a great benefit.

Lithium-ion batteries usually contain graphitic carbons as anode materials. Scientists have investigated the carbonic nanoweb graphdiyne as a novel two-dimensional carbon network for its suitability in battery applications. Graphdiyne is as flat and thin as graphene, which is the one-atomic-layer-thin version of graphite, but it has a higher porosity and adjustable electronic properties. In the journal Angewandte Chemie, researchers describe its simple bottom-up synthesis from tailor-made precursor molecules.

Carbon materials are the most common anode materials in lithium-ion batteries. Their layered structure allows lithium ions to travel in and out of the spaces between layers during battery cycling, they have a highly conductive two-dimensional hexagonal crystal lattice, and they form a stable, porous network for efficient electrolyte penetration. However, the fine-tuning of the structural and electrochemical properties is difficult as these carbon materials are mostly prepared from polymeric carbon matter in a top-down synthesis.

Graphdiyne is a hybrid two-dimensional network made of hexagonal carbon rings bridged by two acetylene units (the "diyne" in the name). Graphdiyne has been suggested as a nanoweb membrane for the separation of isotopes or helium. However, its distinct electronic properties and web-like structure also make graphdiyne suitable for electrochemical applications. Changshui Huang from the Chinese Academy of Sciences, Beijing, and colleagues have investigated the lithium-storage capabilities and electrochemical properties of tailor-made, electronically adjusted graphdiyne derivatives.

The scientists synthesized the graphdiyne derivatives in a bottom-up strategy by adding precursor molecules on a copper foil, which self-organized to form ordered layered nanostructures. Using monomers containing functional groups with interesting electronic properties, the authors prepared functional graphdiynes with distinct electrochemical and morphological properties.

Among these functional groups, those exerting electron-withdrawing effects reduced the band gap of graphdiyne and increased its conductivity, the authors reported. The cyano group was especially effective and, when used as an anodic material, the cyano-modified graphdiyne demonstrated excellent lithium-storage capacity and was stable for thousands of cycles, as the authors reported.

In contrast, when graphdiyne was modified with bulky functional groups (methyl groups) that donate electrons to the graphdiyne network, the authors observed a larger layer spacing, which made the material structure unstable so that the anode only survived a few charge and discharge cycles. The authors also compared both modified graphdiyne materials to an "empty" version where only hydrogen occupied the position of the functional groups in the network.

The authors conclude that modified graphdiyne can be prepared by a bottom-up strategy, which is also best suited to build functional two-dimensional carbon material architectures for batteries, capacitors, and other electrocatalytic devices.

New research on the two-dimensional (2D) material graphene has allowed researchers to create smart adaptive clothing which can lower the body temperature of the wearer in hot climates.

A team of scientists from The University of Manchester's National Graphene Institute have created a prototype garment to demonstrate dynamic thermal radiation control within a piece of clothing by utilising the remarkable thermal properties and flexibility of graphene. The development also opens the door to new applications such as, interactive infrared displays and covert infrared communication on textile.

The human body radiates energy in the form of electromagnetic waves in the infrared spectrum (known as blackbody radiation). In a hot climate it is desirable to make use the full extent of the infrared radiation to lower the body temperature that can be achieved by using infrared-transparent textiles. As for the opposite case, infrared-blocking covers are ideal to minimise the energy loss from the body. Emergency blankets are a common example used to deal with treating extreme cases of body temperature fluctuation.

The collaborative team of scientists demonstrated the dynamic transition between two opposite states by electrically tuning the infrared emissivity (the ability to radiate energy) of the graphene layers integrated onto textiles.

One-atom thick graphene was first isolated and explored in 2004 at The University of Manchester. Its potential uses are vast and research has already led to leaps forward in commercial products including; batteries, mobile phones, sporting goods and automotive.

The new research published today in journal Nano Letters, demonstrates that the smart optical textile technology can change its thermal visibility. The technology uses graphene layers to control of thermal radiation from textile surfaces.

Professor Coskun Kocabas, who led the research, said: "Ability to control the thermal radiation is a key necessity for several critical applications such as temperature management of the body in excessive temperature climates. Thermal blankets are a common example used for this purpose. However, maintaining these functionalities as the surroundings heats up or cools down has been an outstanding challenge."

Prof Kocabas added: "The successful demonstration of the modulation of optical properties on different forms of textile can leverage the ubiquitous use of fibrous architectures and enable new technologies operating in the infrared and other regions of the electromagnetic spectrum for applications including textile displays, communication, adaptive space suits, and fashion".

This study built on the same group's previous research using graphene to create thermal camouflage which would fool infrared cameras. The new research can also be integrated into existing mass-manufacture textile materials such as cotton. To demonstrate, the team developed a prototype product within a t-shirt allowing the wearer to project coded messages invisible to the naked eye but readable by infrared cameras.

"We believe that our results are timely showing the possibility of turning the exceptional optical properties of graphene into novel enabling technologies. The demonstrated capabilities cannot be achieved with conventional materials."

"The next step for this area of research is to address the need for dynamic thermal management of earth-orbiting satellites. Satellites in orbit experience excesses of temperature, when they face the sun, and they freeze in the earth's shadow. Our technology could enable dynamic thermal management of satellites by controlling the thermal radiation and regulate the satellite temperature on demand." said Kocabas.

Professor Sir Kostya Novoselov was also involved in the research: "This is a beautiful effect, intrinsically routed in the unique band structure of graphene. It is really exciting to see that such effects give rise to the high-tech applications." he said.

Advanced materials is one of The University of Manchester's research beacons - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet. #ResearchBeacons