Culture

RICHLAND, Washington -- A protein newly identified as important in type 1 diabetes can delay onset of the disease in diabetic mice, providing a new target for prevention and treatment in people, according to research led by scientists at the U.S. Department of Energy's Pacific Northwest National Laboratory and Indiana University School of Medicine. Because type 1 diabetes is incurable and has serious lifelong health consequences, prevention is a major research goal.

The key to the new study, published online January 9, 2020, in the journal Cell Metabolism, is a technique called mass spectrometry, which can comprehensively detect proteins that are found at extremely low levels in the body, but can have large effects on health.

The multidisciplinary research team of physicians and biochemists used a new strategy to pinpoint proteins in beta cells, a subset of pancreatic islets that increase or decrease in response to immune system attack. Beta cells normally regulate blood sugar levels in the pancreas. In people susceptible to type 1 diabetes (previously called insulin-dependent or juvenile diabetes) these cells are slowly destroyed by the body's own immune system. Here, the researchers focused on how islets respond to inflammation.

The researchers treated human pancreatic islets with substances produced by the body and thought to be involved in the diabetes disease process. They identified a total of 11,324 proteins, with 387 affected by the treatment. Of these 387, they narrowed their focus to one: growth differentiation factor 15 (GDF15).

"We wanted to identify proteins that can intervene in the diabetes disease process," said Ernesto Nakayasu, a biomedical scientist at PNNL and co-lead author of the study. "We became interested in GDF15 because the protein level was suppressed by 70 percent after treatment."

GDF15 is known for its protective effects in different types of cells in the human body but it had never been studied in islets. When the researchers measured levels of GDF15 in pancreas tissue from people with diabetes, they found the protein was depleted in their malfunctioning islet cells.

But the key piece of evidence emerged when the scientists treated non-obese diabetic mice with GDF15, and it reduced development of diabetes by 53%. Non-obese diabetic mice are a common model for testing type 1 diabetes treatments because they spontaneously develop autoimmune diabetes with many similarities to the human disease.

"We hypothesized that reduced GDF15 was not a good thing for islet survival, and indeed that was the case," said Raghu Mirmira, a study principal investigator. "This work opens the way for us to consider these sorts of 'islet protective factors' as therapies to prevent or reverse type 1 diabetes." Mirmira until recently served as professor of pediatric diabetes and director of the Center for Diabetes and Metabolic Diseases at Indiana University School of Medicine. He is now a professor of medicine in the Section of Endocrinology, Diabetes & Metabolism at the University of Chicago.

"This approach differs substantially from current thinking that targets the immune system. While GDF15 may be one new therapy, we identified other proteins that may work in conjunction with GDF15, so this work really represents a treasure-trove of information that can be mined for new therapies," said Mirmira.

PNNL's Tom Metz, the co-principal investigator and an expert in mass spectrometry-based proteomics of islets, agreed, adding, "This study illustrates the power of non-reductionist, comprehensive approaches, such as proteomics, for discovering new information in complex systems. The protective role of GDF15 against islet destruction and its ability to delay onset of type 1 diabetes in the mouse model would have been very difficult to discover without performing the initial comprehensive proteomics analysis of stressed human islets."

The researchers are now working on the idea that low levels of GDF15 in islets may somehow be playing a proactive role in instigating the autoimmune attack that ultimately kills them.

"This thinking is somewhat counterintuitive in the type 1 diabetes field, but it is this kind of out-of-the-box thinking that may lead to therapies we never thought of previously," said Mirmira.

Scientists could soon better investigate the feeding behaviors of extinct dolphin and whale species. A third year student at Japan's Nagoya University has found that the range of motion offered by the joint between the head and neck in modern-day cetaceans, a group of marine mammals that also includes porpoises, accurately reflects how they feed. The authors of the study, published in the Journal of Anatomy, suggest this method could help overcome current limitations in extrapolating the feeding behaviors of extinct cetaceans.

Taro Okamura of Nagoya University and Shin-ichi Fujiwara of the Nagoya University Museum examined the skulls and cervical skeletons of 56 cetaceans that are still in existence, representing 30 different species. They assessed the range of motion of the 'atlanto-occipital joint' in each skeleton, a joint that forms between the base of the skull and the first cervical vertebra. They then categorized each cetacean according to their well-studied feeding behaviors, including how they approach their prey, move it within their oral cavities, and swallow it.

"We found that the range of neck-head flexibility strongly reflects the difference of feeding strategies among whales and dolphins," says Okamura. "This index can be easily applied to reconstruct the feeding strategies of extinct whales and dolphins," he adds.

Cetaceans are known for their diverse behaviors, physiologies, ecologies and diets. Some cetaceans feed on organisms in the open water, while others feed on those found near the ocean floor. Some whales are ram feeders, widely opening their mouths to gather zooplankton and other actively swimming organisms into their mouths while moving forward. Other whales, like the sperm whale, suction their prey into their oral cavities. The orca whale and some dolphins bite the fish they catch into smaller segments, a process that may require head movement. Other dolphins swallow their prey whole.

Until now, scientists have used the structures of teeth, throat bones and lower jaws in cetacean fossils to develop an idea of what their feeding behaviors might have looked like. But these individual features can't accurately predict the behaviors of extinct cetaceans. For example, the teeth of some suction feeders, like those of the sperm whale, aren't suggestive of this kind of feeding. Okamura and Fujiwara propose that using a combination of features, which include the range of motion of the atlanto-occipital joint, could help to develop more accurate descriptions of extinct cetacean feeding behaviors.

In prehistoric times, many different types of cetaceans existed, including ones with walrus-like tusks, extremely long snouts, and an ancient sperm whale with huge predatory teeth. The ancient baleen whale had teeth, whereas modern-day baleen whales have 'baleen,' or fringed plates, in their place. This has created much interest in how baleen whale feeding, for example, has evolved from catching prey with teeth to filtering it with baleen.

The two researchers next plan to determine the atlanto-occipital joint range of motion in some of these cetacean fossils to attempt to develop reconstructions of how they used to feed. Answering these questions could help reveal the evolutionary process of the diverse feeding behaviors among cetaceans.

In a world first, University of Sydney researchers have found evidence of how hydrogen causes embrittlement of steels. When hydrogen moves into steel, it makes the metal become brittle, leading to catastrophic failures. This has been one of the major challenges in moving towards a greener, hydrogen-fuelled future, where steel tanks and pipelines are essential components that must be able to survive in pure hydrogen environments.

Published in Science, the researchers found hydrogen accumulates at microstructures called dislocations and at the boundaries between the individual crystals that make up the steel.

This accumulation weakens the steel along these features, leading to embrittlement.

The researchers also found the first direct evidence that clusters of niobium carbide within the steel trap hydrogen in such a way that it cannot readily move to the dislocations and crystal boundaries to cause embrittlement. This effect has the potential to be used to design steels that can resist embrittlement.

Lead researcher Dr Yi-Sheng Chen from the Australian Centre for Microscopy and Microanalysis and Faculty of Engineering at the University of Sydney said these findings were an important step to finding a safe solution to produce, store and transport hydrogen.

"These findings are vital for designing embrittlement-resistant steel; the carbides offer a solution to ensuring high-strength steels are not prone to early fracture and reduced toughness in the presence of hydrogen," Dr Chen said.

Senior author Professor Julie Cairney from the Australian Centre for Microscopy and Microanalysis and Faculty of Engineering at the University of Sydney said these findings were a positive step towards implementing clean fuels.

"Hydrogen is a low carbon fuel source that could potentially replace fossil fuels. But there are challenges with the use of steel, the world's most important engineering material, to safely store and transport it. This research gives us key insights into how we might be able to improve this situation," Professor Cairney said.

Working in partnership with CITIC Metal, the researchers were able to directly observe hydrogen at microstructures in steels thanks to Microscopy Australia's state-of-the-art custom-designed cryogenic atom probe microscope.

When a non-scientist tries to imagine a scientist, the image that often arises is one of a somewhat remote, rather idealistic genius sitting alone in their room or laboratory and somehow discovering the most amazing things without every having contact with the 'normal' world. But science is just as much a part of life as any other activity. So it's perhaps not all that surprising to learn that - just like in normal life - intuition can occasionally play a major role in scientific progress.

The importance of intuition was made very clear to Professor Samer Ezziddin and his team at the Department of Nuclear Medicine at Saarland University when they followed up on findings made during their medical research work into the treatment of patients with late-stage prostate cancer. The work centres around two receptors on the surface of the tumour. The first is known as prostate-specific membrane antigen (PSMA), a protein molecule that is very prevalent on the surface of prostate tumours. This surface receptor molecule acts as a gateway and provides a channel through which nuclear radiologists can smuggle radioactive substances into the tumour cells and thus destroy these malignant cells from the inside. The more PSMA molecules on the surface, the more radioactivity can be introduced into the cells without needing to increase the total dosage of radioactive substance being administered to the patient.

The second type of receptor is one that male sex hormones, such as testosterone, are able to dock onto. 'Prostate tumours need testosterone like a car needs petrol,' explains Professor Ezzidin. So one of the therapies used to treat prostate cancer involves blocking these receptor sites, which effectively stops the cancer from refuelling. 'One of the drugs used to block these receptors is enzalutamide and enzalutamide therapy is often very successful for a certain period of time, during which the tumour shrinks,' says Samer Ezzidin. 'But after a while - which might be several months, perhaps even two years if things go well - the drug stops working and the tumour starts to grow again.' Typically, the patient will then be taken off the expensive medication, as there would seem to be no reason to continue to administer it if it's no longer effective.

This is where the intuition of the Homburg research team comes to the fore. What may be of no use for one type of therapy (an ineffective drug) might turn out to be beneficial in another form of cancer therapy. 'We suspected, and later on we showed quite definitively, that the density of PSMA sites on the surface of the tumour cell increases when the adrogen receptor to which testosterone attaches is blocked,' says Ezzidin. The gut feeling within the research group, combined with the group's clinical observations, strongly suggested that this mechanism would still function in patients for whom the receptor-blocking drug (enzalutamide) was no longer itself therapeutically effective and was therefore no longer being prescribed.

The intuition of the medical research team proved to be spot on. 'We were able to prove that administering enzalutamide resulted in a significant increase in the PSMA density on the tumour surface, even though the drug was no longer effective in its original therapeutic sense and was no longer being prescribed for that purpose,' explains Samer Ezzidin. Despite the fact that only ten patients were involved the study, Professor Ezzidin believes that the results are compelling. 'After administering enzalutamide, we observed a significant increase in PSMA density on the tumour surface in all patients in the study. This allows us to introduce far more of the radioactive therapeutic agent into the tumour cells and thus irradiate them from the inside with irradiation paths that are down at the micrometre level,' says Ezzidin. As a result, PSMA radioligand therapy will be able to treat prostate tumours more efficiently and more selectively than has been possible in the past (see the following report for more details: https://www.eurekalert.org/pub_releases/2019-11/su-pcr112519.php).

'These findings now need to be subjected to further study and corroborated in a future research project,' explains Professor Ezzidin. 'But we wanted to publish our results as quickly as possible, as our findings may be of help to lots of patients. That's why we decided to first issue this short communication. I expect that even this small-scale study will lead to a drastic change in the therapy management regimens used when treating patients with advanced prostate cancer,' says Samer Ezzidin. And it's very likely that Professor Ezzidin's intuition will once again turn out to be right on the mark.

One of the last obstacles hindering the photography and filming of processes occurring on a scale of attoseconds, i.e. billionths of a billionth of a second, has disappeared. The key to its removal lies in the random nature of the processes responsible for the formation of X-ray laser pulses.

There are only a few X-ray lasers in the world today. These sophisticated devices can be used to record even extremely fast processes such as the changes in the electron states of atoms. The pulses generated by modern X-ray lasers are already short enough to be able to consider taking attophotos or even attofilms. However, what remained a problem was the X-ray optics itself. When an ultra-short X-ray pulse leaves the laser in which it was created, it can be extended in time over a dozen-fold. An international group of physicists under the supervision of Dr. Jakub Szlachetko and Dr. Joanna Czapla-Masztafiak from the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Cracow and Dr. Yves Kayser of the Physikalisch-Technische Bundesanstalt in Berlin has proved in Nature Communications that X-ray optics should no longer be an obstacle. The publication is the result of research conducted at the Linac Coherent Light Source (LCLS) X-ray laser at the SLAC National Accelerator Laboratory in Menlo Park, California.

"The best way to get rid of problems with X-ray optics was... to get rid of X-ray optics", laughs Dr. Szlachetko. "Instead of solving the problem, we found a way around it. It is interesting that we replaced the optics... by chance. Literally! We have shown that much better parameters than the current X-ray laser pulses can be obtained by skilful use of processes of a stochastic nature."

It is not the first case in the history of X-ray lasers when physics itself comes to the aid of designers. In classical lasers, the key element is the optical resonator. This is a system of mirrors that only strengthens photons of a certain wavelength, moving in a certain direction. X-ray lasers were for a long time considered impossible to construct due to the lack of mirrors capable of reflecting X-rays. This obstacle was eliminated when it was noticed that the resonator could be replaced... with relativistic physics alone. When an electron accelerated to velocity close to the velocity of light passes along a system of many alternately oriented magnets, it does not move in a straight line, but moves around it, losing energy at the same time. Relativistic effects then force the electron to emit high-energy photons not in any random direction, but along the original course of the beam of electrons (hence the name: Free-Electron Laser - FEL).

The high hopes associated with X-ray lasers are due to the fact that they can be used to record chemical reactions. Each single laser pulse can provide information about the current electron state of the system being observed (atom or molecule). At the same time, the pulse energy is so high that immediately after recording the image, the illuminated objects cease to exist. Fortunately, the observation process can be repeated many times. The images collected during a longer session enable scientists to accurately reconstruct all the stages of the studied chemical reaction.

"The situation can be compared to attempts to photograph events of the same type with a flash camera. When we take enough photos of a sufficient number of the same events, we can use them to construct a film with high accuracy showing what happens during a single event", explains Dr. Czapla-Masztafiak and explains: "The problem is that the pulses generated in X-ray lasers arise in spontaneous self-reinforcing stimulated emission and cannot be fully controlled".

The spontaneous nature of the pulses means that in X-ray lasers the parameters of subsequent pulses are not exactly the same. The pulses appear once earlier, once later, they also differ slightly in the energy of photons and their number. In the presented analogy, this would correspond to a situation when subsequent photos are taken with different flash units, in addition, activated at random moments.

The inevitable randomness of X-ray pulses forced physicists to mount additional optical diagnostic equipment in FEL lasers. As a result, even if the laser generated an original pulse of attosecond duration, it was extended by X-ray optics to femtoseconds. Now it turns out that to record the electronic states of atoms or molecules in a manner that allows for reconstruction of chemical reactions, impulses with precisely controlled parameters are not needed.

"Removing X-ray optics also allowed us to use of extremely high-energy pulses to study non-linear effects. This means that atoms begin to be transparent to X-rays at some point, which in turn is associated with an increase in absorption in a different range of radiation", explains Dr. Szlachetko.

The new method will be introduced in cooperation with IFJ PAN in experiments carried out using both current X-ray lasers: European XFEL near Hamburg (Germany) and SwissFEL in Villigen (Switzerland). The work related to testing the new technique in the context of chemical experiments was carried out in close cooperation with Dr. Jacinto Sa from the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw and the University of Uppsala.

In the context of the proposed technique, it is worth emphasizing that in the case of classical optics there are some purely physical limitations related to the resolution of the optical instruments, for example the famous diffraction limit. There are no physical limitations in the new method - because there is no optics. So, if X-ray lasers appear with even shorter pulses than those currently generated, the new technique can be successfully used in them.

Parrots are considered extraordinarily clever animals. Alex, the famous Harvard-based African grey parrot, communicated with a vocabulary of more than 500 human words, could answer questions and classify objects spontaneously. Scientists from the Max-Planck-Institute for Ornithology based at the research station outpost for parrot comparative cognition in the Loro Parque in Tenerife, Spain, have shown that parrots exhibit a high level of social intelligence and cooperativeness. They readily help others, even when there is no immediate opportunity for reciprocation. Moreover, they reciprocate received favours and do not appear jealous, if conspecifics obtain a better reward than themselves. This further supports that they have evolved a level of intelligence comparable to that of great apes, crows and dolphins.

In the laboratory in the Max-Planck-outpost research station for comparative cognition run in collaboration with the Loro Parque Fundación, in Puerto de la Cruz, Tenerife, the African grey parrot Bella obtains a few metal tokens from a human experimenter. She has learnt to exchange those tokens with one of the scientist against her favorite food. But there is a problem - the exchange hole in her testing chamber through which the exchange occurs has been blocked.

In the neighboring test chamber there is her friend Kimmi waiting. Her exchange hole for the token exchange is open. However, Bella notices that Kimmi is lacking any tokens. What is he going to do?

Indeed, the parrot female picks up token after token and passes them over to Kimmi though an opening in the wall separating the two neighbouring chambers. The latter, seemingly pleased, accepts those gifts and readily exchanges them against treats. Bella in the meantime, rather relaxed, observes how Kimmi benefits from her generosity, without knowing that at a later point in time, the other may return the favor.

Helping partners

According to the most recent scientific findings, other than humans, only some great apes species behave similarly selfless towards unrelated individuals in comparable studies. In contrast, all other species tested so far in did not seem to pay attention to the wellbeing of conspecifics. They either behaved indifferently or even selfishly in comparable test situations. „Our parrots indeed seem to have grasped that another individual requires their help in order to achieve a goal", says Désirée Brucks, first author of the study. If Kimmi's exchange hole was blocked too however, Bella did not bother to pass over tokens. The African grey parrots therefore appear to recognize exactly when a conspecific actually benefits from their help and when it would not.

In a second study, the same parrots proved their general "prosocial attitude", i.e. their willingness to help and capacity to attend to the wellbeing of others. Besides, they showed the ability to reciprocate the other's previous actions, following a "tit-for-tat" strategy, which is seen as an important prerequisite for the evolution of cooperation. In the experiment, the birds had to decide between two types of tokens. One of them rewarded just the subject, whereas the other token provided food to both the subject and its neighbor. "Initially the parrots chose randomly, without paying any attention to the wellbeing of their neighbor", explains Anastasia Krasheninnikova, first author of this study. „As soon as the parrots were tested alternatingly with their neighbor, they very rapidly learned to choose the token that benefitted both birds."

No jealousy if others get better treatments

Further more, the research team has shown in a third recent study that parrots apparently are not jealous if a conspecific receives a better payoff for the same work performance than themselves, or has to work less hard for the same payoff. „At first, this finding came as a surprise, given that a „sense of fairness" is considered a prerequisite for the evolution of cooperation", says Auguste von Bayern, the leader of the comparative cognition research group. If you are able to detect when somebody is cheating upon you, you can react and switch to a fairer and thus better cooperation partner.

Whereas the parrots remained easygoing, primates, for example, do not put up with such an unequal treatment but show clear signs of anger and at some point boycott the unfair game. Possibly, the explanation for this is that parrots tend to be life-long monogamous, i.e. they remain pair-bonded with a single partner throughout their lives, whereas primates typically maintain affiliative relationships and/or coalitions with several partners in parallel and switch partners often as new opportunities arise. „Given that parrots are so closely bonded with a single individual and thus so mutually interdependent, it does not make any difference if one of them gets a better pay-off once in a while. What counts is that together, they function as a unit that can achieve much more than each of them on their own (in addition to raising their joint offspring). This is probably why parrots are much more tolerant towards unequal treatment than species that are not long-term monogamous, while still being excellent cooperators", explains Auguste von Bayern.

Scientists at Martin Luther University Halle-Wittenberg (MLU) and Georg August University Göttingen have succeeded in proving that a claw disease in cows is primarily genetic. Until now, the occurrence of interdigital hyperplasia has mostly been attributed to poor hygiene conditions in the barn. However, a team led by Professor Hermann Swalve discovered a farm in which the disease occurred frequently and was able to identify the gene responsible. As a result, the disease may now be contained through selective breeding.

"We rarely see such a case where everything fits perfectly together," says Hermann Swalve, Professor of Animal Breeding at the Institute for Agricultural and Nutritional Sciences at MLU. Many factors have to fit in order to find a single gene that is primarily responsible for a disease. Swalve's team, whose findings have now been published in the journal Frontiers in Genetics, succeeded in making the discovery because his research group had been working for years with large cow databases in Germany. In the course of their work, they came across a farm in which interdigital hyperplasia, also known as limax or tyloma, frequently occurred. Three to eight percent of all cows in Germany suffer from the disease at some stage in their lives, however it mostly affects older cows. A further, "stunted" claw emerges between the two claws of the hoof, spreading apart the real claws. "This results in tears to the skin, which in turn provide openings for bacteria and other infectious agents," says Swalve. The animals become lame and their lifespans are shortened.

"We previously carried out studies on the genetics of the disease, but we didn't have enough affected animals at our disposal, so it was difficult to obtain statistical certainty," explains Swalve. It was therefore a stroke of luck to find a farm in north-western Germany where almost 60 per cent of the animals were affected by it. In a genome-wide association study, they compared 45,000 small DNA segments, so-called SNPs, from healthy and sick cows. Initially, they identified two sites that could be related to the disease. One was the gene for tyrosine kinase receptor 2 (ROR2). "Next we compared our results with medical studies on humans and found that this gene also plays a role in the development of human limbs," says Swalve. The team from the University of Göttingen, led by Professor Bertram Brenig, subsequently provided proof that the ROR2 gene actually is involved with the development of the disease. His research group sequenced the entire gene segment and found that a mutation leads to the exchange of an amino acid in the affected cows. In further experiments, Brenig was also able to prove that the defect actually leads to an alteration in protein concentration. "Once we were able to show that the mutation influences gene expression, we were able to conclusively explain how it is connected to the disease," said Brenig.

Swalve is surprised that the genetic background of the disease had been ignored for so long - even though, as early as 1952, Richard Götze, an internationally acclaimed veterinarian from Hanover, suspected that interdigital hyperplasia was almost exclusively genetic. This discovery did not find its way into animal breeding. Only now, with this new study, has Götze's assumption been confirmed. The disease can now be tackled through selective breeding.

Researchers at Radboud university medical center have developed a 'deep learning' system that is better than most pathologists at determining the aggressiveness of prostate cancer. The AI system, which uses tissue samples to arrive at its diagnosis, taught itself to identify prostate cancer based on data from over 1200 patients. The Radboud team is now working with researchers from the Karolinska Institute in Sweden and Kaggle, a Google subsidiary, with the intention to continue developing these methods as part of a major international competition.

Prostate cancer is a frequently occurring type of cancer, but not always aggressive: more men die with prostate cancer than from prostate cancer. However, its treatment has many consequences for the quality of life of patients, so determining aggressiveness is an important step in choosing a treatment. To determine the aggressiveness of the cancer, pieces of tissue (biopsies) are taken from the prostate, which are scored by a pathologist. This 'Gleason score' is then used to classify biopsies into five groups - the Gleason Grade Groups - which indicate the risk of dying from prostate cancer. However, this is a subjective process; whether and how a patient is treated may depend on the pathologist who assesses the tissue.

Better than a pathologist

The researchers at Radboudumc developed an AI system that examines those biopsies the same way a pathologist does. The AI system also determines the Gleason score, and then the system can classify a biopt according to the Gleason Grade Groups. By means of deep learning, the system examined thousands of images of biopsies to learn what a healthy prostate is, and what more or less aggressive prostate cancer tissue looks like. Researcher Wouter Bulten describes this process: "The AI system has now been trained with 5759 biopsies from more than 1200 patients. When we compared the performance of the algorithm with that of 15 pathologists from various countries and with differing levels of experience, our system performed better than ten of them and was comparable to highly experienced pathologists." An additional advantage of such a computer system is that it is consistent and can be used anywhere; the treatment of a patient no longer depends on the pathologist looking at the tissue.

An international competition

As 1.2 million men globally are diagnosed with prostate cancer every year, the development of an AI diagnostic system is interesting for many research groups and companies. "It is advantageous that we are an academic hospital," says Bulten. "We are close to the patient and the practitioner, and have our own database of biopsies." As a next step, the Radboud university medical center team - together with researchers from the Karolinska Institute in Sweden and Kaggle, a subsidiary of Google specialized in data science competitions - wants to hold an international competition in which participants try to beat the Radboudumc algorithm. The insights resulting from this competition will then be used to improve the algorithms.

Background: what is 'deep learning'?

Deep learning is a term used for systems that learn in a way that is similar to how our brain works. It consists of networks of electronic 'neurons', each of which learns to recognize one aspect of the desired image. Then it follows the principles of learning by doing, and practice makes perfect. The system is fed more and more images that include relevant information saying - in this case - whether this is cancer or not, and if so, what the Gleason score is. The system then learns to recognize which characteristics belong to cancer, and the more pictures it sees, the better it can recognize those characteristics in undiagnosed images. (We do something similar with small children: we hold up an apple in front of them and say that it is an apple. At a certain point, you don't have to say it anymore.) A major advantage of these systems is also that they learn much faster than humans and can work 24 hours a day.

The Nijmegen study, authored by Wouter Bulten, Geert Litjens and others, has been published in The Lancet Oncology.

Cardiff University scientists have shed new light on the Earth's climate behaviour during the last known period of global warming over 14 million years ago.

During this period, known as the middle Miocene Climate Optimum, global temperatures were as much as 3 to 4 degrees warmer than today's average temperatures, similar to estimates for 2100. The position of the continents were similar to today and the seas were flourishing with life.

This period, which occurred between 15 and 17 million years ago, has puzzled geologists for decades as they have tried to explain the initial cause of the global warming and the environmental conditions that existed on Earth afterwards.

It is already known that this period of global warming was accompanied by massive volcanic eruptions which covered most of the modern-day Pacific Northwest in the USA, called the Columbia River flood basalts.

Around the same time a significant oil-rich layer of rock, known as the Monterey Formation, was created along the coastline of California as a result of the burial of carbon-rich marine life.

Up until now scientists have struggled to piece together the puzzle and come up with a viable explanation for the origin of the warmth and the link between the volcanic eruptions and the increased amounts of carbon burial.

Prof Carrie Lear, the senior scientist on the study and based at Cardiff University's School of Earth and Ocean Sciences, said: "Our planet has been warm before. We can use ancient fossils to help understand how the climate system works during these times."

In their study, published today in the journal Nature Communications, the team used the chemistry of marine fossils taken from long sediment cores from the Pacific, Atlantic and Indian oceans to fingerprint the temperature and carbon levels of the seawater in which the ancient creatures once lived during the middle Miocene Climate Optimum.

Their results showed that the massive volcanic eruptions of the Columbia River flood basalts released CO2 into the atmosphere and triggered a decline in ocean pH. With global temperatures rising as a consequence of this, sea-levels also rose, flooding large areas of the continents.

This created the ideal conditions to bury large amounts of carbon from the accumulations of marine organisms in sediments, and to transfer volcanic carbon from the atmosphere to the ocean over tens of thousands of years.

"The elevated marine productivity and carbon burial helped to remove some of the carbon dioxide from the volcanoes and acted as a negative feedback, mitigating some, but not all, of the climatic effects associated with the outpouring of volcanic CO2," said lead author of the study Dr Sindia Sosdian from Cardiff University's School of Earth and Ocean Sciences.

Past large episodes of volcanism throughout Earth's history have been linked to mass extinctions and widespread oxygen depletion in the oceans; however, there was no such occurrence in the middle Miocene Climate Optimum.

Co-author of the study Dr Tali Babila from the School of Ocean and Earth Sciences at the Univesity of Southampton added: "During the Miocene Climatic Optimum the response of the oceans and climate was remarkably similar to other massive volcanic eruptions in the geological record. The presence of the Antarctic ice sheet and the relatively slow release of carbon however minimised the magnitude of environmental change and the associated consequences on marine life during this event."

"Thanks to our findings we now have a very clear picture of what was going on over 14 million years ago and this will change the way that scientists look at this period of global warming," continued Dr Sosdian.

"We know that our current climate is warming much faster than the Miocene Climatic Optimum so we won't be able to rely on these slow natural feedbacks to counteract global warming. But this research is still important because it helps us understand how our planet works when it is in a warm mode."

As many as seven to 10 million people in the world are thought to live with Parkinson's disease (PD). Being the second most common neurodegenerative disease, PD severely affects patients' quality of life, not just brining movement abnormalities. Despite its prevalence and negative impact, current medical treatments for PD rely on alleviating PD symptoms with little efforts to explore ways to reverse the symptoms.

It has been firmly believed that abnormal movements of PD begin in the brain where the production of dopamine, a neurotransmitter for movement control, is irreversibly impaired, i.e. in a state of neuronal death. Currently, L-DOPA, a potent PD medication is mainly prescribed to replenish dopamine in the deprived brain. However, such a treatment is symptomatic therapy, rather than a disease-modifying therapy. Long-term use of L-DOPA is well-known to cause serious side effects such as involuntary, erratic, and writhing movements.

Led by Dr. C. Justin Lee along with Dr. Hoon Ryu and Dr. Sang Ryong Jeon, researchers at the Center for Cognition and Sociality within the Institute for Basic Science (IBS), Korea Institute of Science and Technology (KIST), and Asan Medical Center (AMC) have discovered a new mechanism for PD pathology. The researchers reported that the symptoms of PD begin when dopaminergic neurons are "non-functional", even before they die off. Though the neuronal death had been till now believed to be the obvious cause of PD, the study found that the movement abnormalities of PD begin in the earlier stage when dopaminergic neurons, though being alive, cannot synthesize dopamine (in a dormant state). "Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes," said Dr. C. Justin Lee, the corresponding author of the study. Lee adds, "The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD."

The researchers observed when the number of astrocytes abnormally increases due to the destruction of nearby neurons, GABA, an inhibitory neurotransmitter is released in the brains of both animal PD models and human patients in an excessive amount. This excessive output of GABA suppresses dopaminergic neurons, putting the production of dopamine on a hold. Notably, they confirmed that the dormant dopaminergic neurons are alive with the existence of DOPA decarboxylase. Furthermore, they revealed that these neurons could be awakened by treatment with MAO-B inhibitor, which blocks astrocytic GABA synthesis. The awakening of dormant dopaminergic neurons leads to a significant alleviation of PD motor symptoms.

They also used optogenetic tools to inhibit dopaminergic neuron of normal rats, inducing Parkinsonian motor deficits. They also demonstrated that activating the dormant dopaminergic neurons by the optogenetic treatment can alleviate PD motor symptoms. "This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death," said Dr. Hoon Ryu of Brain Science Institute at KIST. "The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD."

Dr. Sang Ryong Jeon of AMC explained, "So far, it had been firmly believed that idiopathic PD is caused by the death of dopaminergic neurons in substantia nigra. However, this research demonstrates that functional inhibition of dopaminergic neurons by surrounding astrocytes is the core cause of PD. It should be a drastic turning point in understanding and treating PD and possibly other neurodegenerative disease as well." With this study, the researchers suggest that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD, especially in early stages of PD in which non-functional yet live dopaminergic neurons are waiting to be awaken.

To date, biodiversity research primarily focused on the number of plant species present in ecosystems. "Most studies so far have used small, artificially established study plots. However, real-world landscapes are much more complex, and, in addition to natural areas, also contain human-dominated elements such as arable land and urban areas", says Pascal Niklaus, professor at the Department of Evolutionary Biology and Environmental Studies at the University of Zurich (UZH).

5,000 Swiss landscapes analyzed

A research team led by Niklaus and part of the Research Priority Program "Global Change and Biodiversity" investigated how different land-cover areas affect vegetation growth in large landscapes. Using aerial imagery, they assessed land-cover in 4,974 landscape plots from all regions in Switzerland. In addition to green areas such as grassland and forest they also considered human-dominated areas including arable fields and settlements. In parallel, they used satellite data to determine plant productivity in these landscapes over a period of 17 years.

Land-cover mixtures are more productive and stable

"We found that landscapes consisting of a mosaic of different land uses were more productive than the average landscape with uniform use", Niklaus summarizes. This positive effect of land-use diversity and productivity held over many regions, climatic conditions and altitude ranges. Landscape mosaics also showed a temporally more stable productivity. In other words, more diverse landscapes are able to mitigate effects of inter-annual climate variation.

Different mechanisms are at play

The positive effects of land-use diversity were unrelated to the number of plant species present in these landscapes. This indicates that areas with different land uses interact and improve the functioning of the entire landscape, similar to the way in which plant species interact in a small patch of vegetation and thereby improve the functioning of the plant community. "In such large landscapes, novel mechanisms must be at play that do not operate in the small study plots traditionally examined in biodiversity experiments", Jacqueline Oehri, first author of the study, says. The specific nature of these mechanisms is the subject of further investigations. The authors speculate that, for example, urban areas and water bodies affect climatic conditions in their surroundings, and that this might improve the productivity of vegetation in these areas.

Strategies for regional planning and landscape management

The way in which different land uses are spatially interwoven thus promotes the functioning of landscapes, in addition to the established beneficial effects of high species diversity. The study's novel approach enables landscapes to be analyzed on a scale that is relevant for regional planning and conservation policies. However, Niklaus emphasizes that "the fact that mixed landscapes function better should not be understood to mean that natural areas should be fragmented by expanding urban settlements".

The folding state of the proteins in live cells often reflect the cell's general health. Australian scientists have developed a molecular probe that senses the state of the proteome--the entire set of the proteins--by measuring the polarity of the protein environment. The fluorescence signal of the probe quantifies unfolding and its chameleon-like color shift maps the cellular regions of enhanced misfolding, says the study published in the journal Angewandte Chemie.

If live cells are stressed, protein-synthesis and folding-correction mechanisms are out of balance. Misfolded proteins remain stuck, enhanced degradation occurs, and inactive proteins and protein debris aggregate to form granules and condensates in the cytoplasm. Such aggregates play an important role in neurodegenerative diseases and cancer. One driving factor for the aggregation of misfolded proteins seems to be the polarity--the electronic distribution in an environment. Yuning Hong and colleagues at La Trobe University Melbourne and The University of Melbourne, Australia, have designed a two-modal fluorogenic probe to monitor protein aggregation in greater detail.

In one mode, the probe senses misfolded proteins. Correctly folded proteins are often stabilized by bridges made of the amino acid cysteine. These bridges are usually deeply buried, whereas misfolded proteins expose the cysteine residues at the surface. When the probe binds to cysteine exposed by a misfolded protein chain, fluorescence is switched on, explain the authors.

In the other mode, the probe assesses the polarity. Polar environments indicate an unbalanced electronic distribution, which can be measured by the dielectric constant. To measure this parameter, the researchers added an electronic "push-pull" chemical group to the fluorogenic probe. They observed that, in polar solutions with a high dielectric constant, the fluorogenic probe called NTPAN-MI emitted its fluorescence signal with a color shift. This "chameleon-like" color change thus indicates a polarity change.

The authors tested the NTPAN-MI probe on a human cell line, which they stressed by adding drugs that interfered with protein synthesis and folding. The scientists observed normal fluorescence in untreated cells, but bright fluorescence when unfolded or misfolded proteins accumulated in cells treated with toxins or infected by virus. In addition, the color shift signaled the polarity of the environment and thus the proteome state of each cellular compartment. The researchers reported that they visualized the "unfolded protein load" in the nucleus for the first time. Previous methods could only measure unfolded proteins in the cytoplasm.

With its two sensing modes--measuring unfolding and the polarity of the protein environment--the NTPAN-MI probe provides a sharper picture of the stress responses of live cells than what can be obtained with only one-modal probes or different methods. The authors point out that their method would allow scientists to obtain more accurate knowledge of the crosstalk of the cellular components in response to stress.

Increased body temperature is the single-most commonly noted abnormal finding for the medical practitioner. While it may be a sign of something relatively innocuous, it can also be an indication of underlying critical illness. In cats, an elevated body temperature equates to a reading in excess of 39.2°C or 102.5°F and, as in humans, it can arise as a result of two major mechanisms: hyperthermia and fever. Hyperthermia refers to a sudden and uncontrolled increase in temperature owing to failure of the body's thermoregulatory mechanism. By contrast, in fever (or pyrexia, from the Greek for 'fire' or 'burning heat'), the body's hypothalamic set-point is increased, secondary to the release of pyrogens, as the body's adaptive response to a pathological state.

In cats, fever typically presents with associated signs of depression and loss of appetite. For the veterinarian getting to the root of the problem in order that appropriate therapy can be implemented, there is a long list of differential diagnoses to consider, including infectious disease agents, neoplasia and immune-mediated diseases, among others. Based on a recent study of over 100 cats presenting to second-opinion veterinarians for investigation of fever, infectious causes are thought to be the most common.

Writing for an international audience of veterinary practitioners and feline researchers, an expert group of feline internists from the USA, Spain and the UK, led by Professor Michael Lappin of Colorado State University, provide an update on infectious agents associated with fever in cats that are transmitted by arthropod vectors. Published in the Journal of Feline Medicine and Surgery, their two-part state-of-the-art review article* focuses on common clinical and laboratory findings, and optimal diagnostic tests, treatments and strategies for prevention of a range of disease agents known or suspected to be transmitted by fleas, ticks and sandflies. Throughout, they stress that prevention of vector-borne infections is always preferable to treating clinically ill cats, and note that there is mounting evidence to show that consistent use of products that either rapidly kill vectors or, preferably, prevent vectors from biting a cat, is desirable.

Links between specific disease agents and fever in cats are not always clear-cut. For example, evidence of exposure to Bartonella species bacteria has been found in cats in many countries around the world, particularly in regions with high humidity and fleas. Well-documented manifestations of bartonellosis in cats include cardiac (endocarditis and myocarditis) and ocular (uveitis) disease, but whether fever will occur is likely influenced by a complex interaction involving both host and organism factors. Nevertheless, Bartonella henselae is common in fleas and known to survive at least 9 days in flea dirt. Professor Lappin stresses that adequate flea control is imperative to lessen the risk of infection in other cats, dogs and, indeed, people, in whom this agent is the cause of cat-scratch disease.

Among the tick-borne agents associated with feline fever are Ehrlichia species. Less is known about the particular causal agents of ehrlichiosis in cats compared with canine ehrlichiosis, but fever, together with lethargy and inappetence, is a commonly reported clinical abnormality in cats with suspected disease. Professor Lappin suggests that testing for these intracellular pathogenic bacteria might be indicated for cats with such signs and points to the importance of using preventive products that either rapidly kill attached ticks or, ideally, stop ticks from biting in the first place since it is known that, in dogs, Ehrlichia canis may be transmitted as early as 3 hours after tick attachment.

Commenting on the rationale for these two articles, the authors write: 'We hope that these pieces of work will help answer many of the questions faced by veterinary clinicians regarding vector-borne pathogens in our feline patients. They represent a collaborative effort to try to ensure the information is relevant to all readers in order to help combat diseases in cats that have traditionally been overlooked.'

Researchers from the University of Amsterdam and Tilburg University published a new paper in the Journal of Marketing that assesses Retailer-Themed Super Saver Events and the effects they have on consumers.

The study forthcoming in the March issue of the Journal of Marketing is titled "Evaluating the Effectiveness of Retailer-Themed Super Saver Events" and is authored by Jonne Guyt and Els Gijsbrechts.

Bigger is often better when it comes to retail promotion innovations: Amazon's Prime Day and Kroger's Cart Buster (also known as mega sales) are cases in point. "Their mega sales are fantastic, so whenever they have one, taking advantage of that is a huge saver," Laurie Hise, founder of the Passionate Penny Pincher site, tells CNBC Make It. "Just get on their sale cycle and follow it."

A new study in the Journal of Marketing assesses these innovative types of events and the effects they have on consumers. Retailer-Themed Super Saver Events (ReTSS) differ from normal day-to-day promotions on several dimensions: They have unusually deep immediate discounts across a broad range of categories; they use a uniform deal format and a common savings theme that is unique to the retailer and communicated through mass media; and they may produce different effects in terms of consumer visits and purchases. Anecdotal evidence suggests that traffic and basket-sizes do increase during the ReTSS period and that such events are "the engine behind revenue growth."

The researchers demonstrate that, through increased awareness and interest (larger perceived monetary and non-monetary benefits), these ReTSS yield different outcomes than regular sales promotions. They analyzed 44 Retailer-Themed Super Saver Events operated by the largest Dutch grocery retailers over four years and find a substantial increase in retailer visits and purchases during the events, especially among nonprimary customers and hard-discount shoppers. The larger part of this lift stems from the use of an overarching event theme. Consumers buy less in anticipation of the event and visit the store more often afterward, but for smaller baskets--typically leading to a null effect in terms of profit. Thus, although not a panacea, ReTSS can be a valuable defense tool by strengthening the retailers' share of wallet among light customers and preventing them from permanently defecting to discount stores (such as Aldi and Lidl).

How should retailers incorporate these results? The more successful events are sufficiently large in scope (number of products on discount during the promotion) and offer the right balance between raising awareness and expectations and honoring promises by offering (deep) enough deals. As for format, whereas percentage-off discounts and BOGOs--which clearly emphasize the monetary advantage--appeal most strongly to consumers, ReTSS with uniform prices seem more profitable for the retailer. Although advertising matters, the key to success is not increasing the advertising budget per se. Instead, the media resonance of the savings theme is of critical importance. This is not surprising, given that most of the incremental gains come from nonregular customers who may be more responsive to sources other than the chain's communication. Hence, apart from creating a unique and easy-to-recognize theme, retailers should strive for more earned rather than owned media impressions and focus on how to make the theme go viral. Retailers must be wary of wear-out, and be ready to craft novel themes. Turning the event theme into a brand of its own and/or using market influencers to promote it may prove fruitful. When it comes to profitability, much of the outcome is determined by how retailers and manufacturers split the bill. The insights provided by the study can aid both manufacturers and retailers in negotiations on how to divide the costs of these promotional events.

We all will experience it at some point, unfortunately: The older we get the more our brains will find it difficult to learn and remember new things. What the reasons underlying these impairments are is yet unclear but scientists at the Center for Regenerative Therapies of TU Dresden (CRTD) wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing.

To investigate this, the research group led by Prof. Federico Calegari used a method developed in his lab to stimulate the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice. Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation.

It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.

Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The teams of Prof. Calegari (CRTD) together with Prof. Gerd Kempermann (German Center for Neurodegenerative Diseases DZNE / CRTD) and Dr. Kentaroh Takagaki (Otto von Guericke University Magdeburg) found the answer to this challenging question and published it this week in the scientific journal Nature Communications.

The answer is "Yes": Old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life.

In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals. It was not only about how fast they were learning but, rather, how different the learning process itself was ", explains Gabriel Berdugo-Vega, first author of the study.

"Also humans have a few stem cells in the brain and these stem cells are known to severely reduce in numbers over the course of life. Identifying the causes underlying cognitive deficits in ageing and rescuing them is crucial for our rapidly ageing societies. Our work demonstrates that age-related impairments can be rescued by hijacking the endogenous neurogenic potential of the brain, thus, rejuvenating its function. Being a human myself with my own stem cells and being the senior author of this study, I felt that I had a personal interest in this topic." says Prof. Federico Calegari, senior author of this study.

The research group of Prof. Federico Calegari focuses on mammalian neural stem cells in the context of development, evolution and cognitive function at the CRTD. The institute is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases.