Culture

An important biological mechanism that is thought to protect brain cells from neurodegenerative diseases such as Alzheimer's and Parkinson's may also be involved in regulating sleep, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The researchers found that a signaling pathway that helps prevent the buildup of abnormal protein aggregates in brain cells is also required for sleep in both fruit flies and zebrafish. The fact that this mechanism is present in two evolutionarily distant species suggests that it may also be present in humans.

There have long been puzzling hints that sleep loss and sleep disorders are connected to neurodegenerative diseases, and the findings, published online today in Current Biology, reveal one possible explanation for the link. If the results were extended to humans, they would point the way to new strategies against both sleep disorders and neurodegenerative diseases.

"Sleep fragmentation, which is characterized by repetitive short sleep interruptions, is one of the most common triggers of excessive daytime tiredness, especially in older people," said principal investigator Nirinjini Naidoo, PhD, a research associate professor of Sleep and Chronobiology. "Now that we know a major pathway that is involved in sleep regulation, we can target it to potentially improve fragmented sleep."

Studies in recent years have suggested that chronic sleep loss increases the risk of Alzheimer's, while people with Alzheimer's have an elevated risk of sleep disturbances. Sleep disturbances are also common features of Parkinson's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and other neurodegenerative diseases.

How the processes underlying neurodegenerative disease might be connected to sleep disturbances has never been clear. But one hint comes from findings in lab animals that the brain during sleep dials up "proteostasis" processes that clear away abnormal and potentially harmful protein aggregates, such as those that clutter the brain in neurodegenerative disorders.

In the new study, Naidoo and her colleagues scrutinized an important proteostasis process called the PERK signaling pathway, which, in response to a buildup of unwanted protein aggregates, causes cells temporarily to stop their assembly of most proteins. The scientists found that when they suppressed PERK signaling in Drosophila fruit flies or in evolutionarily distant zebrafish, using small-molecule compounds that block a key component of the pathway, both sets of animals slept much less than normal. Blocking PERK with genetic techniques in Drosophila brought similar results, while doing the reverse -- forcing the overproduction of PERK -- made the flies sleep more.

PhD candidate Sarah Ly examined tiny groups of neurons that produce a key wakefulness-promoting hormone in Drosophila, and found that knocking down PERK at night, just in these neurons, was enough to make the flies sleep less, whereas overproducing PERK made them sleep more. In one subset of these neurons the researchers were able to verify that boosting or reducing PERK had the effect of suppressing or unleashing production of the wakefulness hormone. "This raises possibility that PERK regulation of sleep occurs within multiple brain circuits," Ly said.

This discovery marks the first time that scientists have identified a specific and bidirectional biological mechanism tying sleep to proteostasis. The findings also point to the possibility that wakefulness tends to increase protein-aggregate accumulation in brain cells, leading to more PERK signaling. This ultimately helps reverse the brain-cell stress by enforcing sleep and allowing effective protein housekeeping to take place.

"Our findings suggest that one of the conserved functions of sleep may be to mitigate cellular stress caused by wakefulness," said Naidoo.

The authors believe that further research into this nexus between sleep and proteostasis has the potential to uncover important new therapeutic strategies for improving sleep quality, reducing the risk of Alzheimer's and other neurodegenerative diseases, and effectively slowing the aging of the brain.

Ewa Strus also co-authored this study. The research was supported by the National Institute of General Medical Sciences (R01GM123783).

Substantial amounts of ammonium salts have been identified in the surface material of the comet 67P/Churyumov-Gerasimenko, researchers report, likely revealing the reservoir of nitrogen that was previously thought to be “missing” in comets. The chemical and isotopic composition of the Sun is thought to reflect that of the solar nebula from which it was born. Comets, which are thought to have condensed long ago in the cold outer reaches of the solar nebula, far from the heat of the forming Sun, should contain the same primordial material. However, the nitrogen-to-carbon ratio (N/C) measured in comets, including Comet 67P, is lower than for the Sun, when it should be the same. The reason for this nitrogen deficiency is unknown. Spectroscopic measurements of Comet 67P’s surface by the Rosetta spacecraft show a ubiquitous, yet unidentified, infrared absorption feature centered around 3.2 micrometers (μm). While several materials, including nitrogen-bearing molecules, have been suggested as the source of the unknown spectral feature, a lack of reference data for plausible compounds has prevented its attribution. Oliver Poch and colleagues used laboratory experiments to simulate various possible comet surface compositions and measured their resulting reflectance spectra, attempting to reproduce the 3.2 μm feature observed on Comet 67P. Among the candidate compounds the authors tested, several nitrogen-containing ammonium salts could reproduce the comet’s unidentified infrared absorption bands. Based on these new findings, Poch et al. conclude that the ammonium ions (NH4+) in these compounds are likely the source for the 3.2-μm feature. The authors identify the semi-volatile ammonium salts as a substantial reservoir of nitrogen, the abundance of which could be high enough to account for the observed N/C discrepancy between comets and the Sun.

Head and neck squamous cell carcinoma (HNSCC) – a group of cancers that affect the the mouth, nose and throat – is a disease driven by mutations in the NOTCH tumor suppressor signaling pathway, according to a new study. It reveals the identity of rare driver mutations in tumor-suppressing genes using a mouse-based in vivo CRISPR screen to evaluate the function of so-called “long tail” mutations. In humans, these mutations are present in 67% of HNSCC patients and converge on NOTCH inactivation, thus promoting tumor development. HNSCC is the 6th most common human cancer and, while curable, has a poor survival rate and claims the lives of roughly 350,000 people worldwide each year. Like other cancers, HNSCC is characterized by a few genes mutated at high frequency in many patients (including the NOTCH tumor suppressor gene), followed by a “long-tail” of hundreds of other individually rare mutations observed in only a few patients. The functional consequences and biological significance of recurrent but rare mutations are generally unknown, but these mutations could potentially shed light on cancer biology and tumor evolution and perhaps lead to novel treatment strategies. Sampath Loganathan and colleagues developed a reverse genetic CRISPR screen that allowed them to identify genes that, upon mutation, predispose mice to developing MNSCC. Through their analysis, Loganathan et al. identified 15 potent tumor suppressor genes that, when mutated, triggered rapid growth of HNSCC in the mice. These genes included ADAM10 and AJUBA, which are also mutated in human HNSCC. The wild type versions of ADAM10 and AJUBA promote NOTCH signaling. These results show that HNSCC-associated mutations converge on inactivation of the NOTCH tumor suppressor signaling pathway.

Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments. The Hero proteins are heat resistant and are widespread in animals from insects to humans.

Most proteins have well-defined folds and twists that form a rigid structure, but the new type has a long, flexible stringlike structure. Researchers found the first of these strange proteins in flies and named it using a combination of an informal Japanese word meaning weak or not rigid and the diminutive suffix normally attached to young boy's names, "hero-hero kun."

Years later, researchers realized the name also fit the English meaning of "hero," a brave defender.

The UTokyo team now reports that Hero proteins can protect other proteins, extend the life span of fruit flies by 30 percent, and protect both fruit flies and lab-grown human motor neurons from dangerous protein clumps, like those observed in patients with neurodegenerative diseases.

An unlikely discovery

The Hero protein was identified by accident in about 2011 when then-graduate student Shintaro Iwasaki encountered an unusually heat-resistant protein that increased stability of Argonaute, the protein at the center of the lab's studies. Iwasaki now leads his own lab at RIKEN.

"It was kind of cool to know that a strange, extremely disordered, heat-resistant protein improved the behavior of Argonaute, but its biological relevance was unclear and, moreover, the protein's sequence seemed unrelated to anything else. So, we didn't know what to do next and just decided to put it on the shelf until years later," said Professor Yukihide Tomari, leader of the research lab and last author of the paper published in PLOS Biology.

Eventually, Kotaro Tsuboyama saw the hero-hero kun protein in a fresh light, initially after joining the lab as a doctoral student and now as a postdoctoral researcher.

Heroes in disguise

Proteins with similar functions usually have similar amino acid sequences even between different species; experts call this evolutionary conservation.

The lack of evolutionary conservation that Tomari's team encountered when they first identified hero-hero kun seems to be a defining characteristic for Hero proteins, making it difficult to predict their function or even identity.

To uncover the true identities of more Hero proteins, researchers grew human and fruit fly cells in the lab, made extracts from the cells, then simply boiled them.

High temperatures normally weaken chemical interactions that support a protein's structure, causing it to unfold and clump together with other unfolded proteins.

"Proteins are generally damaged by heat, but we found that Hero proteins remain intact even at 95 degrees Celsius [203 degrees Fahrenheit] without losing function. It is a bit strange, which is why I think no one has carefully characterized these proteins before," said Tsuboyama.

Next, researchers used an analytic technique called mass spectrometry to identify any proteins that remained in the boiled test tubes.

They found hundreds of Hero proteins in fruit flies and in humans.

Heroes to the rescue

Tsuboyama selected six Hero proteins to study in detail.

When some of the six Hero proteins were mixed with other "client" proteins, those clients kept their shape and function despite high heat, drying, or harsh chemicals that would normally destroy them.

In experiments using lab-grown human motor nerve cells, high levels of Hero proteins stopped cells from developing the protein clumps characteristic of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and restored their normal growth patterns.

The large, sensitive eyes of fruit flies are often used as disease models, because they are deformed by mutations that cause neurodegeneration in humans. Researchers observed that enhancing Hero activity protected flies' eyes from deformation caused by protein clumps associated with ALS. Conversely, eliminating normal Hero activity caused defects in the development of the fly eye.

Moreover, researchers found evidence that Hero proteins can promote longevity when they genetically modified healthy fruit flies to have high levels of individual Hero proteins throughout their whole bodies. Remarkably, some Hero proteins caused flies to live about 30 percent longer lives.

"It appears that Hero proteins naturally exist to keep other proteins happy," said Tomari.

To be continued...

"We saw many positive effects, but so far, we did not find any 'superhero' among those six Hero proteins that can stabilize all client proteins. Some Hero proteins are good for some clients, and others are good for other clients," said Tsuboyama.

Researchers are planning future experiments to identify any patterns or rules about which Hero proteins assist which client molecules in living organisms.

"We hope that, in the long run, Hero proteins can be useful for biotechnological and therapeutic applications," said Tomari.

Researchers of the University of Basel have developed a new method with which individual isolated molecules can be studied precisely - without destroying the molecule or even influencing its quantum state. This highly sensitive technique for probing molecules is widely applicable and paves the way for a range of new applications in the fields of quantum science, spectroscopy and chemistry, as the journal Science reports.

Spectroscopic analyses are based on the interaction of matter with light and represent the most important experimental tool to study the properties of molecules. In typical spectroscopic experiments, a sample containing a large number of molecules is irradiated directly. The molecules can only absorb light at well-defined wavelengths which correspond to energy differences between two of their quantum states. This is referred to as a spectroscopic excitation.

In the course of these experiments, the molecules are perturbed and change their quantum state. In many cases, the molecules even have to be destroyed to detect the spectroscopic excitations. The analysis of the wavelengths and the intensities of these excitations provide information on the chemical structure of the molecules and their motions such as rotations or vibrations.

Inspired by quantum methods developed for the manipulation of atoms, the research group of Prof. Stefan Willitsch at the Department of Chemistry of the University of Basel has developed a new technique which enables spectroscopic measurements on the level of a single molecule, here as an example a single, charged nitrogen molecule. The new technique does not disturb the molecule or even perturb its quantum state.

In their experiments, the molecule is trapped in a radiofrequency trap and cooled down to near the absolute zero point of the temperature scale (approx. -273 °C). To enable cooling, an auxiliary atom (here a single, charged calcium atom) is simultaneously trapped and localized next to the molecule. This spatial proximity is also essential for the subsequent spectroscopic study of the molecule.

A single molecule in an optical lattice

Subsequently, a force is generated on the molecule by focusing two laser beams on the particles to form a so-called optical lattice. The strength of this optical force increases with the proximity of the irradiated wavelength to a spectroscopic excitation in the molecule resulting in a vibration of the molecule within the trap instead of its excitation.

The strength of the vibration is thus related to the proximity to a spectroscopic transition and is transmitted to the neighboring calcium atom from which it is detected with high sensitivity. In this way, the same information on the molecule can be retrieved as in a conventional spectroscopic experiment.

This method, which is a new type of force spectroscopy, introduces several new concepts: First, it relies on single molecules instead of large ensembles. Second, it represents a completely non-invasive technique as detection is accomplished indirectly (via a neighboring atom) and without a direct excitation of spectroscopic transitions. Therefore, the quantum state of the molecule is left intact, so that the measurement can be repeated continuously. As a result, the method is much more sensitive than established spectroscopic methods that rely on the direct excitation and destruction of a large number of molecules.

Applications in extremely precise clocks and building blocks for quantum computers

There is a range of prospective applications of the new method, Prof. Willitsch explains: "Our type of force spectroscopy allows extremely precise measurements on molecules which are not possible with conventional spectroscopic techniques. With the new method, one can study molecular properties and chemical reactions in very sensitively and under precisely defined conditions on the single-molecule level. It also paves the way for investigations of very fundamental questions such as ?Are physical constants really constant or do they vary with time?? A more practical application could be the development of an ultraprecise clock based on a single molecule - or the application of molecules as building blocks for quantum computers."

KANSAS CITY, MO--For the first time, scientists from the Stowers Institute for Medical Research and collaborators have described the structure of an endogenously sourced, functioning neuronal amyloid at atomic resolution. The amyloid is composed of self-aggregated Orb2, the fruit fly version of the mRNA-binding cytoplasmic polyadenylation element-binding (CPEB) protein, which has been linked to long-term memory storage. The results of this work, published online March 13, 2020, in Science, have some very interesting implications.

"We thought the usual way amyloids arise is when a protein, having for some reason gone bad or become misfolded, cues amyloid formation in a stochastic, unregulated process," explains Kausik Si, PhD, Stowers investigator and associate scientific director. "We found instead that amyloids can form at a very specific time, in a very specific cell, in a very specific way."

Amyloids are usually understood in the context of their associated neurotoxic or degenerative states. In the case of Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob diseases, proteins aggregate in an aberrant way to form stable, insoluble deposits that wreak havoc in the nervous system.

However, in 2003, Si and his mentor at the time, Eric Kandel, MD, discovered the existence of an amyloid with adaptive functions in the nervous system while studying CPEB in the sea slug Aplysia californica. Through subsequent studies in mice and the fruit fly Drosophila melanogaster, Si and others showed that in fact, the unique attributes of CPEB and Orb2 protein self-aggregates (amyloids), were essential to their proper functioning at synapses.

These studies have indicated that CPEB/Orb2 exists in different functional and structural states in the brain. The primary form is a monomer that represses translation at synapses, but as memory is formed, these monomers self-assemble into biochemically active aggregates that promote synaptic translation. This transition is necessary for memory persistence.

"They postulated that the amyloid state was likely important, but until this current work, it hadn't been demonstrated definitively that the physical state of the protein is an amyloid," explains Ruben Hervas, PhD, first author of the paper and a senior research associate in the Si Lab.

Hervas studied disease-causing amyloids during graduate school. "I wanted to apply my biophysical background to study the structural features of other amyloid forming proteins - the good ones," he says.

After Hervas joined the lab in 2016, he and Si agreed early on that the best way to study the structure of Orb2 was to use protein from an endogenous source (many fruit flies), rather than recombinant Orb2 extracted from bacteria - although it would be much more difficult.

Recombinant Orb2, unlike endogenous Orb2, is not biochemically active, explains Hervas. "The original environment, the nervous system, is important to preserve the active conformation of the protein, as well as its most interesting properties - relating to its ability to self-aggregate and form a biochemically active amyloid structure linked to memory."

Hervas and the team faced an additional hurdle. "Because the protein is so large, about 700 amino acids, it is not easy to crystallize. For example, amyloid structures solved by X-ray crystallography thus far have only used peptides composed of few amino acids." So, Hervas continues, "cryo-electron microscopy (EM) offered the opportunity to solve this kind of structure."

In the current work, Hervas and colleagues purified Orb2 from approximately three million adult Drosophila heads. In these samples, Orb2 existed as monomers, oligomers, or self-aggregated filaments (amyloids). The researchers first confirmed that the Orb2 filaments were capable of seeding further filament formation, and that the purified Orb2 forms were biochemically active-- that is, capable of repressing protein translation in the monomeric state, and capable of activating protein translation in the oligomeric and filament states.

Their Herculean efforts paid off. Using cryo-EM and samples of over 97% purity, Hervas and colleagues were able to resolve the structure of endogenous Drosophila Orb2 at 2.6-angstrom resolution. They found that endogenous Orb2 formed threefold-symmetric amyloid filaments that were about 75 nanometers long. They confirmed that Orb2 aggregates in cross-beta amyloid structures and discovered that the hairpin-like fold of its protofilament cores, composed of 31 amino acids, pack via hydrophilic interfaces.

This work also provided a partial answer to a very important question - how is it possible that amyloids of a neuronal protein help store memory, when amyloids in general are associated with loss of memory? In their paper, the authors concluded that unlike the hydrophobic core of pathogenic amyloids, the hydrophilic core of Orb2 filaments suggests how some neuronal amyloids could be a stable yet regulatable substrate of memory.

"This finding changes the way we think about proteins folding and assembly," says Si. "The way we think about biology now is: you have a gene, you make a string of amino acids, and once a polypeptide is made it is programmed to go into one conformation because there is a specific function attached to it. If it deviates from that path, a system is there to remove it. But this work suggests that sometimes a cell allows the same protein to form a completely different conformation. How does it do it? When does it do it?"

The conformational flexibility of some proteins opens the possibility that a protein may have more than one function depending on conformational state - a phenomenon Si and his lab members will be keen to study moving forward.

While memory assays in Drosophila are informative, Hervas and colleagues are next looking forward to determining whether such functional amyloids also exist in the nervous system of mice and humans, especially because the nervous system of humans is particularly susceptible to amyloid-based diseases. There are four CPEB isoforms, each one with several variants, in mice and humans, explains Hervas. "Some specific isoforms in mice are also important for memory consolidation, and these are almost identical in protein sequence to corresponding human isoforms."

"We are starting to work with CPEB proteins extracted from the human medial temporal lobe, a structure where long-lasting memories reside. We intend to solve the structure, and then potentially make the connection between memory and protein structure using mouse models."

"The brain is one of the systems that evolved and diversified the most as organisms became more complex," Si reflects. "But if you look at the number of proteins involved, that actually did not dramatically change. One possibility is that more complex biological systems use this conformational space to create more functions. Instead of creating new proteins, just being in a different shape could create new function."

Other coauthors of this work include Younshim Park from the Stowers Institute; Michael J. Rau and James A.J. Fitzpatrick, PhD, from the Washington University in St. Louis; and Wenjuan Zhang, PhD, Alexey G. Murzin, PhD, and Sjors H.W. Scheres, PhD, from the MRC Laboratory of Molecular Biology.

This work was funded in part by the Stowers Institute for Medical Research and by the UK Medical Research Council (award MC_UP_A025_1013, to S.H.W.S.).

Lay Summary of Findings

Proteins are generally thought to adopt a single shape, or "fold," and the shape of a protein determines its function. However, some proteins can adopt a secondary shape, called "amyloid," as they self-assemble. Historically, amyloids have been thought of as non-functional and even disease-causing, especially in the brain, as in the case of Alzheimer's disease.

Surprisingly, though, work by Kausik Si, PhD, of the Stowers Institute for Medical Research, and others has indicated that a protein necessary for long-term memory formation and persistence, called Orb2, may be able to adopt the shape of an amyloid as part of its normal and necessary function. However, it had not been established that Orb2 exists in the brain as a bona fide amyloid, as its structure was unknown, until now.

A report from the Si Lab and collaborators, published online March 13, 2020, in Science, has characterized, at atomic-level resolution, the structure of Orb2 purified from its native source (the brains of millions of fruit flies) and demonstrated that it does indeed exist as a functional amyloid within the brain. This study, led by Ruben Hervas, PhD, is the first time an amyloid with a known biological function has ever been purified and described structurally from the brain. Interestingly, the amyloid (self-assembled) fold of Orb2 promotes the production of memory-related proteins, while the monomeric (single protein) fold of Orb2, inhibits production of memory related proteins, indicating that a protein can take on multiple functions by adopting multiple shapes.

These findings raise two interesting possibilities that will be further pursued in the Si Lab - the possibility that such a functioning neuronal amyloid also exists in humans, and the possibility that other proteins, known to have specific functions, are capable of achieving amyloid states to achieve alternate functions.

Producing a liter of milk in California emits less greenhouse gas and uses less land and water than it did in 1964, according to a recent study from researchers at the University of California, Davis.

"We compared 1964 through 2014 and found a 50 percent reduction in greenhouse gases to produce the same quantity and quality of milk," said senior author Ermias Kebreab, professor and Sesnon Endowed Chair in the Department of Animal Science at UC Davis. "The magnitude of change is surprising."

Scientists conducted a lifecycle environmental assessment of cows from the time they are born to the time they leave the farm gate. The study included such inputs as producing feed for the animals, and the machinery and transportation needed to produce milk.

Cows belch methane, a potent greenhouse gas, as part of their digestive process. The study found the biggest emission cuts came from reductions in these emissions, known as enteric methane, compared to reductions in emissions from manure.

"Reductions in enteric methane intensity (i.e., methane emissions per gallon of milk) are primarily a result of better genetics and breeding and better nutrition for the animals," said Kebreab.

WATER AND LAND USE

In addition, water use in the industry has dropped by 88 percent, due primarily to efficient water use in feed crops and the use of crop byproducts for feed such as almond hulls. Water use in housing and milking also dropped by 55 percent.

The amount of land it takes to produce a liter of milk compared to 1964 has also decreased. This is largely due to improvements in crop genetics and production practices that have increased yields of grain, hay and silage for cows on the same amount of land.

"We've saved an amount of land equal to the size of Connecticut," said Kebreab.

Over the last 50 years, dairy production in California has undergone significant improvements and advancements in animal husbandry, feeding and housing practices, and in animal and plant genetics and crop production methods.

Total greenhouse gas emissions from cows overall has increased in California as more cows are needed to feed a growing population. But cows are now producing much more milk. In the 1960s, one cow could produce about 4,850 kilograms of milk per year. Now a cow can produce more than 10,000 kg annually.

"There is a lot of discussion about how cows have a huge environmental footprint, but no one is talking about how the dairy industry has changed," said Kebreab. "Dairy farmers are doing a lot to help reduce the industry's environmental footprint."

Scientists continue to look for ways to reduce enteric methane emissions through better animal nutrition, including feed additives. In a previous study, Kebreab found that feeding dairy cows a small amount of a seaweed called Asparagopsis armata along with their feed, reduced methane emissions by up to 60 percent.

California is the top dairy producing state, and milk production is the third largest agricultural industry in the United States.

During the 2016 Zika outbreak, news exposure appears to have had a far bigger impact than local disease risk on the number of times people visited Zika-related Wikipedia pages in the U.S. Michele Tizzoni and colleagues at the ISI Foundation in Turin, Italy, present these findings in PLOS Computational Biology.

During an epidemic caused by a newly emerging infection--such as the current coronavirus outbreak--media outlets play an important role in informing the public about risks and ways people can protect themselves. Previous research has explored how public opinion responds to media exposure during an emerging outbreak, but has mostly relied on surveys rather than observational data.

In the new study, Tizzoni and colleagues investigated the relationship between media coverage and the public's collective attention to the 2016 Zika virus epidemic. They analyzed data on the total number of times people in U.S. cities and states accessed Wikipedia pages related to Zika in 2016, and compared those numbers with Zika incidence rates and news media mentions of Zika.

The analysis showed that Zika-related Wikipedia page view counts during the outbreak were highly synchronized with mentions of the virus in web and national TV news at both the national and state level. Although the number of reported Zika cases and the risk of local transmission varied significantly between states, patterns of Wikipedia page views were very similar across the country.

"Wikipedia page view data represent an invaluable and granular resource to study global patterns of collective attention during outbreaks," Tizzoni said. "We can use such critical data to find patterns across a country and how behavior changes by region."

The new findings could help public health officials refine crisis communication techniques. Meanwhile, future research could help clarify whether the findings would hold true for different epidemic scenarios and in different countries, and investigate the influence of social media.

"Wikipedia is a trove of freely available content, but many people might not know that it is also a vast resource for open data that can provide valuable insight into what's capturing the attention of the world at any given moment, "said Miriam Redi, Research Scientist at the Wikimedia Foundation, the nonprofit behind Wikipedia. "We were so thrilled to collaborate with Michele and his team at the ISI Foundation to help provide Wikipedia pageview data for the study, which will soon be released as a freely available, aggregated, anonymized data set, for others in the research community to build on the critical insights provided by the researchers."

Doctors face tough choices during difficult childbirths -- often involving the decision of whether to perform a cesarean section operation. And in the background lies a question: To what extent are these medical decisions motivated by the desire to avoid liability lawsuits?

When doctors' actions are driven by a desire to avoid legal entanglements, it is known as "defensive medicine." When it comes to childbirth, one common perception holds that doctors, at uncertain moments in the delivery process, would be more likely to intervene surgically to avoid other potential problems. Now, a unique study co-authored by an MIT economist sheds light on the practice of defensive medicine, with a surprising result.

The research, based on evidence from the U.S. Military Health System, finds that when doctors have immunity from liability lawsuits, they actually perform slightly more C-section operations, compared to when they are legally liable for those operations -- about 4 percent more, over a 10-year period.

"When you're worried about errors of commission, defensive medicine can lead to [less] treatment of patients," says economist Jonathan Gruber, co-author of a new paper detailing the study's findings.

The paper, "Defensive Medicine and Obstetric Practices: Evidence from the Military Health System," is published this month in the Journal of Empirical Legal Studies. The authors are Gruber, who is the Ford Professor of Economics in the MIT Department of Economics, and Michael Frakes '01 PhD '09, a professor of law and economics at the Duke University School of Law.

"Natural experiment" with military data

The finding adds new information to an area of medicine where legal liability issues loom large. As the scholars note in the paper, 74 percent of obstetricians and gynecologists face malpractice claims by age 45, compared to 55 percent of physicians in the area of internal medicine.

To conduct the study, Gruber and Frakes used Military Health System data to conduct what economists call a "natural experiment," in which two otherwise similar groups of people are divided by one circumstance -- often a policy change or social program.

In this case, the study examines the effects of the Feres Doctrine, stemming from a 1950 legal ruling, that active-duty members of the military receiving treatment from military facilities do not have recourse in case they suffer from negligent care. A significant portion of active-duty personnel receive medical treatment under these circumstances.

However, military personnel can also opt to receive private care outside of military bases. For this reason, military medical policy generates two pools of otherwise similar people, divided by their two care options -- one with no liability for doctors, and one with liability. The idea for doing a study based on this comparison occurred to Gruber while he was working with the Military Health Service on other health care delivery issues.

"For decades, health economists have been searching to find the holy grail of a natural experiment to tell us what would happen if people couldn't sue for malpractice," Gruber notes.

The study examines Military Health System data on 1,016,606 births in military families, from 2003 to 2013. About 44 percent of the deliveries occurred at military health facilities and 56 percent at civilian hospitals. Ultimately, as the study shows, C-sections are about 4 percent more common during the deliveries at military hospitals, compared to the times when mothers in the Military Health System deliver at civilian hospitals.

As Gruber notes, that finding will seem unexpected to those who associate defensive medicine with an increase in operations, treatment, and interventions.

"We tend to think of defensive medicine as ... doctors doing extra testing because they're afraid of getting sued," he says. But this finding indicates that, in childbirth settings, doctors practice defensive medicine by intervening slightly less.

In each specialty, the right balance

The current finding also adds nuance to an earlier paper by Gruber and Frakes, based on inpatient care generally, which found that across medical areas, doctors who cannot be sued tended to spend 5 percent less on the treatment of patients. Doctors who could be sued, then, were spending more on tests and treatments.

Among other things, Gruber observes, that earlier paper suggests that overall, defensive medicine leads doctors to spend more, although "it's not the main driver of U.S. health care spending."

However, as Gruber also notes, what is true of medicine generally need not be true of particular medical specialties.

"This [new] paper is sort of the flip side of the first paper," Gruber notes. Indeed, he notes, the findings of the new paper may suggest that doctors' practices are reasonably optimal, in subtle ways. Because doctors effectively receive more compensation for performing C-sections, they have a financial incentive to perform more of them. And yet, if the application of defensive medicine leads doctors to perform slightly fewer C-sections, that might appropriately adjust the overall rate of interventions.

In any event, across medical specialties, the effects of defensive medicine may vary, and may push doctors toward more or less treatment on aggregate. Continued empirical studies of medical decisions will be necessary to shed more light on the matter.

"The point is, there's a balance," Gruber says, adding: "We think of defensive medicine as playing a negative role, but it can also play a positive role."

The discoloured fish that rest in glass jars in museums across the world are normally used by specialists as references to study the traits that identify certain species. But a new study proposes an additional use for such 'samples.'

Published in the Journal of Applied Ichthyology, the paper suggests using such specimens to estimate the length-weight relationships of fish that are hard to find alive in their natural environment.

"The length-weight relationship of fish, which allow computing the weight from their length, is something marine biologists need for a wide variety of studies. For example, they need them when they are estimating the biomass of certain species by performing visual census either by scuba diving or by using remote observation vehicles or underwater video stations," said Amanda Hay, lead author of the study and a researcher at the Australian Museum Research Institute.

But some fish like those that live in deep waters are so difficult to reach and observe that a museum specimen may be the only known representative of the species. "This is why it is so important to 'extract' as much information as possible from that individual," Hay said.

When live fish are hard to catch for the researchers who study them, the most common practice is to assume that their biological traits equate to those of similar species. Using preserved fish specimens, however, is a more precise way to learn more about elusive species.

The proof of concept prepared by Hay and her colleagues at Canada's Beaty Biodiversity Museum and China's Institute of Oceanology involved measuring 56 preserved adult specimens of 31 species and uploading their results to FishBase, the largest online database on fish.

"FishBase has information for over 30,000 fish species but, of those, only 5,500 have length-weight parameters," said Daniel Pauly, co-author of the study and principal investigator of the Sea Around Us initiative at the University of British Columbia. "This can be improved if researchers in museums and other institutions around the world measure and weigh specimens in their collections and upload the data. This is what we are aiming for."

The paper "The why and how of determining the length-weight relationships of fish from preserved museum specimens" was published today in the Journal of Applied Ichthyology.

In some former Soviet bloc countries, men often die early due to alcohol abuse. Alcoholism-related mortality varies considerably from one region to another, according to a study in the European part of Russia, Belarus, Lithuania and Poland. The most problematic regions in these terms are north-western and western Russia, eastern and north-western Belarus, south-eastern Lithuania, and eastern and central Poland, say an international team of demography researchers that included scholars from HSE University.

Tragic Practices

Heavy drinking often turns out to be fatal. It either leads to death directly, for instance due to acute alcohol poisoning, or provokes serious diseases of the liver (cirrhosis and fibrosis), heart and blood vessels (cardiomyopathy, ischemic heart disease), and brain (blood stroke), as well as some types of cancer. Deaths from external causes, such as car accidents, murder, falling, burns, drowning, and frostbite, are also often related to excessive drinking.

Official statistics show that the share of deaths directly related to alcohol is not high. For example, in Russia in 2015 it was 3.1% of total deaths, or over 58,000 people. But among the able-bodied population, this share was higher at 8.8%.

But even this share is lower than the real one, experts say. Some alcohol poisonings and diseases caused by drinking are registered as 'non-alcohol-related causes of death,' while in reality, alcohol abuse has led to the fatal outcome.

Dangerous levels of alcohol consumption largely explain early mortality of men in European Russia, Belarus, Lithuania and Poland, according to a study conducted by an international team of demographers, including HSE researchers Evgeny Andreev and Sergey Timonin.

These regions share a common past, as well as similar cultural practices and consumption patterns. The researchers believe that this largely determines mortality due to alcohol consumption, which is similar in the four countries.

That said, generalizing can be problematic. The situation with alcohol-related early mortality varies considerably not only by country, but by region inside a given country. There are relatively safe regions and problematic hot spots.

Mortality Hot Spots and Glimmers of Hope

From 2006 to 2014, demographers studied mortality among males ranging in age from 20 to 64 in four economic regions of European Russia: central, north-western, central Black Earth, and Kaliningrad (23 oblasts including Moscow and St. Petersburg), as well as regions in Belarus, Poland, and Lithuania. The total number of geographic areas studied was nearly 1,180.

The study revealed the following:

There are more alcohol-related mortality hot spots in Russia and Belarus, and fewer in Lithuania and Poland.

The most troubled territories are north-western Russia, eastern and north-western Belarus, south-eastern Lithuania, and eastern and central Poland.

Within Russia, the lowest alcohol-related mortality rates are in Moscow, St. Petersburg and the Central Black Earth regions (Lipetsk, Kursk, and Voronezh oblasts), while the highest rates are in north-west and west (Leningrad, Novgorod, Smolensk, and Bryansk oblasts).

Alcohol-related male mortality rates largely explain early mortality among men in general.

Other studies have already shown that peaks in mortality coincide with alcohol consumption peaks. This means that the contribution of drinking in mortality is high.

'Alcohol-related mortality, particularly mortality from acute alcohol poisoning, had defined the general trends of life expectancy in Russia for several decades,' said Sergey Timonin. But today, the situation is changing, and there is a reason for certain optimism. According to the new study, 'the forecasting power of alcohol-related mortality is weakening.' This may mean that alcohol is finally playing a smaller role in early mortality in Russia, the scholar explained.

Hypnotized by the Past

Demographers calculated the standardized mortality ratio (SMR) for alcohol-related mortality in these countries (number of deaths per 100,000). This average indicator has been taken as a unit.

Relative SMRs by region within the countries were then calculated. Any indicator of the coefficient that is higher than one means that the mortality is higher than the average. On the contrary, SMRs less than one indicate lower alcohol-related mortality.

Standardized mortality ratios across the combined territory of Belarus, Lithuania, Poland and European Russia.

Study by S. Timonin, E. Andreev et al.

Demographers say that alcohol-related mortality across the four countries is homogeneous in some parts and mosaic in others.

All these countries face a problem of excessive alcohol consumption, which researchers explain by pointing to their common history. This includes both the socialist past (Poland was long influenced by the Soviet Union, while Belarus and Lithuania were Soviet republics) and history more than a century ago under the Russian Empire, which included a considerable part of Poland along with Belarus and Lithuania.

But risky alcohol consumption practices that formed over a century ago have persisted up to the present.

For example, in central parts of Poland (around ?ód?) and in the east (in areas bordering Belarus), mortality data show that heavy drinking is more widespread than in the other parts of the country.

On the contrary, in regions that have not been impacted by a shared past, such as in southern Poland, which used to be part of Austria-Hungary, alcohol-related mortality is lower. The culture of drinking is obviously less risky there.

'Barrier-free' Environment and Internal Contrasts

Russia demonstrates the highest heterogeneity of regions in terms of alcohol-related mortality.

In the north-west, SMR often exceeds 1.6, and sometimes goes off the scale, breaking the 2.4 barrier. On the other hand, in the southern part, in the Central Black Earth region, this indicator is often just a little higher than 0.5.

In Belarus, on the contrary, the landscape is more homogeneous, and almost hopeless. In most regions, the alcohol-related standardized mortality rate exceeds average levels (higher than one). Only regions bordering Poland in the southwest is the situation better.

The situation is better in Lithuania and Poland: in most regions, SMR is low. In Poland, hot spots are in the central part of the country, as well as in several eastern areas bordering Belarus.

The culture of drinking is obviously 'barrier-free' and crosses national borders. Patterns of alcohol abuse in border regions are almost identical. This is true, for example, for border regions of Russia and Belarus, or Belarus and Lithuania.

In Lithuania, almost all regions close to the border with Belarus have higher alcohol-related mortality.

The safest regions in Belarus are located in the southwestern part of the country closer to the Polish border.

The Kaliningrad oblast, on the contrary, is high in contrast to its neighbours. The 'alcoholic' SMR there is considerably higher than in Poland and Lithuania.

Remote and Rural Regions Fall behind

In addition to shared history, other factors impact alcohol-related mortality. These include a region's socio-economic situation: real household earnings and unemployment levels.

Another important factor is migration from the country's remote regions to its centre: the healthiest and most active people usually migrate. Finally, the illegal alcohol trade is also a factor.

For example, the relative safety of Moscow and St. Petersburg may be explained by higher living standards and cultural habits of the population. Other 'sober' territories are university towns and some closed administrative territories, such as related to defence industry (Zhukovsky, Korolev, Obninsk, Dubna, Protvino, etc).

'The advantage of university towns and closed territories is in the more favourable educational background of the population,' Timonin explained. 'The share of the population with a university degree is considerably higher in these communities as compared to other areas.'

Socio-economic factors largely determine the situation with alcohol-related lethality in the north-western economic region.

Its areas are located between the key centres that attract migrants: Moscow, St. Petersburg, and the Baltic countries.

North-western areas suffer from poor agricultural conditions and have depressed agriculture. This leads to an outflow of the most active populations.

The situation in Belarus is similar: the least developed eastern regions are prone to depopulation.

Finally, when alcohol-related mortality is analysed by the type of settlement, rural areas perform worse than urban ones. The researchers believe this is due to worse access to medical aid, weak leisure infrastructure, and uncertainty regarding the future. Rural areas lack attractive jobs. Younger, healthier and ambitious people leave for the cities.

Cancer researchers have known for years that Black and Hispanic patients have worse outcomes than their non-Hispanic White peers. At least when it comes to adults. But few studies have explored these same disparities in pediatric patients, and fewer still have looked for racial/ethnic differences in treatment outcomes in pediatric brain cancer patients.

A study by University of Colorado Cancer Center investigators working at Children's Hospital Colorado not only confirms worse outcomes for Black and Hispanic pediatric brain cancer patients (compared with non-Hispanic whites), but hints at where in the process of diagnosis and treatment these disparities arise.

Patients whose cancer has already spread by the time they are diagnosed have a poorer prognosis. But the current study finds that at the time of diagnosis, pediatric brain tumor patients of all races/ethnicities presented with cancers of similar stage and aggressiveness - in other words, at the point of diagnosis, there were no disparities. However, Black and Hispanic patients then went on to fare worse than non-Hispanic White patients. Together, these findings suggest that it's not the process of diagnosis, but during the process of treatment and follow-up that the paths of minority and White pediatric brain cancer patients diverge.

"We were surprised," says the study's senior author, Adam Green, MD, CU Cancer Center investigator and pediatric brain cancer specialist at Children's Hospital Colorado. "In general, we expect these disparities to be multi-factorial and have pre- and post-diagnosis components, but these findings suggest these patients are able to get diagnosed appropriately, but after that, treatment and follow up may be where the disparities lie."

Overall, of 1,881 patients under age 19 diagnosed with cancers of the brain and central nervous system between 2000 and 2015, 52 percent of White patients lived five years from diagnosis, whereas only 44 percent of African American patients and 45 percent of Hispanic patients reached a similar milestone.

"If we look overall in pediatric brain and central nervous system cancers, Black and Hispanic patients have a higher risk of dying from these tumors compared with non-Hispanic White patients," Green says. "Even when they presented with similar stage disease as their White counterparts, they still did worse."

Future studies are planned to look deeper into the source of these disparities, but Green suggests there are some obvious factors that health care systems can work on now to ensure equal care and, hopefully, more equal outcomes.

"One thing we don't talk about enough in cancer is how much of a burden going through treatment is on families - financial resources, transportation resources, time resources, shelter and lodging resources, etc.," Green says. "We can plan an effective treatment, but if there are life factors that make it more challenging for some families to get that entire course of treatment successfully, then all the planning we do isn't going to make the treatment as effective as we would like it to be."

Green also suggests that due to the complexity of many of these cases, young brain cancer patients should be seen at centers with experience treating these cancers and that offer multi-disciplinary care, allowing patients to access experts in many different fields including medical oncology, surgery, radiation, pathology, and supportive care such as palliative medicine and even nutrition.

"It's incumbent on us to make sure these families have access to the resources they need to ensure that their children are able to get the highest quality care," Green says.

Scientists have discovered that gorillas really are territorial - and their behaviour is very similar to our own.

Published in the journal Scientific Reports, the research shows for the first time that groups of gorillas recognise "ownership" of specific regions. They are also more likely to avoid contact with other groups the closer they are to the centre of their neighbours' home range, for fear of conflict.

The study, which was carried out by academics from the University of Cambridge, Anglia Ruskin University (ARU), the University of Barcelona, SPAC Scientific Field Station Network, and the University of Vienna, involved monitoring the movements of groups of western lowland gorillas (Gorilla gorilla gorilla).

Western lowland gorillas are difficult to track on foot because they live in dense forests. Instead, the scientists followed eight groups of gorillas using a network of cameras placed at 36 feeding "hotspots" across a 60km2 area of the Odzala-Kokoua National Park in the Republic of Congo.

It was previously thought that gorillas were non-territorial, due to the overlap of home ranges and their tolerance of other groups. This is markedly different to chimpanzees, which display extreme territorial-based violence.

However, this new research discovered that gorillas display more nuanced behaviours, and their movements are strongly influenced by the location of their neighbours - they are less likely to feed at a site visited by another group that day - and the distance from the centre of their neighbours' home range.

Lead author Dr Robin Morrison, who carried out the study during her PhD at the University of Cambridge, said: "Our findings indicate that there is an understanding among gorillas of 'ownership' of areas and the location of neighbouring groups restricts their movement.

"Gorillas don't impose hard boundaries like chimpanzees. Instead, gorilla groups may have regions of priority or even exclusive use close to the centre of their home range, which could feasibly be defended by physical aggression.

"At the same time groups can overlap and even peacefully co-exist in other regions of their ranges. The flexible system of defending and sharing space implies the presence of a complex social structure in gorillas."

Co-author Dr Jacob Dunn, Reader in Evolutionary Biology at Anglia Ruskin University (ARU), said: "This new research changes what we know about how groups of gorillas interact and has implications for what we understand about human evolution.

"Almost all comparative research into human evolution compares us to chimpanzees, with the extreme territorial violence observed in chimpanzees used as evidence that their behaviour provides an evolutionary basis for warfare among humans.

"Our research broadens this out and shows instead just how closely we compare to our next nearest relatives. Gorillas' core areas of dominance and large zones of mutual tolerance could help with our understanding of the social evolution of early human populations, showing both the capacity for violence in defending a specific territory and the between-group affiliations necessary for wider social cooperation."

Intense sunlight damages the chloroplasts that are essential for photosynthesis, and generates toxic products that can lead to cell death. Ludwig-Maximilians-Universitaet (LMU) in Munich biologists have now identified a signaling pathway which mitigates the effects of light stress.

Biological photosynthesis - the process by which solar radiation is converted into chemical energy - is carried out by cyanobacteria, algae and plants, and is vital for the maintenance of animal life on Earth. In plants, photosynthesis takes place in specialized organelles called chloroplasts, which are found in the leaves. Chloroplasts actually evolved from photosynthetic bacteria, which were incorporated into nucleated cells as symbionts. Over the course of evolution, most of the genes they brought with them were transferred to the nucleus of the host, but modern-day chloroplasts still retain a small set of genes that are essential for photosynthesis. As a result, photosynthesis in plants requires an extensive exchange of information between the nucleus and chloroplasts. The network involved is very complex, and many of its components remain to be identified. Using thale cress (Arabidopsis thaliana) as a model system, LMU biologists led by Privatdozentin Dr. Tatjana Kleine have now characterized a previously unknown signaling pathway that makes a significant contribution to stress tolerance and suppresses light-induced programmed cell death. This pathway could potentially be exploited to improve stress resistance in crop plants. The study appears in the journal PNAS.

Exposure of plants to excessively high light levels inevitably generate what 'reactive oxygen species' (ROS), such as 'singlet oxygen' (1O2) in leaf chloroplasts. In high concentrations ROS are toxic to cells, but they also serve as alarm signals that activate countermeasures. "Previous studies had shown that singlet oxygen serves as a signal molecule, and triggers a stress response that can lead to a cessation of growth or even to programmed cell death," Kleine says. "The obvious next step was to identify the proteins involved in the 1O2-induced signaling relay."

In their experiments, Kleine and colleagues made use of a double mutant (flu ex1) of Arabidopsis thaliana. The flu mutation permits the production of singlet oxygen to be activated in a controlled manner by exposure to light, while the ex1 mutation inactivates a gene called EXECUTER1. The EXECUTER1 protein is known to be required to induce programmed cell death. Hence, the ex1 mutation allows the concentration of singlet oxygen to rise without triggering cell death.

To identify other genes involved in 1O2-dependent signaling, the team mutated the flu ex1 strain once more, and screened for mutants in which the cell-death response to 1O2 was restored. This experimental design revealed that a protein called SAFEGUARD1 protects the double mutant from the deleterious consequences of the build-up of singlet oxygen. "Inactivation of the SAFE1 gene in the double mutant again results in cell death. Crucially, this is not due to the 'repair' of EXECUTER1. Therefore, the SAFE1 gene must code for a component of an independent and previously unknown signaling pathway, which is itself induced by singlet oxygen," explains Liangsheng Wang, lead author of the new paper. Notably, loss of SAFE1 is associated with damage to the margins of the membrane stacks (known as 'grana') in which the light-driven reactions occur. The authors therefore propose that 1O2 produced at the grana margins activates an EXECUTER1-independent signaling relay, and that SAFE1 normally suppresses this pathway by protecting the grana margins from damage.

Of all the types of ROS generated by exposure to high light levels, singlet oxygen is the most deleterious to photosynthesis. As an effective inhibitor of the stress reaction induced by the build-up of singlet oxygen, SAFE1 represents a promising starting point for efforts to enhance stress resistance in crop plants. "Perhaps overexpression of the protein would make plants more tolerant to the levels of singlet oxygen that are produced under intense sunlight," says Kleine.

Whether running away from a predator or to win an Olympic gold, how fast we run determines the final outcome. Locomotion is produced when limb muscles contract in a co-ordinated fashion. This, in turn, is caused by electrical impulses sent by nerve cells called motor neurons located in the spinal cord. Earlier work showed that based on an animal's momentary needs, brain circuits select a suitable course of action and set the frequency of motion. Then, just like engaging gears in an automobile, spinal 'speed' modules are selectively activated to achieve a certain speed. Thus, motor neurons belonging to the fast module are activated only during fast frequency movements, but are silent during slower frequency movements. Now, scientists at the National Centre for Biological Sciences (NCBS), Bangalore show that parallel neural pathways that bypass the brain's tight frequency control enable animals to move faster.

In their study, the scientists chose to study speed regulation in larval zebrafish during a reflex behavior called optomotor response. This behavior allows zebrafish to maintain a stable position in streams by generating swims to counter any drift. They evoked this behavior in the lab by playing black and white moving bars (gratings) on a screen placed underneath the fish. While larvae were pinned on a dish to allow measurement of electrical activity from motor neurons, they still responded reliably to the visual stimulus by producing motor commands for swimming. Using this preparation it was possible to probe mechanisms of speed regulation at a single cell level.

Dopamine, a chemical produced by some nerve cells, is released at multiple sites including onto motor neurons. The researchers at NCBS discovered that when the receptors for dopamine were activated, zebrafish larvae swam faster for the same grating stimulus. On closer examination, they found that larvae could swim faster because for every tail beat, the tail made larger amplitude bends. This implies that to achieve faster swims, more motor neurons were activated. Recording the electrical activity of single motor neurons, the researchers found that not only was the slow speed module activated more vigorously after dopamine receptor activation, but fast module motor neurons, which were hitherto silent, were also activated. This was caused by direct actions of dopamine on the motor neurons, which caused the motor neurons to be more excitable.

These results are exciting because they show that motor neurons, which are thought to mostly only relay the command coming to them, are capable of altering behavioral output via modulation of their activity patterns. This study shows that, even after the brain has issued the command for a movement, changing the properties of motor neurons can alter the final behavioral outcome. Such motor neuronal plasticity can be exploited for rehabilitation after spinal cord injury or stroke.