Brain

Scaffold helps cells repair torn meniscus in lab tests

image: A porous scaffold, seen at 250 times magnification, helped heal a torn meniscus. The scaffolded repair was stronger after four weeks than a meniscus that went through the natural healing process.

Image: 
Duke Health

DURHAM, N.C. - About a million times a year, Americans with a torn meniscus in their knee undergo surgery in hopes of a repair. Certain tears can't be fixed or won't heal well, and many patients later suffer osteoarthritis from the injury.

Scientists have tried developing scaffolds or structures from various materials, including plastic and textile fibers, to lay a foundation for new cells. In a paper published June 18 in the journal Scientific Reports, Duke scientists describe a more organic model -- a scaffold derived from a pig's meniscus, which performed better in lab tests than healing without a scaffold.

"A partial meniscus removal is one of the most commonly performed orthopedic surgeries in the U.S.," said Amy McNulty, Ph.D., an assistant professor in orthopedic surgery at Duke and senior author of the paper.

"The damaged tissue must be cut out because it's causing pain or catching, but when the tissue comes out it also alters load-bearing in the knee and often leads to osteoarthritis, so it would be beneficial to try and heal the meniscus in place using a tool like a scaffold," McNulty said.

In lab tests, repairs aided by the scaffold resulted in a stronger meniscus repair after four weeks compared to a meniscus that went through the natural healing process.

A scaffold could be especially valuable when the meniscus tears near the inside of the crescent-shaped tissue where blood doesn't flow. Without a blood supply, a tear in this section won't mend and the tissue is often removed, McNulty said.

The pig-derived scaffold is advantageous over other models including synthetics, because it is processed without chemicals or enzymes, which helps it retain more natural properties, McNulty said. Also, the structure is more porous than other models and even regular meniscus tissue, which allows new cells to move into it more easily to integrate with damaged tissue.

"Cells from the native tissue appear to be naturally attracted to the scaffold -- they want to move into it," McNulty said. "Hopefully, this will lead one day to a scaffold being placed into different tears to augment healing and seamlessly integrate the pieces of damaged tissue."

The next step is testing the scaffold in animal models and eventually in humans, she said.

Credit: 
Duke University Medical Center

Aggressive, non-native wetland plants squelch species richness more than dominant natives do

image: Even when they dominate a wetland site, native plants, right, tend to coexist with a greater diversity of other native plants than when non-native plants, left, are dominant.

Image: 
Greg Spyreas, Michael Jeffords and Susan Post

CHAMPAIGN, Ill. -- Dominant, non-native plants reduce wetland biodiversity and abundance more than native plants do, researchers report in the journal Ecology Letters. Even native plants that dominate wetland landscapes play better with others, the team found.

The researchers analyzed 20 years of data collected by expert botanists from hundreds of randomly selected sites in Illinois. This allowed them to track changes in the variety and abundance of different plants in the same locations over time.

The dominant non-natives are not just choking out many other plants, the researchers report. They also have a broad ecological footprint, taking over wetlands on a regional level, rather than just in individual sites. This negatively affects populations of birds and insects that rely on the native wetlands.

"The more dominant they are, the less room is available for other species," said Illinois Natural History plant ecologist and botanist Greg Spyreas, who conducted the research with INHS plant ecologist David Zaya and colleagues from the U.S. Geological Survey. "These non-natives become more dominant over time and their impact on the rest of the community is fundamentally different," Spyreas said. "They outcompete better. And that's across hundreds of sites."

For example, a European cultivar of reed canary grass has taken hold in many parts of North America. It grows extremely fast, reduces the light available to other plants, produces enormous numbers of seeds and sends out underground stems to quickly colonize a site, Spyreas said.

"It creates this very thick thatch of dead material on the ground that other plants can't penetrate - but it can," he said. "It tolerates drought and flooding very well, whereas a lot of native plants cannot."

Another offender, a non-native common reed, Phragmites, "is notable in its aggressiveness," Zaya said. It can quickly crowd out other wetland species, including native Phragmites.

Not all non-native plants reduce the ecological richness of wetlands, Zaya said.

"There are non-natives that sit in the background and don't affect the wetland community," he said. "Also, many native plants will dominate wetland communities."

Some researchers have hypothesized that it doesn't matter if a dominant plant is native or non-native: Both can drive down the diversity and abundance of other species, Zaya said.

But the new study shows that dominant, non-native species are much more likely to radically diminish the biological diversity of a locale than their native counterparts will.

"When I see native- versus non-native-dominated wetlands, it looks like two totally different worlds," Zaya said. "Each native wetland has its own personality, with a different little flower or forb or rare grass or sedge. No two are the same. But the non-native wetlands tend to look alike. They're the same here as they are in Ohio."

The data also offer insights into how to best maintain wetland diversity, the researchers said.

"If you have a massive database of wetland plants like we do in Illinois, if you look at the numbers, you can isolate the species that are the most problematic," Spyreas said. Five non-native wetland plants are on the "worst offender" list, he said: reed canary grass, a non-native cattail, invasive Phragmites and two European buckthorns.

"If you can eliminate those, you've eliminated 90 percent of the non-native wetland species problem," Spyreas said.

Credit: 
University of Illinois at Urbana-Champaign, News Bureau

Memories form 'barrier' to letting go of objects for people who hoard

New research conducted at the University of Bath has demonstrated important differences in how people with and without hoarding problems discard objects and the role their memories play.

It was already known that hoarding behaviour is driven by a strong emotional connection with objects. But the new experimental findings, published online in the journal Behavior Therapy, show that for people who hoard this connection may be in part attributable to the vivid, positive memories associated with those objects.

In essence, for those with hoarding problems, individual items become an extension of a given memory, becoming a barrier to decluttering and hence exacerbating an individual's problems. Drawing on the new findings, the team behind the study hope that cognitive-behavioural therapy (CBT) for hoarding might be enhanced by training individuals to respond differently to those memories.

Hoarding describes a problem where individuals have considerable difficulty letting go of possessions. Consequently, rooms can become so cluttered over time that living spaces becomes no longer usable for their intended purpose.

According to the Royal College of Psychiatrists, hoarding can be a mental health problem in its own right (known as 'hoarding disorder'). The clutter associated with hoarding can have profound negative effects on the lives of people living with the problem and those around them, particularly with respect to emotional and physical well-being, health and safety, and finances. The fire risks associated with clutter are also be of particular concern.

Lead researcher Dr Nick Stewart, who now works as a Clinical Psychologist at Avon & Wiltshire Mental Health Partnership NHS Trust, explains: "People who hoard are often offered CBT to help them understand the thoughts and feelings associated with their saving and acquiring behaviours. This approach is very beneficial for some people, but not all. Our aim is to understand better the psychological factors that drive hoarding behaviour, to give us clues for how therapy for hoarding might be improved."

The researchers conducted structured interviews with 27 people with clinically-significant hoarding problems, and 28 without such difficulties (the 'control' group).

Participants were asked to recall the memories that came to mind the last time they discarded, or tried to discard, items at home.

Both groups reported positive memories while discarding possessions that they valued (which may describe most possessions in the case of people who hoard). These memories included recollections of acquiring the object, or memories of an event or person associated with the object. Crucially, the control participants (those without a hoarding problem) reported attempts to avoid this positive imagery, while the hoarding participants did not.

Dr Stewart explains: "We can all relate to the experience of being flooded with positive memories when we hold valued possessions in our hands. However, our findings suggest that it's the way in which we respond to these object-related memories that dictates whether we hold onto an object or let it go. The typical population appears to be able to set aside these memories, presumably to ease the task of discarding the objects, and so manage to avoid the accumulation of clutter. The hoarding participants enjoyed the positive memories but reported that they got in the way of their attempts to discard objects."

In the paper, the researchers have suggested ways in which this new insight could be used to enhance CBT for hoarding.

Dr James Gregory, Clinical Research Tutor and Clinical Psychologist at the University of Bath, who supervised the research, said: "Where positive memories, and the mental images associated with them, are getting in the way of discarding objects, therapists could work with people to develop an alternative image to 'compete' with the one that's causing difficulty. This competing image could capture the positive consequences of discarding items, for example, eating a meal with loved ones at a dinner table once it is clear of possessions."

The next step is a follow-on experimental study to see if helping people to 'rescript' memories in this way is helpful for enabling people to let go of objects more easily.

Dr Gregory added: "While memories associated with objects can afford a sense of comfort and security to people who hoard, the resulting clutter can rob people of their quality of life.

"This study is part of a wider effort at Bath to to better understand the special relationship that people have with their possessions. Ultimately we hope to use this knowledge to improve psychological support available and to enhance the wellbeing of people who hoard."

Notes on hoarding:

Up to 1.3 million people in the UK may have a significant hoarding problem (or develop one in the future);

People with hoarding problems may keep items for sentimental reasons or because they find objects beautiful or useful. Most people with hoarding problems have a very strong emotional attachment to objects;

Hoarding can become problematic for several reasons. It can take over a person's life, making it very difficult for them to get around their house. It can also affect work performance, personal hygiene and cause relationships to suffer;

Household clutter can also pose a health risk to the person and anyone who lives in or visits their house. For example, it can become a fire risk and block exits in the event of a fire, or cause trips and falls;

The main treatment is cognitive behavioural therapy (CBT). The therapist will help the person to understand what makes it difficult to throw things away and the reasons why the clutter has built up. This will be combined with practical tasks and a plan to work on.

On hoarding research at Bath:

The Bath team is currently leading work to explore the potential of immersive VR technologies in modelling treasured items, giving those with hoarding tendencies a form of exposure therapy and the opportunity to discard items in a virtual world.

Credit: 
University of Bath

A sound idea: a step towards quantum computing

image: Laser pulses.

Image: 
University of Tsukuba

Tsukuba, Japan - A team at the University of Tsukuba studied a novel process for creating coherent lattice waves inside silicon crystals using ultrashort laser pulses. Using theoretical calculations combined with experimental results that were obtained at the University of Pittsburgh, they were able to show that coherent vibrational signals could be maintained inside the samples. This research may lead to quantum computers based on existing silicon devices that can rapidly perform tasks out of the reach of even the fastest supercomputers now available.

From home PCs to business servers, computers are a central part of our everyday life, and their power continues to grow at an astounding rate. However, there are two big problems looming on the horizon for classical computers. The first is a fundamental limit on how many transistors we can pack into a single processor. Eventually, a totally new approach will be needed if we are to continue to increase their processing capacity. The second is that even the most powerful computers struggle with certain important problems, such as the cryptographic algorithms that keep your credit card number safe on the internet, or the optimization of routes for delivering packages.

The solution to both problems may be quantum computers, which take advantage of the rules of physics that govern very small length scales, as with atoms and electrons. In the quantum regime, electrons act more like waves than billiard balls, with positions that are "smeared-out" rather than definite. In addition, various components can become entangled, such that the properties of each one cannot be completely described without reference to the other. An effective quantum computer must maintain the coherence of these entangled states long enough to perform calculations.

In the current research, a team at the University of Tsukuba and Hrvoje Petek, RK Mellon Chair of Physics and Astronomy at the University of Pittsburgh used very short laser pulses to excite electrons inside a silicon crystal. "The use of existing silicon for quantum computing will make the transition to quantum computers much easier," first author Dr. Yohei Watanabe explains. The energetic electrons created coherent vibrations of the silicon structure, such that the motions of the electron and the silicon atoms became entangled. The state of the system was then probed after a variable delay time with a second laser pulse.

Based on their theoretical model, the scientists were able to explain oscillations observed in the charge generated as a function of delay time. "This experiment reveals the underlying quantum mechanical effects governing the coherent vibrations," says senior author Prof. Muneaki Hase, who performed the experiments. "In this way, the project represents a first step towards affordable consumer quantum computers."

Credit: 
University of Tsukuba

Your nose knows when it comes to stronger memories

Memories are stronger when the original experiences are accompanied by unpleasant odors, a team of researchers has found. The study broadens our understanding of what can drive Pavlovian responses and points to how negative experiences influence our ability to recall past events.

"These results demonstrate that bad smells are capable of producing memory enhancements in both adolescents and adults, pointing to new ways to study how we learn from and remember positive and negative experiences," explains Catherine Hartley, an assistant professor in New York University's Department of Psychology and the senior author of the paper, which appears in the journal Learning and Memory.

"Because our findings spanned different age groups, this study suggests that aversive odors might be used in the future to examine emotional learning and memory processes across development," adds Alexandra Cohen, an NYU postdoctoral fellow and the paper's lead author.

The impact of negative experiences on memory has long been shown--and is familiar to us. For example, if you are bitten by a dog, you may develop a negative memory of the dog that bit you, and your negative association may also go on to generalize to all dogs. Moreover, because of the trauma surrounding the bite, you are likely to have a better recollection of it than you would other past experiences with dogs.

"The generalization and persistence in memory of learned negative associations are core features of anxiety disorders, which often emerge during adolescence," notes Hartley.

In order to better understand how learned negative associations influence memory during this stage of development, the researchers designed and administered a Pavlovian learning task to individuals aged 13 to 25. Mild electrical shocks are often used in this type of learning task. In this study, the researchers used bad smells because they can be ethically administered in studying children.

The task included the viewing of a series of images belonging to one of two conceptual categories: objects (e.g., a chair) and scenes (e.g., a snow-capped mountain). As the study's participants viewed the images, they wore a nasal mask connected to an olfactometer. While participants viewed images from one category, unpleasant smells were sometimes circulated through the device to the mask; while viewing images from the other category, unscented air was used. This allowed the researchers to examine memory for images associated with a bad smell as well as for generalization to related images. In other words, if the image of a chair was associated with a bad smell, would memory be enhanced only for the chair or for objects in general?

What constitutes a "bad" odor is somewhat subjective. In order to determine which odors the participants found unlikable, the researchers had the subjects--prior to the start of the experiment--breathe in a variety of odors and indicate which ones they thought were unpleasant. The odors were blends of chemical compounds provided by a local perfumer and included scents such as rotting fish and manure.

As the subjects viewed the images, the scientists measured perspiration from the palm of the subjects' hands as an index of arousal--a common research technique used to confirm the creation of a negative association (in this case, of a bad smell). A day later, researchers tested participants' memory for the images.

Their findings showed that both adolescents and adults showed better memory specifically for images paired with the bad smell 24 hours after they saw these images. They also found that individuals with larger arousal responses at the point when they might experience either a bad smell or clean air while viewing the image, regardless of whether or not a smell was actually delivered, had better memory 24 hours later. This suggests that unpredictability or surprise associated with the outcome leads to better memory.

Credit: 
New York University

Statin therapy reduced the risk of stroke and possibly other cardiovascular complications in cancer patients following radiation

DALLAS, June 19, 2019 -- Cancer patients taking cholesterol-lowering statin medication following radiation therapy of the chest, neck or head had significantly reduced risk of suffering a stroke, and possibly other cardiovascular complications, according to new research in Journal of the American Heart Association, the Open Access Journal of the American Heart Association/American Stroke Association.

This is the first large study to explore whether statins reduce cardiovascular complications in patients who have radiation therapy for chest, head or neck cancer.

More than half of cancer patients are treated with radiation therapy, which uses high doses of radiation to kill cancer cells and shrink tumors. While radiation treatment has become more precise and long-term survival rates have improved, the radiation can affect nearby healthy cells and cause side effects many years later.

Radiation therapy side effects include scarring or thickening of arteries, and over time that can lead to blockages that cause heart attack and stroke. In fact, the authors point out that cardiovascular disease is the leading cause of illness and death among cancer survivors.

The newly published study looked at whether statin medication, which reduces the formation of plaques that block blood vessels, might lower the risk of cardiovascular and cerebrovascular disease after radiation therapy to the chest, neck or head. The researchers found that the use of statins was associated with a 32% reduction in stroke.

There was also a strong trend toward reduction in overall cardiovascular events, such as heart attacks and stroke, and death due to those cardiovascular events, although the authors said the 15% reduction they found was not statistically significant due to the high-risk population of patients in the study.

"Statins decrease cholesterol levels and have anti-inflammatory properties. Multiple studies have revealed the beneficial effects of statin therapy on reducing the risks of vascular disease in a variety of populations," said study author Negar Mousavi, M.D., M.H.Sc., at McGill University Health Center in Montreal, Canada. "Statins are protective in patients with heart disease, previous strokes and with high cholesterol levels."

For the study, the researchers studied data from 5,718 heart attack and stroke patients over age 65 (with a mean age of 75) at McGill University Health Centre in Montreal, Canada, who had undergone radiation therapy for chest, head or neck cancer from 2000 to 2011. The majority -- 4,166 patients -- were taking statins. Most of the people in the study had underlying cardiovascular disease.

"Our study demonstrated that statin therapy could be favorable even with the competing risks of cancer and cancer-related mortality in patients who received radiation therapy," said Mousavi who added, "No other agent is recommended with enough evidence to reduce the risk of vascular events among cancer patients receiving radiation to the head, neck or chest."

However, the authors point out that there is a need for prospective studies to explore the role of statins after radiation therapy in wider populations and to establish definitive guidelines on the management of radiation-induced vascular disease.

Credit: 
American Heart Association

Unexpected culprit -- wetlands as source of methane

image: Undergraduate student Cain Silvey checking methane concentration in a field mesocosm with swamp milkweed in Dayton, Ohio that was part of the constructed wetland research area. The blue plastic tubes protect tree seedlings that are part of a different restoration project.

Image: 
Karla Jarecke

Wetlands are an important part of the Earth's natural water management system. The complex system of plants, soil, and aquatic life serves as a reservoir that captures and cleans water. However, as cities have expanded, many wetlands were drained for construction. In addition, many areas of land in the Midwest were drained to increase uses for agriculture to feed a growing world.

Draining wetlands disconnected the natural flow and retention of water, a system that had worked well for millennia. One solution to wetland draining was to rebuild these wetlands in another area (more convenient to humans). These are referred to as "constructed wetlands." In other cases, constructed wetlands are built to rebuild an area no longer used for agriculture.

How these constructed wetlands are built and managed can make a big environmental impact. Karla Jarecke and researchers from several universities have been studying wetlands' impact on greenhouse gas methane.

"Globally, wetlands are the largest natural source of methane to the atmosphere," says Jarecke. "Methane has a much bigger impact than carbon dioxide on global warming - an impact 25 times greater."

Both natural and constructed wetlands emit methane. Due to their nature - wetlands are, after all, wet - soil microbes and plants are forced to metabolize under anaerobic conditions. And, this leads to methane production.

The soil microbes are responsible for the production of methane in wetlands. The methane then gets to the atmosphere via diffusion, transport through plant tissue, and the episodic release of gas bubbles. The hydrologic stability of wetland soils, as well as the transport efficiency through plants, can affect how much and how often methane is released from the soil.

"Understanding the conditions under which methane is produced and released in wetlands could lead to solutions to reduce methane emissions," says Jarecke.

But, studying large areas like wetlands can prove impossible. So, Jarecke and her colleagues made "mesocosms" of wetlands - manageable, outdoor chambers where methane emissions could more easily be measured. Mesocosms are structural research areas that bridge the gap between lab studies and large field studies.

The study focused on two common wetland plants and their potential role in methane emissions: swamp milkweed and northern water plantain. Plants and soils were collected from a constructed wetland in Dayton, Ohio. They were then transported to Lincoln, Nebraska to create wetland mesocosms. The Dayton site had formerly been drained and used for agriculture and was rebuilt as wetland in 2012.

The researchers harvested seedlings of swamp milkweed and northern water plantain from the wetland and transplanted them into soils collected in PVC pipe. They covered individual plants with clear acrylic cylinders during gas sampling. This helped them measure and quantify methane emissions from the soil-plant mesocosms. The study was performed in the summer of 2013.

Besides comparing the emissions of the two plant species, the researchers studied the effects of hydrology - or the saturation of the soil. "While the controls of hydrology and plant species on methane emissions are individually well-studied, the two are rarely studied together," says Jarecke.

This recent study concluded that water level and saturation influenced methane emissions more than the type of plant species. While methane emissions differed between laboratory mesocosms with water plantain and mesocosms with swamp milkweed, methane emissions did not differ in field mesocosms with each of the two species. In the field, soil saturation had a greater effect on methane emissions.

Finding plant species that reduce microbial methane production could be a key to better wetland management. For example, plants that deliver oxygen to the rooting zone can suppress microbial methane production. In addition, future research is needed to understand how varying soil saturation affects methane emissions. This information could be valuable for designing wetland topography that creates hydrologic conditions for increased carbon storage and reduced methane emissions.

Future research might focus on longer periods of time. "Methane emissions likely change as restored wetlands mature," says Jarecke. "Organic matter from root systems, decaying plants and other materials will build up. This helps restore hydrologic stability. Other research indicates that it can take just a few years to restore hydrologic aspects of a restored wetland. However, biogeochemical and biodiversity aspects can take decades or longer to recover."

Credit: 
American Society of Agronomy

Scientists identify plant that flowers in Brazilian savanna one day after fire

image: Rapid resprouting and flowering of Bulbostylis paradoxa is proof of the Cerrado biome's superb resilience and its capacity to evolve through fire.

Image: 
Alessandra Fidelis / personal archive

Plants in the Brazilian savanna, the Cerrado, have evolved to deal with fire. When fire is used intelligently as part of a carefully planned land management method, it is indispensable to the conservation of this superb ecosystem, the world's most biodiverse savanna. Two months suffice for the Cerrado to burst into flower after a fire (read more at agencia.fapesp.br/26064 and agencia.fapesp.br/26542).

The study "From ashes to flowers: a savanna sedge initiates flowers 24 h after fire", published recently in the journal Ecology, confirms this observation.

"The species is Bulbostylis paradoxa, a sedge [perennial herb similar to rushes and grasses] belonging to the family Cyperaceae," Alessandra Fidelis, first author of the article, told. "Its common name in Brazil is cabelo-de-índio ['Amerindian hair']."

Fidelis is a professor at São Paulo State University (UNESP) in Rio Claro, Brazil, and conducted the study with support from São Paulo Research Foundation - FAPESP as part of the project "How does the fire season affect Cerrado vegetation?".

The Cerrado is a unique type of savanna. Its capacity to grow back and flower after burning is a key difference in comparison to African and Australian savannas.

This had already been reported in the nineteenth and early twentieth centuries by naturalists who visited Brazil, such as French botanist Augustin de Saint-Hilaire (1779-1853) and Danish plant ecologist Eugen Warming (1841-1924).

Leopoldo Magno Coutinho (1934-2016), a professor at the University of São Paulo (USP), focused on it in his habilitation.

Fidelis has been studying postfire regeneration of the Cerrado since 2009, but in this study, she was struck by the speed with which B. paradoxa flowers after being completely charred in a wildfire. The article is indeed a first in this respect. "It's the only event of its kind described worldwide to date," she said.

B. paradoxa is distributed throughout South America and is found from Venezuela to the south of the continent. It flowers on a significant scale only after fires. "In our experiments with burning as a careful management practice, we found that plants of this species reduced to carbonized stumps began exhibiting white spots 24 hours after the fire. These spots were incipient inflorescences," Fidelis recalled.

"In little more than a week, the flowers were fully formed and ready for pollination. The speed of this response is a significant advantage for the plant, enabling it to flower, fructify and disperse windborne seeds in the open, with the soil uncovered and without barriers or competitors. Only 40 days after a fire, it's very hard to find seeds because they've dispersed."

More generally, the abundant seeds available after fires in the Cerrado are an important resource for predators, such as ants and birds. Resprouting leaves are tender and palatable to large mammals, such as deer and cattle.

Burning is a problem when it results from arson or uncontrolled wildfires that spread disastrously owing to a buildup of combustible material after years without properly managed burning.

"The Cerrado has evolved through fire," Fidelis said. "Its vegetation regenerates easily. Species that did not occur before a fire may appear in certain areas. The animals may suffer losses, however, as many of them are trapped in fires. It is crucial to bear in mind that the Cerrado contains gallery forest, valley forest and palm marshes, where fire-sensitive species may fail to recover after a major burning. Hence, careful fire management is important. Preventive burning at the right time, with total area zoning and a rotating fire schedule for demarcated patches, is the best defense against disasters due to uncontrolled wildfire."

Expansion of the agricultural frontier, with large-scale monocultures and the intensive use of machinery and herbicides, leaving the soil completely clear and subject to invasion by signalgrass and molasses grass, is currently the main threat to the Cerrado's survival. Improper use of fire is the next most important threat. Together, these two factors endanger the continued existence of the entire ecosystem.

Some of Brazil's most important rivers originate in the Cerrado, including the Xingu, Tocantins, Araguaia, São Francisco, Parnaíba, Gurupi, Jequitinhonha, Paraná and Paraguay rivers. In addition to the irreparable loss of biodiversity, destruction of the Cerrado jeopardizes the basins of these rivers as a major source of fresh water and hydropower potential.

Credit: 
Fundação de Amparo à Pesquisa do Estado de São Paulo

Uncovering hidden protein structures

image: From left to right: Professor Karin Hauser, Annika Krüger und PD, Dr. Aswin Mangerich

Image: 
Jespah Holthof, University of Konstanz

Combining research-oriented teaching and interdisciplinary collaboration pays off: Researchers at the University of Konstanz develop a novel spectroscopic approach to investigate hitherto difficult-to-observe protein structures. On "campus.kn", the online magazine of the University of Konstanz, we report on the new approach and its origin at the interface between chemistry and biology.

Using infrared (IR) spectrosocopy, researchers at the University of Konstanz were able to uncover the interaction between the p53 protein, a tumour suppressor that controls the cell cycle, and poly(ADP-ribose) (PAR) and deoxyribonucleic acid (DNA) at the molecular level. The nucleic acid-like biopolymer PAR serves as a cellular signal transmitter and helps to regulate protein activity. By studying the interaction between p53 and PAR, the researchers were able to learn more about molecular reactions to cellular stress in response to, for example, DNA damage, which represents a potential tumour risk. Their basic research on the processes behind DNA damage is, on the one hand, paramount to understanding how cancer develops and how cells age. On the other hand, the innovative scientific approach is advancing the research carried out in their field. Their research results were published in issue 9 (21 May 2019) of the scientific journal Nucleic Acids Research by the Oxford University Press.

In a new article published on "campus.kn", the online magazine of the University of Konstanz, we tell the story of the project's development, which builds on interdisciplinary linkages especially between early career researchers: https://www.campus.uni-konstanz.de/en/science/uncovering-hidden-protein-structures

Credit: 
University of Konstanz

Hydrogenation of white phosphorus leads way to safer chemical technology

White phosphorus is well-known for being a highly toxic compound with suffocating scent. Its high reactivity is the reason for it to be stored with oxygen access in inert media. It's also infamous for its military use in bombs and grenades.

Meanwhile, KFU scientists are hard at work to tame the dangerous compound. Project head Zufar Gafurov explains, "We have suggested an effective method of selective electric synthesis of P-H and P-C bonds contiaining derivatives directly from white phosphorus, which may help avoid the use of existing chlorine oxygenation technology. We have found completely new ways of obtaining organophosphorous compounds directly from white phosphorus."

The proposed technological process comprises electrolysis of white phosphorus and an acid on a lead cathode with resulting synthesis of oxygen radicals. The electrolyser is a non-flowing cell without a diaphragm. This new method is in line with contemporary strict environmental requirements.

"Soft conditions, high speed, selectivity and easy control are the advantages of this method for industrial applications. Furthermore, it's very clean in comparison with traditional methods of organic chemistry," adds Dr. Gafurov.

The research group plans to move further in its work on white phosphorus.

Credit: 
Kazan Federal University

Redundancies in T cells

Oncologists have had great success with cancer immunotherapy in recent years, especially with the approach known as immune checkpoint inhibition, which was recognised with last year's Nobel prize for medicine. Tumour cells have the ability to curb the activity of patients' own T cells, causing the T cells to leave the tumour alone. To do this, they use a molecular "handshake", where molecules on the surface of tumour cells interact with checkpoint molecules, as they are known, on the surface of T cells. However, if patients are administered particular antibodies (checkpoint inhibitors) that render this interaction impossible, the T cells can attack and eliminate the tumour.

One of the key checkpoint molecules is PD-1. Until now, there had been little research into just how the PD-1 handshake signal is transmitted within T cells to prevent the cells being activated. A team of scientists at ETH Zurich and Aix-Marseille University has now taken a closer look at important molecules in the biochemical signalling pathway of PD-1, including the enzyme SHP-2.

Cancer researchers are targeting this enzyme to further increase the efficacy of cancer immunotherapy. The scientists in Zurich and Marseille have now shown that when SHP-2 is lacking, a related molecule, SHP-1, performs its role. "SHP-1 and SHP-2 can replace each other," says Peter Blattmann, a postdoc in the group led by Matthias Gstaiger, Senior Scientist at the Institute of Molecular Systems Biology at ETH Zurich. "So it's not enough to attack just one of these molecules - you have to target both simultaneously."

"Investigating how T cells transmit checkpoint molecule signals internally holds potential not only for cancer research, but also immunology in general," Gstaiger says. "We're dealing with molecules that activate immune cells and molecules that inhibit those cells. Like yin and yang, these molecules maintain the equilibrium in the immune system and prevent immune reactions from getting out of hand."

To ascertain which molecules in fact interact with the PD-1 surface molecule, the researchers conducted experiments with mouse T cells, isolating the PD-1 molecule and several dozen molecules that bind to PD-1. They were able to identify these molecules using SWATH-MS, a mass spectrometry approach that was developed at ETH Zurich.

Credit: 
ETH Zurich

Changes in obesity among low-income children enrolled in WIC

Bottom Line: This study looked at changes in overweight and obesity among low-income young children enrolled in the food assistance Special Supplemental Nutrition Program for Women, Infants and Children (WIC) from 2010 to 2016. The analysis included 12.4 million children 2 to 4 years old. Obesity declined between 2010 and 2016 to 13.9% from 15.9%; overweight and obesity combined declined to 29.1% from 32.5%. Declines were seen overall and in all age, sex and racial/ethnic subgroups. Reasons for the declines are unknown but could include WIC food package revisions, along with local, state and national initiatives. A limitation of the study is that fewer children were enrolled in WIC in recent years.

Credit: 
JAMA Network

Gold adds the shine of reversible assembly to protein cages

image: Protein cages using gold ions.

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University of Tsukuba

Tsukuba, Japan - Protein cages--capsule-like structures made up of numerous protein molecules--perform roles in nature that have inspired their application in areas such as drug delivery. Their controlled assembly is therefore of particular research interest; however, the stimuli responsive disassembly of protein cages has not yet been reported. Now, an international research team has reported gold-directed reversible assembly of 3D protein cages. Their findings are published in Nature Research.

Reported methods for preparing protein cages based on protein-protein interactions, such as hydrogen bonding and hydrophobic interactions, can result in stable cages; however, such assemblies are static and once formed do not offer any means of smart control. In contrast, assembly that uses metal ions to facilitate interactions between proteins provides a release mechanism.

Although metal-driven assembly of proteins has been reported, examples of 3D cage structures prepared this way are rare. The researchers engineered a ring-shaped protein known as TRAP (trp RNA-binding attenuating protein) so that it exhibited equally spaced thiol groups of cysteine moieties. Adding a source of gold ions to the proteins in solution led to the assembly of 3D protein cages, based on gold-sulfur interactions, within minutes.

"By modifying the protein building blocks we have been able to direct the assembly of cages in a way that also provides us with control of their stability," study author Kenji Iwasaki explains. "The proteins assembled within minutes of introducing gold into the system and cryo-electron microscopy allowed us to clearly see the formed structures, which have a diameter of approximately 22 nm."

Detailed analysis of the shape of the protein cages revealed that the structures are made up of 24 rings arranged to give six square apertures. This arrangement is known as a snub cube, an Archimedean solid that the researchers believe has not previously been observed in nature.

The cage structures were shown to be stable over a range of temperatures, including at 95 °C for multiple hours, and were also found to be robust in the presence of a range of chemicals capable of disrupting hydrogen-bonded structures. However, in the presence of reducing agents, including biologically relevant anti-oxidants present in the body, the cages could be disassembled.

"The reversible control of cage stability is an exciting feature in terms of providing smart properties for dynamic cargo delivery applications," Professor Iwasaki explains. "However, beyond these practical features, the observation of an unprecedented structural architecture that has not, to our knowledge, been observed in nature and has parallels in Islamic artwork, has provided an interesting dimension to our findings."

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University of Tsukuba

Is sexting associated with sexual behaviors, mental health among teens?

Bottom Line: This study, called a systematic review and meta-analysis, combined the results of 23 studies with nearly 42,000 participants to summarize associations between sexting by adolescents, sexual behavior and mental health risk factors. The results suggest sexting was associated with sexual activity, multiple sex partners, a lack of contraception use, delinquent behavior, anxiety/depression, alcohol and drug use, and smoking. Some associations between sexting, sexual behaviors and mental health factors were stronger in younger compared with older adolescents. This kind of study can only suggest correlations, not causation, and other variables, such as intention and context, can mediate the observed associations. For example, sexual exploration among adolescents is normal, sexting can have relatively harmless intentions and sexting within the context of a romantic relationship may not indicate risky behavior. That's why more research is needed to understand what the intersections of sexting, sexual behaviors and mental health risk factors mean.

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JAMA Network

From function to form

Sequencing the first human genome was a herculean effort that took 13 years, hundreds of researchers around the globe and billions of dollars.

But recent advances in technology have transformed genome sequencing into a fairly mundane affair with millions of people having sequenced at least parts of their genomes using DNA collection kits available at drug stores.

Although these leaps in scientists' ability to perform genetic analyses have yielded untold insights into human heritage, disease and health, the precise meaning behind DNA sequences--how the order of the "letters" in each DNA strand instruct the body's proteins what to become and what to do--remains unclear.

Now, in a scientific first, scientists in the Blavatnik Institute at Harvard Medical School have shown it is possible to determine the 3D structures of a gene by assessing the effects of lab-made genetic mutations on protein functions.

The team's findings, published June 17 in Nature Genetics, represent a significant step toward linking sequence data with its function in cells. The tool is freely available at https://github.com/debbiemarkslab/3D_from_DMS_Extended_Data

The current study will be published in parallel with research from a team led by Jörn Schmiedel and Ben Lehner at the Barcelona Institute of Technology that independently arrived at similar results, employing the concept but using a different technique, thus affirming the utility of the approach.

The computational approach used in the study is known as deep-mutational scanning and involves the use of high-throughput sequencing to synthesize various genetic mutations and then determine the mutations' impact on protein function.

By contrast, previous efforts--including work by researchers in the current study--relied on machine learning to glean such 3D structures from naturally occurring, rather than lab-made, DNA samples.

In the current study, researchers identified functional interactions within DNA sequences containing instructions for four different proteins and one RNA. From these, the researchers constructed 3D structures of the proteins--a spatial configuration that can lend valuable clues about the work these proteins perform in cells.

"We live in a three-dimensional world where structure determines function," said study senior investigator Debora Marks, an associate professor of systems biology at Harvard Medical School, who led the team with HMS post-doctoral researcher Kelly Brock and doctoral student Nathan Rollins of Harvard University.

"Understanding what shapes and conformations proteins take inside cells can help us predict their function and the effects that variations in these structures can have on cell function or malfunction."

Such insight, Marks said, represents a marked advance toward a better understanding of individual protein variations in disease and health and can inform the development of precision drugs that target specific parts of the proteins. Each protein in the human body is made of a string of combinations of 20 different amino acids, Marks explained. The amino-acid makeup of the protein is important, but how these amino acids fold, interlace and relate to each other three-dimensionally is just as critical in determining protein function and dysfunction.

Researchers have long relied on methods such as x-ray crystallography, cryogenic electron microscopy (cryo-EM) or nuclear magnetic resonance imaging (NMRI) to determine protein structures. However, these methods can be time-consuming and require expensive, highly specialized equipment. Some proteins, such as those bound to membranes or those that tend to aggregate, or clump--such as amyloids in the brain--aren't amenable to these visualization techniques at all.

Searching for a better way, Marks and her colleagues from Harvard Medical School, the Dana-Farber Cancer Institute and the Broad Institute turned to mutational libraries--synthetic DNA sequences developed by other researchers in which the pattern of DNA was changed to alter individual amino acids.

The team was interested specifically in libraries containing simultaneous mutations in separate amino acids within the same sequence. They sought mutation pairs that affected protein function and fitness interdependently of one another, a biologic effect known as epistasis. The strongest instances of epistasis, the investigators reasoned, should be mediated by direct interactions between the amino acid partners in 3D. Strong epistasis in a scan with enough mutation pairs should thus reveal sufficient 3D interactions to glean and build the full 3D structure.

The team used proteins derived from humans, yeast and rice, including a two-protein complex, as well as a ribozyme, a piece of RNA with enzyme-like function. Each of these molecules was well-studied and had existing structures derived through other means, which allowed the team to validate the precision of their final predictions.

The researchers fed information from these libraries into a computer program, which they used to generate the 3D structures of the molecules. Surprisingly, data from these epistatic mutations were enough to generate structures that closely mimicked those derived from the established methods, with variations in physical positions as small as 1.8 angstroms.

Although this method is amenable for use in small proteins, Marks noted, larger proteins present a greater challenge. For example, a protein composed of 300 amino acids would have 16 million possible mutation pair sequences. While sequence synthesis is becoming vastly more efficient and may soon shoot past this limitation, it remains difficult to create libraries of that size.

However, additional work showed that running this full dataset isn't necessary; running just a fraction of the possible mutational combinations produced accurate 3D structures. The team showed that libraries as small as one-twentieth of the original size could get the job done when applying simple rules for selecting mutants to synthesize. As the method evolves, strategies for even more efficient libraries will likely emerge and perhaps circumvent the synthesis challenge altogether.

Marks and her colleagues noted that this method can be expanded far beyond the types of molecules that they studied here. For example, she said, their work is already spurring collaborations with other groups interested in learning the structures of proteins that assume different shapes to perform different functions. In addition, the approach might also be used to study other types of RNA, a broad class of molecules that are heavily involved in human disease but have few solved structures.

"This approach doesn't replace x-ray crystallography or nuclear magnetic resonance as ways to derive 3D structure," Marks said. "But it's another tool in our toolbox for better understanding these structures and learning how they work."

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Harvard Medical School