Culture

Nagoya University researchers and colleagues have revealed the nerve circuitry regulating the response of a tiny soil worm to changing temperatures. The findings, published in the journal Proceedings of the National Academy of Sciences, help clarify one way the nervous system translates external signals into behaviours.

One of the fundamental questions of neurobiology is: how does the brain determine if an external stimulus is good or bad? Animal behaviour depends on this ability. For example, the scent of a predator elicits a fear response, while the scent of a potential mate elicits mating behaviour.

The nematode Caenorhabditis elegans is about one millimetre long and lives in the soil, feeding on microbes. It is often used as a model organism for biological studies in diverse fields, such as development, neurobiology and aging.

Generally, a lab C. elegans will migrate towards a cooler temperature when placed in a warmer environment than the one it was cultivated in, and vice versa. Molecular neurobiologists Shunji Nakano and Ikue Mori of Nagoya University and colleagues wanted to understand the molecular and neurological underpinnings behind this behaviour.

Using genetic and imaging tools, the scientists found that a temperature-sensing nerve cell in the worms, called AFD, transmits signals that activate or inhibit its receiving nerve cell, called AIY.

The scientists exposed freely moving worms to either a good or bad external temperature stimulus. The first 'good' signal started below the worms' cultivation temperature and gradually warmed towards it. The other 'bad' signal started at the cultivation temperature and gradually warmed above it.

AFD was activated by both warming signals. But it then sent stimulating molecules to AIY in the case of the good signal, and inhibiting ones during the bad one. The result shows how the same nerve cell can send signals that convey opposite messages.

Genetic studies further revealed three specific genes, and the enzymes and proteins they encode, that are involved in this response: kin-4, mec-2, and dgk-1. "These three genes are evolutionarily conserved in mammals, including humans," says Nakano. "A similar mechanism thus might be present in the nervous systems of higher organisms."

The team next plans to identify other stimuli that elicit similar neuronal responses in C. elegans.

BEER-SHEVA, ISRAEL...March 13, 2020 - Although aquaculture in treated wastewater is practiced worldwide, there is scant scientific research concerning whether organic micropollutants are present at safe levels for consumption.

A new study in Aquaculture by researchers at Ben-Gurion University of the Negev has determined that organic micropollutants (OMPs) in the water - trace elements of heavy metals, pharmaceuticals and personal care products as well as pesticides, solvents, and detergents - result in minimal accumulation in fish. Additionally, the wastewater does not appear to affect other commercially important traits of fish.

"The presence of micropollutants in water can lead to toxic biological effects in fish including mutations, and feminization of male fish from being exposed to endocrine disrupting OMPs," says Prof. Dina Zilberg, a researcher in the BGU French Associates Institute for Agriculture and Biotechnology of Drylands, Jacob Blaustein Institutes for Desert Research.

Tertiary wastewater treatment (TTWW) is the third and final stage of the cleaning process that improves wastewater quality before it is reused, recycled or discharged to the environment. The treatment removes remaining inorganic compounds and substances, such as the nitrogen and phosphorus, but not the organic compounds.

In the laboratory study, juvenile Carp (Cyprinus carpio) were raised in 0%, 50% and 100% TTWW for five months. Seven out of 40 screened OMPs were detected in the water samples at least once. Out of the 19 analyzed OMPs in fish tissues, four were detected in exposed fish. Carbamazepine, an anticonvulsant and diclofenac, an anti-inflammatory, were detected in the muscle and liver of fish grown in 50% and 100% TTWW at measurable concentrations. Carbamazepine-epoxide and Benadryl (diphenhydramine) concentrations were below the limit of quantification (LOQ) in the muscle of the exposed fish, while diphenhydramine was detected above the LOQ level in two liver samples of fish grown in 100% TTWW.

"Based on the findings, TTWW can be successfully used for growing fish, and TTWW-grown fish met all the existing standards for heavy metals accumulation," Zilberg says. "However, further investigation on OMPs accumulation in different species of edible fish with different feeding habits is required to ensure public health when using TTWW for aquaculture."

Research conducted by the Royal Veterinary College (RVC), in collaboration with Max Planck Institute of Colloids and Interfaces and University College London (UCL), has found new insights into how a bone acts as an organ to regulate its shape and quantity to protect itself from breaking.

Bones can change their shape throughout our life by regulating bone formation and resorption processes, which is often a response to forces which press, pull and twist the skeleton during everyday movements and exercise. The purpose of this shaping is to limit any risk of fracture.

Straight vs. curved

Understanding that a bone's fracture resistance is based on engineering rules which would predict a completely straight shape to be optimal, the research team sought to understand why most of our bones are curved if the goal of these changes in shape is to prevent fracture. Whilst undertaking this study, the team knew that other important questions would likely also be answered, for instance, learning whether the beneficial effects of exercise on our skeletons might be long-lived.

Researchers from the Max Planck Institute of Colloids and Interfaces in collaboration with researchers from RVC and UCL used computational methods on 4D in vivo high-resolution micro-computed tomography to monitor shape changes in an entire bone over an extended period after highly controlled exposure to a known force. The team employed a novel approach to quantify 3D bone formation and resorption surfaces validated by conventional histology and how these relate to local stress in bone tissue caused by physiological force.

The research was undertaken to reveal the location and extent of force-related resorption and formation at the whole bone level and to determine if the changes are, as has been predicted for many years, rapidly reversible.

Curving process needs to be highly targeted

The results indicate that the bone's response to these forces varies along its length to make the bone more curved in most parts and that these shape changes are very long-lived. The researchers found that the curving process needed to be highly targeted; some short-term gains were rapidly lost through resorption, but others were preserved.

From precise mapping of the change over-time, researchers showed that the reversible and preserved bone changes were distinguishable on the basis that they initially targeted either local resorption or formation. It was a surprise to the team that the preserved increases in bone curvature operate independently of local stress levels.

Increased curvature engenders a built-in warning mechanism

The findings provide experimental evidence by which 'Harold Frost's long-held theoretical framework' can be adjusted with an added hierarchy based upon fracture resistance. While some benefits of exercise-related load will gradually disappear, others will be preferentially retained. They also indicate that increased curvature engenders a built-in warning mechanism predicting how best to respond to physiological forces in the future.

The changes in curvature do not compromise the strength, as increased quantity compensates for this beneficial change in bone shape. Hajar Razi, Postdoctoral Researcher at the Max Planck Institute of Colloids and Interfaces, explains: "We know for quite some time that bone adapts to mechanical forces, here in this study we show that, at the organ-level, this adaptation is non-linear with respect to the local mechanical stimuli. In fact, bone response to mechanical stimulation we observed implies an adaptation to a bigger goal: to achieve a larger bone curvature adjusted for load predictability."

This study implies that new 'intelligent' bone therapies, which interact with physiological forces to selectively preserve overall curvature to resist fracture, would be more desirable. Existing osteoporosis treatments do not currently target the bone regions that most dramatically contribute to bending strength; they instead have generalised anti-resorptive/pro-formative effects. Follow-up tracking of bone shape modifications after orthopaedic surgery may also be beneficial and a more long-term view should be taken to monitoring the effects of exercise on skeletal health.

Spain boasts the highest strawberry production rate in Europe and, in order to maintain this key economic sector, is always looking to use innovation and research tools to keep being number one within the strawberry market.

This is the mission in which the Biotechnology and Plant Drug Analysis research group from the University of Cordoba plays an important role. They study strawberry fruit ripening, by analyzing the genes related to fruit quality in terms of color, firmness, aroma, taste and texture parameters, seeking to find the best product to be put on the market.

In the process of this research endeavor to improve characteristics and organoleptic properties of this berry, they have described a gene that plays a very important role in the regulation of the ripening process. This is a transcription factor (FaPRE1), which is the gene in charge of translating the genetic signal and making genes for color, aroma and other characteristics specifically express themselves.

Strawberry development is controlled by two master hormones: ABA, which determines the moment when ripening (with color, aroma and hydration changes) starts, and auxins, that are in charge of growth, meaning that these hormones are the ones that decide when strawberries reach the right size, color and taste to be put on the market. The importance of the newly described gene lies in its role as a sentinel of the ripening process since its job of regulating expression is twofold: when the moment arrives to ripen, it manages to silence development genes (auxins) and to begin the expression of ripening genes (ABA).

In this way, the newly described gene appears suddenly when ripening is going to start and it makes sure that only the ripening genes are activated (up to 600 different ones), which will make the fruit bear aromas, colors and tastes that will make it appealing to be eaten and have its seeds spread. In the end, it all comes down to self-perpetuation of the species.

This gene, described in the article published by researchers Laura Medina, Félix Martínez, Francisco Javier Molina, José A. Mercado, Enrique Moyano, Antonio Rodríguez, José Luis Caballero, Rosario Blanco and Juan Muñoz (research group leader), is considered to be atypical because it needs to work as a team in order to accomplish gene transcription. In other words, it has the possibility to enhance and silence genes when working with another basic transcription factor, that has the function of binding to DNA.

With the characterization of this gene, the group takes a step further towards achieving a map of important gene regulation. In order to complete it, they are studying a regulator gene set that will complete the map.

As far as marketing and making sure Spain continues to be the leader in the field of strawberry production are concerned, this advance with help to find specific markers that allow for identifying plants with better genetic characteristics.

A ketogenic diet can lead to several flu-like symptoms within the first few weeks on the diet, according to a new study published in Frontiers in Nutrition. These symptoms peak in the first 7 days and dwindle after four weeks and range in severity, as reported by users on social media. These reports reveal common but yet unknown symptoms, such as flu fatigue, nausea, dizziness, decreased energy, feeling faint and heartbeat alterations.

"The experiences of symptoms by many people strengthens the evidence for side-effects following the initiation of a ketogenic diet," says Dr. Emmanuelle Bostock of the Menzies Institute for Medical Research of the University of Tasmania, in Australia. "These consumers have the most immediate experience of effects and side-effects and many choose to report and share these in online forums."

The effectiveness of the keto diet has only been established for intractable epilepsy, but despite this, a ketogenic diet is often self-administered for weight loss, cognitive and memory enhancement, type II diabetes or cancer. A commonly discussed side effect of this diet is the so-called "keto flu", a cluster of transient symptoms that occur within the first few weeks on the diet. To better understand how these symptoms evolve, Bostock and her collaborators identified 43 online forums referring to "keto flu" and manually gathered personal experiences of 101 people describing symptoms, severity and time course.

"We focused on social media because of its widespread use for discussion of health topics, which makes it practical to harness the experience of people who have tried the treatment in question," explains Bostock. "In the present study, we responsibly and respectfully used public domain online forum posts and analysed their content to produce new insights into side-effects of the ketogenic diet."

In line with prior medical research, Bostock and her colleagues found reports of headache, difficulty concentrating and gastrointestinal discomfort, following the initiation of a keto diet. Additionally, they reveal further common symptoms, such as flu, fatigue, nausea, dizziness, decreased energy, feeling faint and heartbeat alterations. Consumers often experienced more than one symptom, with differing degrees of severity.

But there is also good news for people experiencing such a "keto flu". The results of this study highlight the sudden onset of symptoms, peaking in the first and dwindling after four weeks. Once symptoms manifested, most of them resolved within little more than two weeks. Online forum user conversations were generally supportive, sharing remedies to others based on popular beliefs, such as maintaining hydration and correcting electrolyte imbalances.

The results of this study were limited to conversation threads in online forums and therefore lack of any confirmatory evidence that ketone levels were raised. Likewise, experiences of online forum users may not be representative of the larger pool of individuals on keto diet. Nevertheless, the symptom patterns yielded may indicate key lines of questioning for future survey-based approaches.

"Taken together, such reports can bring an illness or side effects into focus and can complement clinical observations and questionnaire-based research," says Bostock. "We see potential for research of this nature to inform all aspects of health care on a continuous basis."

Ten years after producing the first sample of the now widely studied family of nanomaterials, called MXenes, Drexel University researchers have discovered a different way to make the atom-thin material that presents a number of new opportunities for using it. The new discovery removes water from the MXene-making process, which means the materials can be used in applications in which water is a contaminant or hampers performance, such as battery electrodes and next-generation solar cells.

The discovery, which was reported recently in the journal Chem, offers a new recipe for the chemical etching solution that carves away layers from a ceramic precursor material, called MAX phase, to create the two-dimensional layered material, MXene.

"Water has been used in the MXene-making processes to dilute the etching acid and as a solvent to neutralize the reaction, but it is not always desirable to have traces of it in the finished product," said Michel Barsoum, PhD, Distinguished professor in Drexel's College of Engineering. "We have been working for some time to explore other etchants for the MAX P-phase and now we have found just the right combination of chemicals to do it."

MXenes have gained attention recently as a versatile, durable, conductive material that could one day improve energy storage technology, enable functional textiles and improve telecommunications.

Typically, they are produced by using a concentrated acid, to carve away atomic layers from a MAX phase material, then washed with water - leaving flakes of the 2D layered material that can be pressed into thin films for microchips and battery electrodes, or used to spray paint antennas and coat devices to block electromagnetic interference.

The process reported by Barsoum and his colleagues uses an organic solvent and ammonium dihydrogen fluoride - a chemical commonly used to etch glass - to etch the MAX phase. This solution does the etching, in part because it breaks down into hydrofluoric acid, but it does not require water to dilute it or to wash away the by-products of the etching process.

Making MXenes in this way alters their interior chemical structure in a way that makes them better suited for use in some types of batteries and solar cells - where water could slow the chemical reactions that store and/or convert energy, or in some cases even cause corrosion.

"MXenes have shown tremendous potential for improving energy storage devices, but this discovery makes them even more promising," said Varun Natu, a doctoral researcher in Drexel's College of Engineering and first author of the paper. "It is known that even slight presence of water in lithium or sodium ion batteries using organic electrolytes, can be detrimental to their performance. In this work we show that MXene films synthesized in propylene carbonate - when tested as anodes in a sodium ion battery - exhibit nearly double the capacity of the same composition etched in water. In addition, MXenes can now easily be integrated with materials which degrade in water, like certain polymers, quantum dots and perovskites."

In addition to better equipping MXenes for these applications, and others yet to be explored, the new process also allows the etching solution to be recovered and reused. This could prove valuable as researchers and companies look into the most efficient way to scale up the production process.

Researchers involved with this work, including Vibha Kalra, PhD, an associate professor in the College of Engineering, have been exploring ways to improve battery performance and safety by developing new types of electrodes. This discovery could bring new options to bear in these efforts, as well as growing Drexel's body of MXene research.

"This finding opens up a huge new field of research: Non-aqueous etching of MXenes. We believe that this work will prove useful not only to the MXene community, but also to researchers throughout the field material science," Barsoum said.

Individuals with Down syndrome are at a much greater risk of developing Alzheimer's disease, with inflammation of the brain starting early in life and the risk of Alzheimer's reaching nearly 80% by the age of 60.

The root cause of Alzheimer's disease is unknown. However, its frequency in patients with Down syndrome suggests that targeting inflammation in preclinical models of that syndrome could be an attractive strategy for designing therapies to promote healthier aging.

In one such preclinical model of Down syndrome, administering specialized lipids, known as resolvins, reduced inflammation and prevented memory loss, according to a recent article in Glia.

The findings were reported by researchers at the Medical University of South Carolina (MUSC), the Center for Alzheimer's Research at the Karolinska Institute in Sweden and the Knoebel Institute for Healthy Aging at the University of Denver.

"We have an ancient pathway that helps us return our damaged bodies to normal, which is known as the resolution response," said lead author Eric D. Hamlett, Ph.D., assistant professor in the Department of Pathology and Laboratory Medicine at MUSC. "In our model, we can now engage this response with the specialized lipids and, in a more natural way, calm down long-term inflammation."

While the Down syndrome model does not produce the same brain 'tangles' that normally would be observed with Alzheimer's disease, constant brain inflammation begins early in life and leads to similar neuronal damage. In humans, long-term inflammation is often seen alongside other indicators of Alzheimer's in the brain, but it is not yet known how these conditions get started.

Chronic brain inflammation typically leads to progressive memory loss. Surprisingly, a sustained treatment regime with the lipid reversed memory loss in the Down syndrome model without having any adverse effects, reinforcing its role as a potential therapeutic.

The tragic progression of memory loss and dementia due to Alzheimer's represents a breakdown of the brain's ability to self-maintain and to limit wild fluctuations in condition. However, self-maintenance can be disrupted by injuries, pathogens and sometimes by aging.

The disruption of self-maintenance can manifest as prolonged inflammation, which can result in devastating effects if left unchecked. Down syndrome is one such condition that can result in this sustained inflammation response.

Typically, the inflammation caused by a disease is resolved by the body naturally. However, when the body cannot do so, long-term inflammation can result. With the body on high-alert but unable to rectify the problem, progressive damage can occur as our normal tissues are caught in the crossfire.

"Our bodies first need to be able to respond to a problem and then have a separate and equally important response to resolve the inflammation mechanism," explained Hamlett.

Gaining insights into the role of inflammation in a healthy brain could bring us closer to identifying key mechanisms in our body that are activated in response to damage and age. Understanding how these mechanisms are activated could allow us to control the balances our bodies must achieve every day, leading to breakthroughs in regenerative medicine and potential new therapies that halt the progression of dementia.

Brevity of inflammation is crucial to healthy healing, and using these naturally produced lipids may be the first step in understanding our body's most ancient system of recovery.

Highlight

Study results call into question the utility of testing blood pressure load--the proportion of elevated blood pressure readings detected over 24 hours--for diagnosing hypertension in children.

Washington, DC -- Results from a new study provide insights on evaluating high blood pressure in children. The findings appear in an upcoming issue of CJASN.

Diagnostic workup for hypertension in children may include wearing a device that monitors blood pressure over 24 hours. Blood pressure load--the proportion of elevated blood pressure readings detected over 24 hours--is used in addition to average blood pressure as part of the criteria for diagnosing hypertension in children. Use of blood pressure load in everyday practice may lead to confusion in scenarios where a child has elevated blood pressure load but normal average blood pressure, however, and it's unclear how a high blood pressure load (with normal average blood pressure) affects long-term health.

To provide insight, Jason Lee, MD (University of California, San Francisco) and his colleagues studied 533 children with chronic kidney disease who underwent 24-hour blood pressure monitoring, along with tests related to kidney and heart health over several years. Based on 24-hour blood pressure data, the team grouped children as having normal blood pressure, high blood pressure load but without high average blood pressure, and high average blood pressure.

One-quarter of the children had high blood pressure load. Having high blood pressure load by itself was not associated with higher risks of developing kidney failure or a condition called left ventricular hypertrophy (thickening of the heart), which can develop in response high blood pressure.

"Our data suggest that the proportion of readings on a 24-hour blood pressure test that are high may not provide additional insight beyond the average blood pressure values surrounding a child's risk for developing cardiac disease or worsening kidney disease," said Dr. Lee. "However, having a high average blood pressure on a 24-hour blood pressure test does strongly predict a child's cardiac and kidney disease risk."

Microbiologists have long adopted the language of human settlement to describe how bacteria live and grow: They "invade" and "colonize." Relations dwelling in close proximity are "colonies."

By pairing super-resolution imaging technology with a computational algorithm, a new study in Nature Communications confirms that this metaphor is more apt than scientists may have realized. The findings show that, as individual bacteria multiply and grow into a dense and sticky biofilm, such as the community that forms dental plaque, their growth patterns and dynamics mirror those seen in the growth of cities.

"We take this 'satellite-level' view, following hundreds of bacteria distributed on a surface from their initial colonization to biofilm formation," says Hyun (Michel) Koo, a professor in Penn's School of Dental Medicine and senior author on the work. "And what we see is that, remarkably, the spatial and structural features of their growth are analogous to what we see in urbanization."

This new perspective on how biofilms grow could help inform efforts to either promote the growth of beneficial microbes or break up and kill undesirable biofilms with therapeutics.

The idea for the research emerged from conversations among Koo; Geelsu Hwang, a Penn Dental Medicine assistant professor who applies engineering to problems of oral health; and Amauri Paula, a physicist who worked as a visiting professor with Koo's lab.

"Usually when people study biofilms, they analyze a single cell in a narrow field of view as it multiplies, becomes a cluster, and starts to build up," says Koo. "But we wondered if we followed multiple individual cells simultaneously whether we could identify some patterns at large length-scales."

Hwang developed powerful time-lapse imaging tools, employing confocal laser scanning microscopy capable of analyzing surface topography and tracking bacteria populating a surface down to the individual cell in three dimensions over time. Meanwhile, Paula worked to build an algorithm that could analyze the behavior of this growth over time.

For their study, they used the microbe Streptococcus mutans, an oral pathogen responsible for causing cavities when it forms a the biofilm known more commonly as dental plaque and releases acids that decay tooth enamel.

They distributed the bacteria on a tooth enamel-like material and followed hundreds of individual microbes during several hours as they divided and grew.

Overall, the growth patterns were reminiscent of the formation of urban areas, the team found. Some individual "settlers" grew, expanding into small bacteria "villages." Then, as the boundaries of the villages grew and, in some cases met, they joined to form larger villages and eventually "cities." Some of these cities then merged to form larger "megacities."

Surprising the researchers, their results showed that only a subset of the bacteria grew. "We thought that the majority of the individual bacteria would end up growing," says Koo. "But the actual number was less than 40%, with the rest either dying off or being engulfed by the growth of other microcolonies."

They also didn't expect a lack of inhibition when this engulfment took place. They thought that, as different microcolonies met, they might compete with one another, causing the two edges to perhaps repel.

"Instead they merge and begin to grow as a single unit," says Koo.

On both the individual bacteria and biofilm-wide scale, the researchers confirmed that the gluelike secretion known as extracellular polymeric substances (EPS) enabled bacteria to pack together closely and firmly in the biofilm. When they introduced an enzyme that digested EPS, the communities dissolved and returned to a collection of individual bacteria.

"Without EPS, they lose the ability to densely pack and form these 'cities,'" says Koo.

Finally, the researchers experimented to see how the addition of a microbial "friend" or "foe" would influence the original bacteria's growth. The "foe" was Streptococcus oralis, a bacteria that can inhibit the growth of S. mutans. This addition dramatically impaired the ability of S. mutans to form larger "cities," like disruptive neighbors that can affect the collective growth of the community.

The "friend"--the fungus Candida albicans, which Koo and others have found to interact with S. mutans in biofilms and to contribute to tooth decay--did not affect the biofilm's growth rate but did help bridge adjacent microcolonies, enabling the development of larger "cities."

Koo cautions about taking the urbanization metaphor of biofilm growth too far but underscores the useful lessons that can result from studying the system holistically and by looking at the events under both "close-up" and "bird's eye" views.

"It's a useful analogy, but it should be taken with a grain of salt," Koo says. "We're not saying these bacteria are anthropomorphic. But taking this perspective of biofilm growth gives us a multiscale, multidimensional picture of how they grow that we've not seen before."

Prehistoric humans left Africa for the first time about 2 million years ago. The research community has been aware of this for some time. Now, novel research reveals that hyenas apparently did the same thing.

'Our new study shows that prehistoric humans and hyenas left Africa at approximately the same time. And like humans, spotted hyenas have had extensive and complex migration between continents. We can observe repeated gene flow events between Africa and Eurasia', says Michael Westbury, corresponding author and postdoc at GLOBE Institute at the University of Copenhagen.

The researchers collaborated with researchers at the University of Potsdam and sequenced complete genomes from both modern spotted hyenas in Africa and subfossils of the extinct cave hyena from Europe and Asia.

Separate lineages

The two kinds of hyena - spotted and cave - were previously believed to form a closely related evolutionary lineage. DNA analyses published 15 years ago showed that the two types of hyena were genetically intermingled. Today, however, thanks to technological advances, the researchers have been able to obtain a lot more genetic data and show that this genetic intermingling is limited. The new study thus reveals an ancient separation.

'The results nicely illustrate the power of palaeogenome analyses. The relationship of spotted and cave hyenas could not be resolved using morphological or short mitochondrial DNA sequence data and was actually discussed quite controversially for decades', says Michael Hofreiter Professor at the University of Potsdam.

While prehistoric hyenas show some similarities with humans in their trans-continental migration patterns, the researchers also found signs that modern humans of the species Homo sapiens had a detrimental impact on hyenas.

'Historical population sizes of spotted hyenas seem to correlate negatively with that of humans after about 100,000 years ago, echoing similar results we found for herbivores', says Rasmus Heller, Assistant Professor at the Department of Biology at the University of Copenhagen.

In addition, he explains that humans are believed to have played a role in the extinction of cave hyenas around the end of the last ice age.

That means that coexistence between humans and hyenas - like that between humans and other large mammals - may have changed from being relatively benign to detrimental as humans became more advanced.

The researchers argue that their study reveals new aspects of when and how animals moved across continents in prehistory.

"Our results conforms with the hypothesis that animal migration may have occurred in pulses during which several species migrated more or less at the same time, possibly as a response to climate change. More comparative work is needed to confirm this hypothesis", says postdoc Michael Westbury, postdoc at GLOBE Institute.

Among the hallmarks of Alzheimer's disease are the Alzheimer fibrils: deposits of the protein tau, which accumulate in nerve cells in the form of fibres and disrupt communication between nerve cells. But how does this fibre formation take place? Why do such harmful deposits develop from the originally useful protein tau, which normally stabilizes cells? This question was addressed by a team of researchers from the University of Konstanz and Utrecht University (Netherlands), led by Konstanz chemist Professor Malte Drescher. Using structural analyses, the researchers brought to light a surprising biochemical mechanism in which a molecular chaperone - a helper protein - plays an unusual role. The research results are going to be published on 13 March 2020 in the journal Science Advances and are available as a preprint version at https://www.biorxiv.org/content/10.1101/614289v3.

Unlike most other proteins, tau does not have a clearly defined structure: Tau is an "intrinsically disordered protein" that can take many shapes. "We can imagine it like a rope: it can be sometimes elongated, sometimes bent, sometimes looped," says Malte Drescher. Despite all the variance, tau tends to assume a characteristically recurved structure, comparable to the shape of a paper clip.

An unusual molecular chaperone

A peculiarity occurs as soon as the chaperone HSP-90 ("Heat Shock Protein 90") encounters tau. "Normally, it is the job of chaperones to bring newly produced proteins into the correct form. Thus they exert a helper function in the development of protein structure. We were wondering: What might their helper function be in an intrinsically disordered protein such as tau?" summarizes Drescher.

Using structural analyses, Drescher and his team were able to show that the chaperone causes the paper clip conformation of tau to open: It folds the "brackets" of the paper clip outwards. "The area in the middle of the paper clip is thus exposed and made accessible. This area is known to be responsible for aggregation, i.e. for attachment of further tau proteins to the molecule," explains biophysicist Sabrina Weickert, lead author of the study and a doctoral researcher under Malte Drescher's supervision. In their unfolded form, tau molecules can therefore be stacked on top of each other with a perfect fit (oligomerization).

"This oligomerization by HSP-90 came as a big surprise," explains Malte Drescher: "A chaperone is actually responsible for exactly the opposite: It is supposed to bring a protein into a defined form and under no circumstances contribute to the formation of a 'protein pile'," says Drescher.

Responsible for Alzheimer's or secretly a defence mechanism?

Is the presence of the chaperone thus a pre-requisite for the formation of Alzheimer fibrils? Is the chaperone, of all molecules, ultimately the one that causes the development of Alzheimer's disease? The researchers will pursue this question in further studies. However, Malte Drescher suspects precisely the opposite: "I would argue exactly the other way round: It could even be a trick the body does to prevent Alzheimer's," Drescher contemplates. The tau oligomers produced by HSP-90 have one crucial peculiarity: They do not continue to grow to form the typical pronounced Alzheimer fibrils.

"The oligomerization by HSP-90 might possibly be a defence mechanism in which the chaperone forces the tau proteins into the form of small oligomer layers. Although this is not advantageous, it effectively prevents formation of longer, Alzheimer-typical fibrils," Drescher suggests. Should this assumption prove true, the chaperone would fulfil its stated purpose: In this case, it would prevent the development of long Alzheimer fibrils by making a gambit and binding tau into smaller, less dangerous stacks.

Spin labels

The protein tau is only a few nanometres in size, i.e. a billionth of a metre, and is not visible to the naked eye or light microscopes. Otherwise typical experiments for structure determination such as X-ray structure analysis fail, because tau as an intrinsically disordered protein is so extremely flexible. In order to determine the structural changes of the protein anyway, the researchers therefore resorted to a sophisticated method: They attached tiny probe molecules, "spin labels", to key positions of the molecule, including the outer "brackets" of the paper clip conformation. "The probes are magnetic and sense each other. We measure the interaction between the probes and can thus determine the distance between their positions," explains Malte Drescher. In this way, they can indirectly detect the conformation of the molecule and its structural changes.

The series of experiments took place in vitro, with purified tau and HSP-90 molecules in the test tube. "We now want to bring the experiment into the cell in order to observe the biochemical mechanism under the real-world conditions inside a cell," says Malte Drescher, giving an outlook on future research work. The long-term goal is to better understand the development of Alzheimer's disease and to find methods to prevent it.

Research published today in Science Advances sheds new light on the molecular machinery that enables the shape, growth and movement of neurons. It is the first time scientists have revealed how the brain shuttles genetic code within its cells, a process believed to be crucial for the formation and storage of long-term memories.

Brain cells, also known as neurons, are complex, specialised cells with long branches. To grow, neurons build proteins at specific locations of a branch so that they can form new protrusions, control the direction they move in and establish connections with other neurons. This process is especially important during brain development, helping different types of neurons find their place in the wider brain tissue. The genetic blueprint to build thousands of different types of useful proteins continuously travel around the cell's branches in the form of mRNA, which is genetic information copied from DNA.

How neurons, the longest type of animal cell, get the correct genetic blueprints to the right place at the right time is an unanswered question. It was thought that they are transported by kinesins, elongated proteins with two feet that walk one foot over another to a target destination, but there was no direct evidence to prove this. Every living cell has a network of self-assembling highways to transport large molecular materials from one side to the other. Different vehicles busily move thousands of different cargoes around, with kinesins being the most common type.

Now scientists at the Centre for Genomic Regulation (CRG) in Barcelona have found that a type of kinesin called KIF3A/B can transport mRNAs, using another protein called adenomatous polyposis coli (APC) as an adaptor that binds both the kinesin and the mRNA-cargo. The proteins transport at least two types of mRNA which code for tubulin and actin, two types of proteins that neurons use to build their cellular skeleton. This is essential to shape the cell so that it can form new connections with other neurons.

The findings are of interest because mRNAs play a key role in the storage and formation of memories. Previous studies show that mRNAs coding for the protein beta-actin continuously travel along synapses, the junction between two neurons. When synapses repeatedly receive a signal, the mRNA is used to make beta-actin proteins, which are important for reinforcing synapses and strengthening the attachment between two neurons. Repeatedly stimulating a synapse continuously reinforces the junction, which is thought to be how memories form.

"Spanish neuroscientist Santiago Ramon y Cajal first proposed that our brains store memories by strengthening neuronal synapses, changing shape so that brain cells would firmly grasp one another and conduct signals more efficiently," says Sebastian Maurer, researcher at the Centre for Genomic Regulation and lead author of the study. "More than a century later we are describing one essential mechanism likely underlying his theories, showing just how ahead of his time he was."

The researchers synthetically recreated cellular self-assembling highways using pure components in a test tube,?revealing the function of individual building blocks and how they work together to transport mRNAs. Purified proteins suspected to be important for neuronal mRNA transport were labelled with different fluorescent dyes and studied with a highly sensitive microscope that can detect the rapid movement of single molecules.?

The researchers found that mRNAs and their adaptor APC switch on the kinesin's ignition, activating the protein. Transported mRNAs were found to have a special localization signal that control the efficiency by which different mRNAs are loaded onto the kinesin. Even slight alterations to this signal affected the mRNA's journey to its target destination, showing the sophisticated mechanisms brain cells develop to control the logistics of thousands of different messages. When not carrying cargo, the kinesins shifted to energy saving mode to save fuel until their next job.

"Finding the exact vehicle needed to transport mRNA is like looking for a needle in a haystack, which is why most people thought what it was impossible" says Sebastian Mauer. "But we did it, which would not have been possible without the CRG or the Spanish government's public funding for risky projects."

"We will continue to investigate the transport systems that make up a neuron's complex logistical network. Understanding the molecular machinery underlying the development of brain cells will be key to combating global challenges like dementia and neurogenerative diseases."

Adaptive immunity is a powerful defense mechanism in vertebrates. A finely tuned interplay of different cell types provides a pathogen-specific immune response to eliminate for example bacteria and viruses. Max Planck researchers now identify the mechanistic basis of antigen receptor gene assembly that more than 500 million years ago independently evolved in one of the two sister branches of vertebrates. The results by the scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg are an important step to answering the question which of the many functions that are carried out by the immune system of living vertebrates are absolutely essential. The findings may help to understand the causes and consequences of failing immune functions and autoimmune syndromes.

Pathogens such as viruses and bacteria have been at war with their hosts for millions of years. The arms race between the immune system of the hosts and infectious pathogens is considered to be a critical driver of evolution. All vertebrates, including humans, developed a very sophisticated self-protection device, which is called the adaptive immune system. Specialized immune cells called T cells and B cells detect and destroy invading pathogens. One of its key features and its secret weapon is immunological memory. The cells remember infections leading to an even more efficient reaction to the same pathogen when re-exposed.

Searching for the design principles of adaptive immunity

In recent years, researchers have found that adaptive immunity has evolved at least twice independently in the early phases of vertebrate evolution. Vertebrates are commonly divided into two groups. Animals of the most numerous group all possess a jaw, and hence are called "jawed" vertebrates; they encompass such diverse creatures as sharks and humans. By contrast, a small group of vertebrates lacks jaws, and hence these animals are called "jawless" vertebrates; lampreys and hagfish belong to this group.

"The basic design of the adaptive immune systems in these two groups of vertebrates are surprisingly similar, considering that these groups evolved independently for more than 500 million years," explains Thomas Boehm, Director at the Max Planck Institute of Immunobiology and Epigenetics. The scientists know that all vertebrates share the two lineages of T and B cells that are equipped with receptors capable of recognizing foreign structures, often referred to as antigens. Because the immune system has to distinguish between very different types of antigens, the structures of the receptors also vary; they are made up of similar but not identical building blocks that are produced in a random fashion during the development of T and B cells.

Dissecting adaptive immunity with CRISPR/Cas9

One of the big surprises of recent research was that the building blocks of antigen receptors of jawless and jawed vertebrates are structurally different, yet serve the same purpose during immune defence. "Lampreys use short peptides, called leucine-rich repeats and arrange them like strings on a bead to form the so-called variable lymphocyte receptors. However, up to now, it was unclear how these strings are stitched together," explains Ryo Morimoto first-author of the study. This important question has now been answered by the Max Planck researchers in Freiburg, working together with scientists at the French INRA in Rennes.

To do this, the scientists succeeded for the first time in using the famous gene scissor CRISPR/Cas9 to study gene function in the immune system of lampreys. By using CRISPR/Cas9, they specifically destroyed a gene in lampreys that they long suspected to be required for the assembly of a particular class of variable lymphocyte receptor genes, which contain the blueprint of lamprey antibodies. Indeed, when the so-called cytidine deaminase gene 2 (CDA2) was crippled, the lamprey could no longer produce antibodies.

Shared tool-kit to create antibodies

The CDA2 gene is of great interest to immunologists, because it is related to a gene, called AID, of jawed vertebrates that helps to refine the specificity of their antibodies. "It seems, that nature has chosen molecules from a shared tool-kit to support the formation of useful antibodies in both types of vertebrates. These results are an important advance in our understanding of the evolution and function of the immune system of vertebrates," says Thomas Boehm. Now that the scientists have successfully used gene scissors to investigate immune gene function in lampreys, they plan to test the role of many other genes that are suspected of supporting immune functions in these ancient vertebrates.

By collecting more information using this genetic approach, they hope to eventually reconstruct the key components of the immune system of the first-ever vertebrate. Doing this will allow them to learn which of the many functions that are now carried out by the immune system of living vertebrates are absolutely essential and which can be dispensed with. Ultimately, the Max Planck researchers hope to use this information to better understand the consequences of failing immune protection in human patients suffering from autoimmune diseases and cancers.

URBANA, Ill. - Edamame may be a niche crop in the United States, but growers and processors still need the best possible information to make sound management decisions. That's why USDA Agricultural Research Service (USDA-ARS) and University of Illinois researchers are making new plant density recommendations for machine-harvested edamame, at less than half the rate suggested by seed companies.

"Until now, edamame processors and growers had no research-based information to determine crop density. While some seed companies make recommendations, the basis for these recommendations is unclear," says Marty Williams, ecologist with USDA-ARS and the Department of Crop Sciences at Illinois.

Seed companies recommend plant densities from 80,100 to 139,200 plants per acre, and at $11 to $22 per pound of edamame seed, the cost adds up very quickly. Williams says these recommendations may be based on what works for grain-type soybean, but they're not necessarily appropriate for edamame, which is harvested while pods are bright green and seeds are still immature.

To get a better handle on what's realistic and profitable for the crop, Williams and crop sciences graduate student Daljeet Dhaliwal planted four edamame cultivars at five densities, ranging from 10,000 to 160,000 plants per acre. They measured multiple growth, harvest, and processing characteristics for each cultivar at all five densities, over two years. Finally, they derived the economically optimal planting density (EOPD) based on the cost of seed, yield of marketable pods, and sales price.

"Results identified that the EOPD for machine-harvested edamame ranged from 35,200 to 48,600 plants per acre," Dhaliwal says. "That's less than half of what's recommended by seed companies."

Lower densities were more profitable, in part, because increasing plant density led to a lower ratio of pod mass to vegetative mass.

"We showed that higher plant densities change the architecture of the crop. For the most part, as plants are added beyond the EOPD, the crop is less suitable for mechanical harvest. It's taller, with more leaf area, and fewer marketable pods. Obviously, we need enough plants to utilize available resources, but there are diminishing returns beyond the EOPD," Williams says.

The new report underscores that edamame agronomy is not interchangeable with grain-type soybean. For the U.S. edamame market to maximize profitability and become competitive with China, Williams says, growers and processors should follow research-backed recommendations specific to the unique aspects of the crop.

Erythropoietin, or Epo for short, is a notorious doping agent. It promotes the formation of red blood cells, leading thereby to enhanced physical performance - at least, that is what we have believed until now. However, as a growth factor, it also protects and regenerates nerve cells in the brain. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have now revealed how Epo achieves this effect. They have discovered that cognitive challenges trigger a slight oxygen deficit (termed 'functional hypoxia' by the researchers) in the brain's nerve cells. This increases production of Epo and its receptors in the active nerve cells, stimulating neighbouring precursor cells to form new nerve cells and causing the nerve cells to connect to one another more effectively.

The growth factor erythropoietin is among others responsible for stimulating the production of red blood cells. In anaemia patients it promotes blood formation. It is also a highly potent substance used for illegal performance enhancement in sports.

"Administering Epo improves regeneration after a stroke (termed 'neuroprotection' or 'neurogeneration'), reducing damage in the brain. Patients with mental health disorders such as schizophrenia, depression, bipolar disorder or multiple sclerosis who have been treated with Epo have shown a significant improvement in cognitive performance," says Hannelore Ehrenreich of the Max Planck Institute of Experimental Medicine. Along with her colleagues, she has spent many years researching the role played by Epo in the brain.

More neurons

Ehrenreich and her team have been using mice in animal studies for a systematic investigation into which bodily mechanism lies at the root of Epo's effect on enhanced brain performance. The results of her research indicate that in adult mice, there is a 20 percent increase in the formation of nerve cells in the pyramidal layer of the hippocampus - a brain region crucial for learning and memory - after the growth factor is administered. "The nerve cells also form better networks with other nerve cells, and do this more quickly, making them more efficient at exchanging signals", says Ehrenreich.

The researchers gave the mice running wheels with irregularly-spaced spokes. "Running in these wheels requires the mice to learn complex sequences of movement that are particularly challenging for the brain," explains Ehrenreich. The results demonstrate that the mice learn the movements required for the wheels more quickly after Epo treatment. The rodents also show significantly better endurance.

Higher oxygen requirements

It was important to the Göttingen researchers to understand the mechanisms behind these potent Epo effects. They wanted to track down the physiological significance of the Epo system in the brain. In a series of targeted experiments, they were able to prove that when learning complex motor tasks, nerve cells require more oxygen than is normally available to them. The resulting minor oxygen deficiency (relative hypoxia) triggers the signal for increased Epo production in the nerve cells. "This is a self-reinforcing process: Cognitive exertion leads to minor hypoxia, which we term 'functional hypoxia', which in turn stimulates the production of Epo and its receptors in the corresponding active nerve cells. Epo subsequently increases the activity of these nerve cells, induces the formation of new nerve cells from neighbouring precursor cells, and increases their complex interconnection, leading to a measurable improvement in cognitive performance in humans and mice," explained Ehrenreich.

The self-reinforcing cycle of mental and cognitive challenge, activity-induced hypoxia and Epo production can be influenced in various ways: "Cognitive performance can be improved through consistent learning and mental training via Epo production in the stimulated nerve cells. A similar effect can be achieved in patients by administering additional Epo," says Ehrenreich.

Original publication

Debia Wakhloo, Franziska Scharkowski, Yasmina Curto, Umer Javed Butt, Vikas Bansal, Agnes A. Steixner-Kumar, Liane Wüstefeld, Ashish Rajput, Sahab Arinrad, Matthias R. Zillmann, Anna Seelbach, Imam Hassouna, Katharina Schneider, Abdul Qadir Ibrahim, Hauke B. Werner, Henrik Martens, Kamilla Miskowiak, Sonja M. Wojcik, Stefan Bonn, Juan Nacher, Klaus-Armin Nave and Hannelore Ehrenreich
Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Nature Communications; 9 March, 2020 (Doi: 10.1038/s41467-020-15041-1)

Journal

Nature Communications

DOI

10.1038/s41467-020-15041-1