Culture

It is an open question how we can ensure that our crop plants remain productive in a changing climate. Plants are confronted with similar climate adaptation challenges when colonising new regions, as climate conditions can change quickly across latitudes and landscapes. Despite the relevance of the question, there is very limited basic scientific insight into how plants tackle this challenge and adapt to local climate conditions. Researchers from Denmark, Japan, Austria and Germany have now published the results of their research on this very subject.

The researchers studied the plant Lotus japonicus, which - with relatively limited genomic changes - has been able to adapt to diverse Japanese climates ranging from subtropical to temperate. Using a combination of field experiments and genome sequencing, the researchers were able to infer the colonisation history of L. japonicus in Japan and identify areas in the genome where plant populations adapted to warm and cold climates, respectively, showed extreme genetic differentiation. At the same time, they showed that some of these genomic regions were strongly associated with plant winter survival and flowering.

This is the first time researchers have identified specific genomic regions that have changed in response to natural selection to allow the plant species to adapt to new climatic conditions.

Professor Mikkel Heide Schierup states: "One of the great questions of evolutionary biology is how natural selection can lead to genetic adaptation to new environments, and here we directly observed an example of this in Lotus japonicus."

And Associate Professor Stig Uggerhøj Andersen adds: "Yes, and it is fascinating that we have identified specific traits, including winter survival, that have been under selection during plant local adaptation to contrasting climates. At the same time, we observed extreme genetic signatures of selection in specific genomic regions. This link between selection signatures and specific traits is critical for understanding the process of local adaptation."

"The rapid adaptation of L. japonicus to widely different climates indicates that genetic variation underlying the adaptations was already present before plant colonisation. This is promising for other plant species on a planet with rapid climate change, since it will allow more rapid adaptation," adds Professor Schierup.

"In this case, the different climates have resulted in distinct plant populations adapted to their own local environments. These populations appear to be preserved because certain genotypes are an advantage in warm climates, but a disadvantage in cold climates and vice versa," concludes Dr. Andersen.

A study led by researchers at UCL has discovered the mechanism that allows the brain to monitor its own blood supply, a finding in rats which may help to find new treatments for human conditions including hypertension (high blood pressure) and dementia.

For decades, scientists have suspected that the brain had a way of monitoring and regulating its own blood flow separate from the body-wide blood pressure control system, but until now no one had proven this.

The brain needs more blood than any other organ to satisfy neurons' relentless, high demand for oxygen, so it makes sense that it would have a way of buffering itself from blood flow fluctuations in the wider body. Disturbances to brain blood flow are a known cause in many diseases - for example, sustained reduction in brain blood flow is a likely cause of cognitive decline, dementia, and neurodegenerative disease such as Alzheimer's disease.

In a study published in Nature Communications, researchers from UCL, the University of Auckland and Bristol University, found a new function for the star-shaped brain glial cells, known as astrocytes. These cells function as specialised brain blood flow sensors that operate to self-protect the brain from potentially damaging reductions in blood supply.

Astrocytes are strategically positioned between the brain blood vessels and important nerve cells, which control the heart and peripheral circulation, ultimately determining the arterial blood pressure.

In the laboratory-based study in rats, the researchers found that decreases in brain blood flow caused astrocytes to release a chemical signal, which stimulated the specialised nerve cells to increase blood pressure and restore/maintain blood flow (and oxygen supply) to the brain.

Professor Alexander Gourine (UCL Division of Biosciences), who led the study, said: "We are very excited about this observation: there has never been a formal description of a blood flow or blood pressure sensor within the brain before.

"Our new data identify astrocytes as brain blood flow sensors that are critically important for setting the level of systemic (arterial) blood pressure and in doing so ensure that the brain receives a sufficient amount of oxygen and nutrients to support the uninterrupted operation of the information processing machinery."

Co-author Professor Julian Paton, (University of Auckland), said: "These astrocyte cells are exquisitely sensitive to reductions in brain blood flow. When blood supply is reduced, they release a chemical signal to nearby nerve cells that raise blood pressure, restoring blood flow to the brain. What we have discovered is that the brain has an automatic way to make sure that brain blood flow is preserved.

"Unfortunately, in pathological conditions this is happening at the expense of generating higher blood pressure in the rest of the body. This suggests that increasing brain blood flow by reducing activity in these blood flow sensing astrocytes may be a way to lower blood pressure in people with hypertension. It may also be a way to combat migraines and strokes. On the other hand, sensitising these cells may help in conditions of dementia to improve brain blood flow."

Corresponding author, Dr Nephtali Marina-Gonzalez, (UCL Division of Medicine), said: "In disease situations where blood supply to the brain is reduced, the mechanisms we describe can over-react causing migraines, high blood pressure and strokes. The identity of the brain blood flow sensor will make it possible to search for novel targeted treatment strategies to alleviate these diseases".

University of Tartu scientists hope create a solution for chronic infections that do not respond to antibiotic treatment after having discovered mechanisms for listening in on sleeping bacteria.

Having recently published a research article on the topic in Scientific Reports with his team, Senior Research Fellow in Molecular Microbiology Arvi Jõers writes about the ability of bacteria to listen in on one other and what this discovery means for medicine.

The life of bacteria is not easy. If there is sufficient food, they multiply rapidly, but they do not tend to store it. Once bacteria are out of food, it is over for them: their metabolism slows down and they enter a sleep-like state. In such a state, bacteria are quite resilient to environmental conditions and can even live through difficult times. In this, they are similar to a bear in hibernation - minimal energy is spent while waiting for better times ahead.

These arrive with new food.

Once there is enough food again, all bacteria wake up and start multiplying rapidly. However, bacteria can be more hesitant if there is little food and it is not of the best quality. Is it even worth leaving a secure state for such a lousy meal? Perhaps it is not even real food, but some sort of trick? Naturally, bacteria do not follow this line of thought. Instead, they have developed mechanisms in the course of evolution that offer solutions to such dilemmas.

One particular sign of the environment being sufficiently good for bacteria to grow and multiply is the growth of other bacteria. University of Tartu scientists discovered that sleeping bacteria can learn about the growth of other bacteria by spying on them.

Namely, as bacteria grow, they expel material from their cell walls into the environment. The cell wall is quite a rigid structure that surrounds each bacterial cell and protects it from the external environment. For a bacterium to grow bigger, the cell wall must become softer and give in to a certain degree. As a result of changes like this, part of the cell wall material enters the environment, sending sleeping bacteria a message that conditions have improved and others have enough food to grow.

Once sleeping bacteria identify material originating from the cell walls of other bacteria in the environment, they wake up quickly and in great numbers in order to get their share of the newly arrived nutrients.

Sleeping bacteria unwilling to wake up pose a serious problem in medicine. Antibiotics are, above all, known to kill actively growing bacteria and they do not often work on sleeping bacterial cells. Thus, sleeping bacteria can survive a course of antibiotics in the human body and start to grow again later when the person has finished the treatment. These cells are called persister cells and they can cause long-term chronic infections that do not respond to antibiotic treatment.

If scientists could now use this new knowledge to trick sleeping bacteria and lure them into waking up with some substance similar to a cell wall, there would be hope of killing them with antibiotics on the first try. This would allow bacterial infections to be treated with one course of treatment.

"This demonstrates that contact with both parents after a divorce is important," says Professor Eivind Meland at the Department of Global Public Health and Care, University of Bergen.

According to numbers from the Norwegian Institute of Public Health around 40 per cent of all teenagers have experienced a divorce.

"We wanted to explore what happens to the communication between parents and children after a divorce and how this impact the children's future health," Meland explains.

The study included 1225 youths from the former region of Sogn of Fjordane. They were asked if they found it easy or difficult to talk with their parents. The answers were graded from "very easy" to "very hard or lost contact".

The researchers also asked the children about their health complaints and self-esteem. The health complaints included various physical and psychological symptoms, such as headaches, dizziness, stomach aches, anxiety, depression and trouble sleeping.

They asked the children in 2011 and in 2013. In 2011 213 of these children had divorced parents. Two years later the number had increased to 270.

"The divorce did not seem to affect how they communicate with their mother, but are strongly connected to conversational difficulties with father," Meland says.

"We also see that closeness to both father and mother impacts the children's health two year after the divorce."

More health complaints when the children had lost contact with their father

The researchers observed a clear connection between how easy the children found to talk with their father after divorce and health complaints later in life:

"Those children that reported having lost contact or who find it difficult to talk with their father after divorce also had most health complaints," says Meland.

They also saw a clear connection between the divorce and conversational difficulties between children and fathers:

"It seems like conversational difficulties between children and father was present also before the divorce, but we also see that the divorce weakens the relationship between the children and their fathers," Meland states.

If the children reported having a good relationship with both parents after the divorce, the divorce did not seem to affect the self-esteem or health to the children in any negative manner.

Daughters find it hardest to talk with their father

The study also shows that the girls have more difficulties talking with their fathers than the boys. Daughters also reported having more health complaints, but the consequence of conversational difficulties seemed to be the same for both sexes:

"In the data we can see the tendency that girls suffer more from having lost contact with their fathers, but the difference is not significant," the researcher says.

A neglected subject

The data included information on which parent was the child's main caregiver and where the children lived, but it was not considered reliable enough to be included in the article. It suggested that three times as many children reported having lost contact with their fathers than with their mothers:

"If the divorce is taken to court, it is the mother that most often ends up with the status as the main caregiver," says Meland, but adds that he sees a tendency towards that the parents decide to share the custody.

Meland strongly believes that the importance of maintaining a close relationship between father and child after a divorce is a neglected subject:

"Our research clearly shows that a strong relationship with both parents is important for the children's health. This should impact the family policy," says Meland.

How can the complex relationships between wildlife, natural ecosystems and humans in a large number of habitats be captured with reasonable effort? Researchers need sound data over long periods of time and complex mathematical models. Can environmental stakeholders produce a similar result? An international team led by Professor Robert Arlinghaus from the Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB) and the Humboldt-Universität zu Berlin have developed a method for combining the empirical knowledge of fishery stakeholders in such a way that the result corresponds to the best scientific understanding. This is of particular interest when human and financial resources are insufficient to achieve a profound scientific understanding or when, for example, fish stock data cannot be retroactively recorded.

The study published in Nature Sustainability shows that the collective of users of fish stocks is able to identify the ecological cause-effect relationships of the population biology of the top predatory fish species pike in a way that corresponds exactly to the best scientific knowledge. The study by the international team of fisheries biologists, computer scientists and social scientists is the first evidence that the collective intelligence of nature users is able to accurately capture complex human-environment relationships.

In the study, around 220 anglers, fisheries managers and angling club managers identified factors that alone or in interaction with each other determine the development of pike populations, for example nutrients, aquatic plants, cormorants, fishing and angling or water temperature. The individual ideas on pike biology - the so-called mental models - were mathematically combined into a collective understanding of the ecological relationships. The knowledge of 17 fisheries biologists served as a reference.

The result is astonishing: if the anglers' ecological ideas are brought together, the result corresponds almost exactly to the best scientific knowledge on pike biology. "And the result is better the more actors are involved in the collective solution," explains study leader Professor Robert Arlinghaus from IGB.

Many are not necessarily better, they must also be diverse

Sounds like a primal democratic solution. "It's not quite that simple. It is important that the ideas of different types of stakeholders - anglers; fisheries managers and angling club managers - are given due consideration," notes lead author Payam Aminpour, PhD student at Michigan State University. Using only the knowledge of one type of stakeholder can lead to the accumulation of misconceptions and myths that arise from exchanges within this subgroup. "If only one stakeholder group is considered, the collective outcome deteriorates the more people are involved in the solution," Robert Arlinghaus notes.

The wisdom of the crowd (WOC) comes into play when a multi-level analytical approach is chosen. First, the collective knowledge within a user subgroup is determined and then the results are summarized across groups. "Our study shows that it makes sense to take into account the knowledge of as many different types of nature users or interest groups as possible, such as anglers, hunters, foresters, administrators and conservationists. And if as many opinions as possible are then incorporated within each group, the overall result will be particularly good," summarizes Robert Arlinghaus.

The researchers argue that the WOC-principle of resource users should be applied more systematically than today in the investigation and subsequent management of nature and the environment. This is especially true when human and financial resources are not sufficient to achieve a deep scientific understanding. For example, it is difficult to scientifically assess the state of fish stocks in thousands of lakes or to retrospectively estimate the development in a fishing area for which there are no accompanying scientific studies. A concrete example of application, on which Robert Arlinghaus and his team are currently researching, are the pike populations in the inner coastal waters, the so-called Bodden waters, around Rügen. Here, too, the team relies on the wisdom of anglers and fishers, for the hopeful benefit of all.

Philadelphia, January 14, 2020 - While subtle differences in the number of genes copied from one individual and passed down to the next can be found in many healthy people, their role in disease may be much greater than previously thought.

A large, multicenter study led by researchers at Children's Hospital of Philadelphia (CHOP) compared the genomic data of more than 100,000 people of European ancestry and discovered how relatively rare, albeit recurrent, genetic variations can influence a variety of common diseases.

In addition, existing drugs could be repurposed to target these conditions - ranging from autoimmune diseases to neuropsychological diseases and even cancer - now that the genetic underpinnings of these conditions are known. The findings were published online on January 14, 2019 in the journal Nature Communications.

A copy number variation (CNV) is either a gain or loss of genomic information and occurs when the number of copies of a particular gene or genomic region varies from one individual to the next. Rare CNVs are events that often predispose people to medical conditions, whereas more common CNVs are usually well-tolerated and are common in healthy people. However, there are previously established examples in which CNVs can negatively impact a person's health. In fact, prior studies suggest they could have a widespread impact on human health, but most of those studies were based on limited sample sizes, thereby not providing researchers with a complete picture of their true significance.

"This analysis provides us with a dense map of the impact of rare recurrent copy number variations, which represent an important source of genetic variation in our genome, often predisposing us to, and sometimes causing, complex diseases," said senior author Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP. "Our study showed that previous methods are likely not capturing the accurate incidence or prevalence of rare copy number variation regions that directly impact human health."

The study team genotyped 100,028 individuals from populations of European ancestry using either genome-wide SNP arrays or array comparative genomic hybridization platforms. The vast majority (more than 99%) of the CNV regions uncovered, while individually rare, were recurrent, meaning that they occurred in at least two individuals.

Among these regions that are most clinically relevant are those with homozygous deletions, or the loss of both alleles or both copies of a gene from the same chromosomal pair. The study team identified 375 previously unreported regions like this. In addition to confirming disease-associated CNV regions from previous studies, the researchers discovered several previously unreported regions that match genes that are already of clinical interest, in some cases because drugs that target relevant pathways may already exist.

Some specific regions of interest identified in this study include the chr7p15.3 deletion associated with autoimmune diseases, since it overlaps with the gene that encodes for ITGB8a, a well-established drug target for ovarian cancer; a homozygous deletion region associated with autoimmunity at chr2q34 that that interrupts the coding region of the gene ERBB4, a key oncogene that can be targeted by multiple FDA-approved small molecule inhibitors; and the locus chr19p13.3, which encodes the gene HCN2 and could be a potential target for therapies to treat both epilepsy and pain.

"The number of gene candidates found in our study that warrant further studies establishes the strong correlation between regions of copy number variations and what we already know about the genome," Hakonarson said. "While ongoing, large scale studies focusing on new discoveriers are important, we believe that further investigating these newly identified regions in parallel will continue to yield even more clinically relevant information and accelerate precision medicine."

A research group from the Biodiversity Unit of the University of Turku studies the diversity of parasitoid insects around the world. Parasitoid wasps (Hymenoptera) are one of the most species rich animal taxa on Earth, but their tropical diversity is still poorly known. In the latest study, the group discovered 15 new, sizeable species that parasitise spiders in the lowland rainforests of the Amazon and the cloud forests of the Andes.

The researchers from the Biodiversity Unit of the University of Turku have studied the diversity of tropical parasitoid insects for almost 20 years already. During their research, they have discovered large numbers of new species from different parts of the world. In the newest study, the research group sampled parasitoid wasps of the genus Acrotaphus, which parasitise spiders. The diversity of the insects was studied in e.g. the tropical Andes and the lowland rainforest areas of the Amazon. The research was conducted in cooperation with the Brazilian INPA (Instituto Nacional de Pesquisas da Amazônia) research unit.

- Acrotaphus wasps are fascinating because they are very sizeable parasitoids. The largest species can grow multiple centimetres in length and are also very colourful. Previously, only 11 species of the genus were known, so this new research gives significant new information on the diversity of insects in rain forests, tells postdoctoral researcher and lead author of the new study Diego Pádua, who has worked both for the INPA and the Biodiversity Unit of the University of Turku.

The parasitoid Acrotaphus wasps parasitise on spiders. A female Acrotaphus attacks a spider in its web and temporarily paralyses it with a venomous sting. After this, the wasp lays a single egg on the spider, and a larva hatches from the egg. The larva gradually consumes the spider and eventually pupates.

- The Acrotaphus wasps we studied are very interesting as they are able to manipulate the behaviour of the host spider in a complex way. During the time period preceding the host spider's death, it does not spin a normal web for catching prey. Instead, the parasitoid wasp manipulates it into spinning a special web which protects the developing pupa from predators. Host manipulation is a rare phenomenon in the nature, which makes these parasitoid wasps very exciting in terms of their evolution, tells Ilari E. Sääksjärvi, Professor of Biodiversity research from the University of Turku.

The University of Turku and INPA continue to study the diversity of the parasitoid wasps in collaboration in the west Amazon area and in the Andes. On each research trip, the researchers discover many new species with unknown habits.

One of the skin's defences against environmental assault can help tumours to grow when skin is exposed to chronic inflammation, finds a study in mice published today in eLife.

The IgE antibody is most commonly known for its inadvertent involvement in allergic reactions, but it is commonly found in healthy skin and believed to protect against harmful substances or parasitic infections. However, this study shows that chronic inflammation caused by repeated exposure to skin-irritating chemicals may turn this helpful defence into a harmful one. Learning more about this process may help scientists develop ways to prevent or treat skin cancer.

"Chronic inflammation has been linked to many types of cancers, and may cause these by enabling the growth and survival of cells with cancer-causing mutations," explains lead author Mark Hayes, who was a postdoctoral scientist at the Department of Immunology and Inflammation, Imperial College London, UK, at the time the study was carried out. "But the exact steps in this process and the role of IgE were not previously clear."

To learn more, Hayes and his colleagues looked at what happened after inflammation-causing substances were applied to the skin. They saw an increase in the amount of IgE produced and that immune cells called basophils were attracted to the skin. When the basophils were activated by IgE, they stimulated skin cells to divide and grow.

"IgE fortifies the skin barrier defences by promoting cell growth to thicken the surface of the skin in response to noxious stimuli," Hayes notes. "However, this response should be temporary. If it persists in the long term, it may lead to tumour growth."

The team found that in mice with cancer-causing mutations, chronic activation of IgE caused by inflammation subverts its protective effects and supports the growth of precancerous skin cells into tumours. On the other hand, mice lacking IgE were protected from developing these tumours in response to inflammation.

Surprisingly, the results of a previous study by the team showed that IgE protects mice against cancer-causing substances that damage DNA. This suggests that the mechanism of tumour growth, and the role of IgE in this process, may depend on different kinds of environmental exposure.

"Our previous and current findings reveal a strong link between IgE and cancer," says senior author Jessica Strid, Reader in Cellular Immunology at the Department of Immunology and Inflammation, Imperial College London. "But the biological consequences of IgE engagement in the skin clearly depends on the nature of the antibodies and the microenvironment in which the tumour grows."

BOSTON, Mass., January 14, 2020 -- Emulate, Inc. announced today a published study in collaboration with Johns Hopkins University School of Medicine, that demonstrated superior functionality of the Duodenum Intestine-Chip populated with organoids, compared to organoids alone. The study, published in the peer-reviewed journal, eLife, showed that the Intestine-Chip produced a nearly identical global transcriptomic profile compared to human intestine duodenum tissue, whereas the signature from the organoids alone had significant differences from the human intestine tissue. The authors further showed that the similarities at the transcriptomic level also resulted in significantly more accurate physiological function of the Intestine-Chip compared to organoids alone. These results demonstrate the potential of the Intestine-Chip to provide a robust system to accurately recreate human intestine tissues for highly predictive and human-relevant preclinical drug assessment, including drug transport, metabolism, and drug-drug interactions.

In this research, Emulate scientists in collaboration with scientist at Johns Hopkins University School of Medicine established the Duodenum Intestine-Chip from organoids derived from endoscopic biopsies of healthy adult human donors and primary human intestinal microvascular endothelial cells derived from human small intestine. The Intestine-Chip recreated the barrier function and multilineage differentiation of adult human intestinal tissue. Global gene expression was assessed by RNA-sequencing analysis and showed that the profile of the Intestine-Chip and freshly isolated human adult duodenum tissue were remarkably similar; in contrast, the organoids alone from the same donor showed significant differences in RNA-sequencing analysis. Additionally, the biology for drug transporters and drug metabolizing enzymes of the intestine remained intact in the Duodenum Intestine-chip, which is not effectively modeled with current animal testing due to the species-specific nature of these drug transporters, drug metabolizing enzymes, and the factors regulating them.

"Using our Intestine-Chip, we are able to accurately recreate key functions of the human duodenum. These findings show a path forward to using a more human-relevant and robust system to better predict pharmacokinetics and drug-drug interaction," said Geraldine A. Hamilton, President and Chief Scientific Officer of Emulate. "Today, we see the value of using our Intestine-Chip product with organoids as a leading-edge preclinical testing method. Further in the future, we envision exciting potential applications for our Intestine-Chip to utilize cells isolated from individual patients to be used for personalized medicine."

Findings from the published functional testing demonstrated that the Duodenum Intestine-Chip more accurately recreated several aspects of the human intestine, compared to organoids or Caco-2 models, including:

Expression of drug transporters. Expression levels of several important transporters for efflux (MDR1, CVRP, MRP2, and MRP3) and uptake (PEPT1, OATP2B1, OCT1, and SLC40A1) were similar for the Duodenum Intestine-Chip and freshly isolated duodenal tissue, but not in the previously described Caco-2 Intestine-Chip which showed significant variation in expression of OATPB1 and OCT1.

Localization and function of drug transporters. In vivo-relevant localization of the luminal efflux pumps, MDR1 and BCRP, and the uptake pump PEPT1 were shown to co-distribute together with villin, a marker specific for apical cell membrane, at the intestinal cell brush border in Duodenum Intestine-Chip. The MDR1 activity was confirmed by measuring the intracellular accumulation of rhodamine 123 in the presence and absence of specific MDR1 inhibitor, vinblastine, across the Duodenum Intestine-Chip.

Drug-mediated CYP3A4 expression and induction potential. The Duodenum Intestine-Chip expressed CYP3A4 gene and protein levels at significantly higher levels than the Caco 2 Intestine-Chip, reaching levels similar to that observed in the adult human duodenum. Expected CYP3A4 induction was observed in the Duodenum Intestine-Chip when exposed to rifampicin and vitamin D3, two prototypical CYP3A4 inducers. The Caco 2 Intestine-Chip showed induction when exposed to vitamin D3 but not rifampicin.

Study results were derived from testing of the Duodenum Intestine-Chip established from individual donors of biopsy-derived organoids. The ability to establish the Duodenum Intestine-Chip composed of the cells isolated from individual patients opens the possibility of personalized medicine. Applications include personalized preclinical testing and personalized clinical pharmacology to assess a range of measures, including: inter-individual differences in drug disposition and responses, studies of the effect of genetic polymorphisms on pharmacokinetics and pharmacodynamics, as well as decoupling of the effect of various factors such as age, sex, disease state, and diet on metabolism, clearance, and bioavailability of drugs.

Worcester, Mass. - January 14, 2020 - Researchers at Worcester Polytechnic Institute (WPI) have developed a tool to identify molecular receptors in worms that are involved in sensing pheromones related to mating, an advance that could speed up neuroscience research into pheromones by eliminating months of work.

Associate professor of biology and biotechnology Jagan Srinivasan, doctoral candidate in biology Douglas K. Reilly, and researchers at Cornell University published their findings in Organic & Biomolecular Chemistry, a journal of the Royal Society of Chemistry in the United Kingdom.

Pheromones are chemicals produced by animals that send signals to other animals and trigger social responses, such as mating. Srinivasan and Reilly study pheromones in microscopic worms known as Caenorhabditis elegans, or C. elegans, to better understand how the sense of smell works. Their research could have implications for human research because C. elegans has a nervous system that mimics the basic mechanisms of smell in humans, and loss of the sense of smell is associated with neurodegenerative disorders such as Alzheimer's disease.

Srinivasan and Reilly developed a process that more quickly isolates pheromone receptors in C. elegans. Receptors are specialized proteins that act as docking stations for molecules. When worms are exposed to pheromones, the pheromones latch onto the molecular receptors in the worms.

Isolating a specific molecular receptor traditionally has been a long, laborious process because the worms possess more than 1,000 molecular receptors. Srinivasan described the traditional process--which takes three or four months--as hunting for a needle in a haystack. The new method he and Reilly developed takes about a month.

"Here we are saving months of work, we're streamlining the process, and we're getting a targeted approach," Srinivasan said.

In their study, Srinivasan and Reilly attached a chemical known as an alkyne to an ascaroside, a pheromone produced by C. elegans to attract male worms for mating.

"We wanted to find a way that we could take a pheromone and link it to a probe, yet it would still be biologically active so a male would sense it and respond to it with the right receptor," Reilly said. "Then we wouldn't have to screen 1,200 receptors that are in the genome."

For this study, the researchers focused on the process rather than the resulting receptor, which they said could be a subject of further research. Their probe methods could also be applied to other pheromones and to other research organisms, such as flies, to better understand how receptors function, they said.

"We're looking at this mate attractant pheromone, but there are people looking at pheromones involved in foraging for food and other actions," Reilly said. "For those, we can start to ask what receptors are sensing the pheromone we're using."

In addition, Srinivasan said, "Applications of this new technology could help identify receptors in parasitic nematodes that cause damage to agricultural crops."

BOSTON - How cool is this: the Massachusetts General Hospital (MGH) laboratory that invented cryolipolisis or "Coolsculpting," a popular non-surgical method for reducing fat under the skin, is developing a new form of the technology that can selectively reduce fat almost anywhere in the body using a safe, injectable ice solution or "slurry."

The technology, not yet approved for use in humans, is designed for removal of fat in the abdomen or other parts of the body - virtually anywhere that can be reached with a hypodermic needle. Fat is a normal part of our bodies, but in excess or with some diseases can be life-threatening.

The new technique is described in a paper published online ahead of print in the journal Plastic and Reconstructive Surgery. As one of the reviewers of the paper said, "this treatment has the potential to become one of the most performed cosmetic procedures in plastic surgery practice."

"The appeal of this technique is that it's easy and convenient to do," says lead author Lilit Garibyan, MD, PhD, investigator in the Wellman Center for Photomedicine at MGH and the Department of Dermatology at Harvard Medical School. "With Coolsculpting, which is a topical cooling technique, the patient has to sit there for almost an hour for enough heat to diffuse from the fat underneath the skin. With this new technique the doctor can do a simple injection that takes just less than a minute, the patient can go home, and then the fat gradually disappears."

Cryolipolysis is currently the leading non-invasive fat removal technology because of its minor side effects and non-invasive nature. The Coolsculpting method is limited, however, by the amount of fat that can be removed per treatment, and is not practical for reaching more deeply seated fat surrounding organs or other body structures.

The MGH team's innovative spin on the technique involves the use of an injectable ice "slurry," a sterile solution of normal saline and glycerol (a common food ingredient) containing approximately 20% to 40% small ice particles, similar in texture to slush. The solution can be injected directly into fat deposits, causing the fat cells (adipocytes) to crystallize and die and fat deposits to shrink. The killed adipocytes are gradually eliminated by the body over a period of weeks. "One of the cool things about this is how the injected slurry causes selective effects on fat," said Rox Anderson, MD, a co-author and leader of the Wellman Center. "Even if the slurry is injected into other tissue such as muscle, there is no significant injury."

As the investigators report, injection of the ice solution into pigs resulted in a 55% reduction in fat thickness compared to that of pigs injected with the same but melted ice solution. There was no damage to skin or muscle at the injection site, and no systemic side effects or abnormalities seen.

Unlike topical cooling, slurry injection can target and remove fat tissue at essentially any depth and any site that can be accessed by a needle or catheter. Injection of physiological ice slurry could be a transformative method for nonsurgical body contouring.

Researchers are busy analysing some of the final data sent back from the Cassini spacecraft which has been in orbit around Saturn for more than 13 years until the end of its mission in September 2017.

For the last leg of its journey, Cassini was put on a particularly daring orbit passing between Saturn and its rings which brought it closer to Saturn than ever before. This allowed scientists to obtain images of Saturn's ultraviolet auroras in unprecedented resolution.

The new observations are detailed in two new studies published in Geophysical Research Letters and JGR: Space Physics.

Saturn's auroras are generated by the interaction of the solar wind, a stream of energetic particles emitted by the Sun, with Saturn's rapidly rotating magnetic field. They are located in the planet's polar regions and known to be highly dynamic, often pulsating and flashing as different dynamic processes occur in the planet's plasma environment.

Lancaster University PhD student and lead author of the research Alexander Bader said: "Surprisingly many questions revolving around Saturn's auroras remain unanswered, even after the outstanding success of the Cassini mission.

"This last set of close-up images gives us unique highly detailed views of the small-scale structures which couldn't be discerned in previous observations by Cassini or the Hubble Space Telescope. We have some ideas about what their origin could be, but there is still a lot of analysis to be done."

Satellite imagery alone will hardly be enough to unravel the aurora's mysteries - the energetic particles causing the bright lightshows around Saturn's poles originate far away from the planet's surface where magnetic field lines twist and clouds of plasma interact with one another. When located in the right region, Cassini was sometimes embedded in the particle stream connecting the auroras to the magnetosphere.

First analysis of the spacecraft's particle measurements recorded during these times showed that Saturn's auroras, like Jupiter's, are generated by much more energetic particles than Earth's. However, the underlying physical mechanisms appear to show similarities between all the three.

Even though Cassini's mission is over, the data it provided remains full of surprises and will continue to help researchers understand the workings of giant planet auroras, especially in combination with Juno observations of Jupiter's magnetosphere.

National guidelines recommend that men with prostate cancer eat a vegetable-rich diet, suggesting it might decrease cancer progression and death. But in a Phase III randomized clinical trial, patients with prostate cancer assigned to eat seven or more servings of vegetables and fruits daily saw no extra protection from the increased consumption of micronutrients.

"These data indicate that, despite prevailing scientific and public opinion, eating more vegetables will not alter the course of prostate cancer. It will not, to the best of our knowledge, suppress or cure it," said J. Kellogg Parsons, MD, University of California San Diego School of Medicine and Moores Cancer Center professor of urology and study lead investigator. "However, while eating a healthy diet rich in fruits and vegetables and getting more exercise may not cure cancer, it may keep the body stronger and healthier, which may help patients tolerate cancer treatments."

The Men's Eating and Living (MEAL) study, published January 14, 2020 in the Journal of the American Medical Association and led by UC San Diego Moores Cancer Center and Roswell Park Comprehensive Cancer Center investigators, enrolled 478 men aged 50 to 80 years at 91 sites in the United States. The patients had been diagnosed with early-stage prostate adenocarcinoma and enrolled in an active surveillance program in which patients defer immediate treatment until the disease advances.

Patients were randomized to a control group that received written information about diet and prostate cancer or to a telephone counseling behavioral intervention program that encouraged participants to eat foods high in carotenoids, such as leafy greens, carrots and tomatoes, and cruciferous vegetables such as broccoli and cabbage. Both groups were monitored for two years.

"Patients assigned to the intervention increased their intake of fruits and vegetables to a statistically significant degree, and significantly more than control patients did. These findings were supported by significant changes in the blood carotenoid levels of patients. Nonetheless, these data fail to support prevailing assertions in clinical guidelines and the popular media that diets high in micronutrient-rich vegetables improve cancer-specific outcomes among prostate cancer survivors," said James Marshall, PhD, Distinguished Professor with the Department of Cancer Prevention and Population Sciences at Roswell Park, co-senior author on the study with John Pierce, PhD, Professor Emeritus of Cancer Prevention at UC San Diego School of Medicine.

The study is the first randomized clinical trial to test the effect of dietary intervention on prostate cancer. It was conceived based on preliminary scientific data and on inquiries from patients who wondered if a change in diet would influence their diagnosis or treatment, said Parsons, a urologic oncologist at UC San Diego Health, San Diego's only National Cancer Institute-Designated Comprehensive Cancer Center.

"The most common question I receive from men on active surveillance is, 'Can I decrease the chances that I will need treatment for prostate cancer by changing my diet?' We now have good evidence that a diet rich in fruits and vegetables and light on red meat is not likely to impact need for treatment," said co-author James Mohler, MD, professor of oncology with Roswell Park's department of urology. "But this study does not provide justification for eating anything you want, either. The overall health benefits of a diet that's relatively low in fat and rich in fruits, vegetables and healthy grains are well-established."

The impact of nutrition on diseases is an ongoing conversation among researchers and clinicians. Scientific studies have identified a strong role for changing diet to improve outcomes in diabetes and cardiovascular disease, but not in cancer, said Parsons.

Although the MEAL study revealed no positive impact on prostate cancer, it did demonstrate that behavioral modification can lead patients to make healthier food choices, said Parsons.

"We designed a simple and inexpensive program that proved we could change people's diets for the better. We hoped that through nutrition we could alter disease outcomes and then use those data to build a network of diet counselors to help men with prostate cancer eat more vegetables," said Parsons. "It's still an endeavor worth considering, possibly in patients with advanced prostate cancer."

Philadelphia (January 13, 2020) - Bronchiolitis, a lung infection that is one of the most common reasons for hospitalizations in young children, is most prevalent during the winter months and is usually treated with albuterol delivered via inhalers, despite evidence showing no benefit in most patients. A multidisciplinary team of researchers from Children's Hospital of Philadelphia (CHOP) redesigned the hospital's standard treatment for the infection and reduced albuterol use without compromising care.

The research was published in the December issue of Pediatrics.

"Given the frequency of albuterol usage and the drug's potential side effects, we wanted to improve the value of the medical care provided to children with bronchiolitis and searched for ways to reduce use," said Michelle Dunn, M.D., attending physician in general pediatrics at CHOP and lead author of the study. "We set out to revise our treatment plan, or clinical pathway, to reflect the current American Academy of Pediatrics (AAP) guidelines and educate clinicians about the recommended changes."

The AAP updated its bronchiolitis guidelines in 2014, recommending against the use of bronchodilators like albuterol in typical patients with bronchiolitis. To bring its clinical practice in line with those recommendations, the CHOP team used a multidisciplinary approach -- with a goal of reducing the use of albuterol for bronchiolitis in infants in both emergency department and inpatient settings.

To do so, the team modified emergency department and inpatient treatment plans to state explicitly that bronchodilators were not recommended for infants with a typical presentation of bronchiolitis, which involves symptoms of a viral upper respiratory infection that progress to the lower respiratory tract. The team also educated nurses, respiratory therapists and physicians on the new guidelines and modified the electronic health record system, creating a "do not order" option that stated bronchodilators were not recommended for routine use.

After implementing the new protocols, albuterol use in infants with bronchiolitis declined from 43% to 20% in the emergency department and from 18% to 11% in inpatient settings, which prevented more than 600 infants from receiving an unnecessary treatment. The team measured patient admission rates, length of stay and revisit rates and found the reduced albuterol use did not impact those metrics.

The study period covered October 2014 through March 2017, which included three winter seasons. During that time, CHOP had 5,115 emergency department visits and 1,948 hospitalizations for bronchiolitis. Of those, 3,834 emergency department visits and 1,119 inpatient hospitalizations were included in the study.

"The methods used in this study can be applied to other diagnoses where there is potential overuse of testing and interventions," said Joseph J. Zorc, MD, MSCE, attending physician in emergency medicine at CHOP and senior author of the study. "The next step for improving bronchiolitis care at CHOP is focusing on the use of the high-flow nasal cannula, an emerging therapy for infants with severe bronchiolitis."

COLUMBUS, Ohio - A new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) shows how resistance to a promising targeted drug develops in patients with a rare, lethal cancer of the bile ducts called cholangiocarcinoma.

The study, reported in the journal Molecular Cancer Therapeutics, also suggests that adding another drug at the time of progression might re-sensitize tumor cells to the initial drug, called an FGFR inhibitor.

"While the majority of patients with FGFR-positive cholangiocarcinoma benefit from new FGFR inhibitors in clinical trials, most patients unfortunately develop cancers resistant to the drugs," says study leader Sameek Roychowdhury, MD, PhD, a medial oncologist and researcher at the OSUCCC - James. "We believe that this study is an important step in understanding drug resistance, and improving the treatment of this and other cancers caused by abnormal FGFR gene mutations."

Findings also suggest that monitoring fragments of circulating tumor DNA for acquired mutations that cause resistance to FGFR inhibitors may reveal the presence of resistance mutations and mark the time a patient should begin taking the additional drug, an mTOR inhibitor.

The successful treatment of cholangiocarcinoma is challenging because the disease is usually diagnosed at an advanced stage that has a five-year survival rate of 2%. Patients diagnosed earlier also have low five-year survival due to high rates of disease recurrence. Abnormal activation of the FGFR gene happens in 15 to 20% of people with cholangiocarcinoma, and FGFR inhibitors show effectiveness in 70 to 80% of those patients until resistance develops. There are six studies of FGFR inhibitors in clinical trials at the OSUCCC - James.

"A better understanding of how treatment resistance develops and how to prevent it is critical for improving the treatment of cholangiocarcinoma and other cancers caused by FGFR mutations," says first author Melanie Krook, PhD, a postdoctoral fellow in Roychowdhury's lab.

"Our findings suggest that cholangiocarcinoma patients treated with an FGFR targeted therapy could potential benefit from combination therapies with other drugs such as mTOR inhibitors. Additional laboratory studies are needed to identify the optimal lead strategies for this combination," she adds.

For this study, Roychowdhury, Krook and colleagues examined the FGFR (fibroblast growth factor receptor) gene in the cancer cells of a cholangiocarcinoma patient who died after experiencing disease progression and developing resistance to the FGFR inhibitor infigratinib.

The researchers identified two acquired FGFR mutations in the patient's tumor cells that conferred resistance to FGFR inhibitors. They then used cancer cell lines to learn that the mutations led to activation of the mTOR biochemical pathway. This enabled the cancer cells to grow even in the presence of FGFR inhibitors. Adding an mTOR inhibitor to the cells restored their sensitivity to FGFR inhibitors.

Key findings

Two acquired FGFR2 mutations, p.E565A and p.L617M, were shown to drive resistance to the FGFR inhibitor infigratinib.

The p.E565A mutation upregulates the mTOR signaling pathway, which desensitizes cholangiocarcinoma cell lines to infigratinib and other FGFR inhibitors.

A drug that inhibited the mTOR pathway restored the sensitivity of the cells to infigratinib and other FGFR inhibitors.

"Overall, our findings suggest that an mTOR inhibitor administered at the time of progression may re-sensitize tumor cells to an FGFR inhibitor in patients who develop resistance to these agents," Roychowdhury says.