Earth

DURHAM, N.C.-- Biomedical engineers at Duke University have developed a method to address failures in a promising anti-cancer drug, bringing together tools from genome engineering, protein engineering and biomaterials science to improve the efficacy, accuracy and longevity of certain cancer therapies.

Using a combination of CRISPR-based targeting, a protein "depot" that allows for sustained release of the drug and a highly potent binding system, the team showed that their new strategy could overcome three critical problems that limit the efficacy of many cancer drugs-- their limited potency, their quick elimination from the body, and the ability of cancer cells to develop resistance to the drug.

The research appeared online Sept. 4 in the journal Science Advances.

More than 20 years ago, researchers discovered that the protein drug TRAIL, short for TNF-related apoptosis-inducing ligand, could effectively kill cancer cells without harming healthy cells -- at least, in the lab. TRAIL works by binding to specific protein receptors on cancer cells, ominously called death receptors, sending a signal that causes the cells to self-destruct. Although initial experiments showed the drug worked in a variety of cancer cell lines, including melanoma, lymphoma, pancreatic, prostate, lung, colon and breast cancer, TRAIL and similar drugs surprised researchers by showing limited success in clinical trials.

After more study, scientists pinpointed three reasons why the promising drug failed: TRAIL wasn't potent enough, the drug was being cleared from the body too quickly and some cancer cells were resistant to the therapy.

Using a combination of three tools -- a highly potent protein drug, a "depot" that allows for sustained release of the drug, and CRISPR/Cas9 based gene editing to pinpoint the cause of resistance to the drug -- the Duke team, which included Mandana Manzari, a recent PhD graduate, Ashutosh Chilkoti, the chair of Duke biomedical engineering, and Kris Wood, an assistant professor of pharmacology and cancer biology, demonstrated that their new strategy could provide a solution to these problems and give protein-based anti-cancer "biologics" like TRAIL that failed in the clinic a second chance.

"The real significance of this research for me is the true cross-disciplinary nature of it," said Manzari, first author on the paper and now a post-doctoral researcher at the Memorial Sloan Kettering Cancer Center in New York. "This is really the first example I've seen where we're bringing in pharmacology, drug delivery, and genomics to pinpoint the exact circumstances that cause a biologic to fail and then develop solutions."

The first step of the process involved addressing TRAIL's limited potency. Typically, cells have multiple death receptors, but a specific receptor called death receptor 5 (DR5) is more prevalent in certain cancer cells. TRAIL, a three-part protein, binds to DR5 and links three death receptors together, sending a signal for cells to self-destruct. TRAIL can also bind to other death receptors and "decoy" receptors on normal cells. A more potent drug would be specific for a given death receptor, like DR5 that is present on cancer cells, and link together larger numbers of the receptor on a cell surface to send a stronger death signal to the cancer cell.

Manzari produced a highly potent, six-part death receptor agonist (DRA) that could bind six death receptors together and indude a much stronger self-destruct signal.

Next, the team examined how to prevent the super-potent death receptor agonist from being cleared from the body too quickly. They genetically fused the DRA to a temperature-responsive protein called elastin-like polypeptide (ELP), which forms a gel-like "depot" within a room-temperature solution. After the solution is injected under the skin, it dissolves, releasing the DRA over a longer period of time.

Finally, Chilkoti and Manzari partnered with Kris Wood to better understand what caused certain cells to resist death by TRAIL or death receptor agonist (DRA). The team systematically disabled various genes in the cancer cells using CRISPR/Cas9 until they could deduce which were responsible for TRAIL or DRA resistance. Then they selected drugs to target the proteins produced by those genes and paired them with the DRA slow-release depot.

"This work opens another exciting avenue for targeting a critical cell death pathway in cancer, an area of increasing interest in the translational cancer therapeutics community," Wood said.

"When we figured out the genes that drive resistance, we were able to map them to commercially-available drugs that could specifically target the proteins that come from those genes," said Manzari. "It basically gave us a platform to figure out what drugs we can combine with the DRA in cases where this drug or other protein drugs don't work well to nip that resistance in the bud."

With their triple-whammy tool, the team was able to effectively overcome intrinsic resistance, repress tumor growth and extend survival in mice that were implanted with colorectal cancers from human patients that are highly resistant to treatment with TRAIL.

Now, the researchers are considering how they could apply this method to other protein and small-molecule drugs that face similar barriers that limit their effectiveness.

"I think the thing that really sets this approach apart is designing each piece of the platform rationally to address a specific problem and bringing them all together holistically to solve three critical problems that limit not just TRAIL, but many new cancer therapies," Chilkoti said.

"Typically the protein engineering is one platform, the ELP strategy is one platform and the genomic screen strategy is its own platform," Manzari said. "This is a good example of true synergy of engineering, pharmacology, genomics and materials. People always talk about bringing those together, and this is a clear example of that."

We're all a little short on sleep during the work week. A new study adds to the mounting evidence about just how harmful lack of sleep can be. In the Journal of Lipid Research, researchers at Pennsylvania State University report that just a few days of sleep deprivation can make participants feel less full after eating and metabolize the fat in food differently.

Sleep disruption has been known to be have harmful effects on metabolism for some time. Orfeu Buxton, a professor at Penn State and one of the senior authors of the new study, contributed to a lot of the research demonstrating that long-term sleep restriction puts people at a higher risk of obesity and diabetes. However, Buxton said, most of those studies have focused on glucose metabolism, which is important for diabetes, while relatively few have assessed digestion of lipids from food.

Kelly Ness, now a postdoctoral fellow at the University of Washington, ran the study when she was a graduate student in Buxton's lab. After participants spent a week getting plenty of sleep at home, she said, the 15 healthy men in their 20s checked into the sleep lab for the ten-night study. For five of those nights the participants spent no more than five hours in bed each night.

During the study, Ness said, she and other researchers collected data but also spent time, "interacting with the subjects, playing games with them, talking with them--helping to keep them awake and engaged and positive."

To find out how the uncomfortable schedule affected metabolism, the researchers gave participants a standardized high-fat dinner, a bowl of chili mac, after four nights of sleep restriction. "It was very palatable--none of our subjects had trouble finishing it--but very calorically dense," Ness said. Most participants felt less satisfied after eating the same rich meal while sleep deprived than when they had eaten it well-rested.

Then researchers compared blood samples from the study participants. They found that sleep restriction affected the postprandial lipid response, leading to faster clearance of lipids from the blood after a meal. That could predispose people to put on weight. "The lipids weren't evaporating--they were being stored," Buxton explained.

The simulated workweek ended with a simulated Friday and Saturday night when participants could spend ten hours in bed catching up on missed shut-eye. After the first night, they ate one last bowl of chili mac. Although participants' metabolic handling of fat from food was slightly better after a night of recovery sleep, they didn't recover to the baseline healthy level.

This study was highly controlled, which makes it an imperfect model for the real world, Ness said. It focused on healthy young people, who are usually at a lower risk of cardiovascular disease, and all of the participants were men. The researchers also wondered whether giving more recovery time would change the magnitude of recovery they observed.

Nonetheless, according to Buxton, the study gives worthwhile insight into how we handle fat digestion. "This study's importance relies on its translational relevance. A high-fat meal in the evening, at dinnertime--and real food, not something infused into the vein? That's a typical exposure. That's very American."

For decades geoscientists have been trying to detect the influence of climate on the formation of rivers, but up to now there has been no systematic evidence.

A new study, led by scientists from the University of Bristol and published today in the journal Nature, discovers a clear climatic signature on rivers globally that challenges existing theories.

If you walk from a river's source to its mouth, you walk a path that descends in elevation. In some rivers, this path will descend steeply out of the uplands, and then flatten out in the lowlands. This results in an elevational profile (which we call the long profile) that has a concave up shape, similar to the shape of the inside of a bowl as you trace it from the inside rim to the bottom. In contrast, a straight long profile descends evenly in elevation, like a ramp, along the path as you walk from the source to the mouth.

The new research by Chen et al. shows that while river long profiles tend to be concave up in humid regions, they become progressively straighter in drier regions.

Lead author Shiuan-An Chen from the University of Bristol's School of Geographical Sciences, said: "The long profile is formed gradually over tens of thousands to millions of years, so it tells a bigger story about the climate history of region. We would expect climate to affect the river long profile because it controls how much water flows in rivers and the associated force of water to move sediment along the riverbed."

Up until now scientists have lacked a large, systematic dataset of rivers that spans the range of climate zones on Earth, enabling full exploration of the links between climate and river form. The research team produced a new, freely available, database of river long profiles, generated from data originally collected by NASA's space shuttle. They used specialist software developed by co-author Dr Stuart Grieve at Queen Mary University of London to develop a new long profile database that includes over 330,000 rivers across the globe.

The study shows for the first time at the global scale that there are distinct differences in river long profile shapes across climate zones, and that the reason behind these differences lies in the expression of aridity in streamflow in rivers.

In humid regions, rivers tend to have flow in them all year round which continually moves sediment and erodes the overall profile into a concave up shape.

As the climate becomes progressively arid (from semi-arid, to arid, to hyper-arid), rivers only flow a few times per year when it rains, moving sediment infrequently.

Additionally, arid rivers tend to experience brief, intense rainstorms, which do not create flow over the entire river length.

These links between climate, streamflow and long profile shape are explained in the paper using a numerical model which simulates the evolution of river profiles over time in response to streamflow characteristics.

The authors show that regardless of all other potential controls on river profiles, streamflow characteristics have a dominant effect on the final profile shape. They demonstrate that the differences in the climatic expression of streamflow explain the variations in profile shape across climatic regions in their database.

Dr Katerina Michaelides, also from Bristol's School of Geographical Sciences, who led the research added:

"Traditional theory included in textbooks for decades describes that river long profiles evolve to be concave up. Existing theories are biased towards observations made in humid rivers, which are far better studied and more represented in published research than dryland rivers.

"Our study shows that many river profiles around the world are not concave up and that straighter profiles tend to be more common in arid environments."

"I think dryland rivers have been understudied and under-appreciated, especially given that drylands cover ~40% of the global land surface. Their streamflow expression gives unique insights into the climatic influence on land surface topography."

Dr Stuart Grieve from Queen Mary University of London said: "Combining satellite data with high performance computing is revolutionizing our discipline; allowing us to understand how our planet is changing at unprecedented scales. Our analysis of these data only scratches the surface of the potential that this fusion of data, computer power and geoscientific insight can offer us to understand our planet, as well as others in the solar system."

Bottom Line: For adolescent girls but not boys, bigger waistlines and greater fat mass were associated with being an evening chronotype who prefers going to bed and waking up later and greater social jet lag because of later sleep timing on weekends versus weekdays, independent of sleep duration and other lifestyle factors. This observational study of 804 adolescents (418 girls and 386 boys; average age 13) from eastern Massachusetts included data from wrist monitors, questionnaires and body measurements. Chronotype was measured based on a scale with higher scores indicating evening versus morning preferences for adolescents; social jet lag was the difference in sleep midpoint in hours from midnight on weekends (free days) versus weekdays (school days) with higher values meaning that sleep timing shifted later on free days. There were no associations with a cardiometabolic risk score. A limitation of the study is that causal inferences cannot be made about the associations. The findings suggest that obesity prevention efforts should consider regular patterns of sleep and wake times, in addition to more and better-quality sleep.

Author: Elizabeth M. Cespedes Feliciano, Sc.D., Sc.M., of Kaiser Permanente Northern California, Oakland, and coauthors

(doi:10.1001/jamapediatrics.2019.3089)

Editor's Note: The article contains conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Lymphomas in the central nervous system are rare but dangerous. Scientists at the German Cancer Research Center (DKFZ) have now discovered which molecular mechanism leads to lymphomas forming metastases in the central nervous system. Using a mouse model, the researchers showed that chronic inflammatory processes in aging brains lead to lymphoma cells that have entered the brain tissue being retained instead of being released directly back into the blood. They also identified key molecules of this mechanism in tissue samples from patients with lymphomas of the central nervous system. The researchers therefore hope to have identified a potential approach for developing new therapeutic approaches.

Lymphomas of the central nervous system (CNS) are a rare and very aggressive form of lymph gland cancer. Patients with secondary CNS lymphomas in particular have a poor prognosis. These CNS lymphomas are metastatic lymphomas that first occur in other parts of the body, such as the spleen. Up to now, it was largely unclear how lymphoma cells enter the brain and become lodged there. "We have now demonstrated that inflammatory processes in the brain play a key role," explained Mathias Heikenwälder from the German Cancer Research Center (DKFZ) in Heidelberg. In collaboration with colleagues from the Helmholtz Center Munich and TU Munich, Heikenwälder and his team managed to discover the underlying cell biology mechanisms.

An important factor in connection with chronical inflammation in the brain is NF-kappaB. This transcription factor determines which genes are active in a cell and plays an important role in regulation of the immune response. Moreover, there are increasing indications that NF-kappaB and its signaling pathway are also important in connection with CNS lymphomas.

In order to examine inflammatory processes in the brain, the researchers bred genetically modified mice in which NF-kappaB is permanently active in the CNS. "Very early on, these animals develop inflammation in the brain. We also find such inflammatory reactions in brains from lymphoma patients whose tissues we've examined." Heikenwälder explained.

His team injected lymphoma cells into these animals and the rodents did in fact develop metastatic lymphomas in the CNS. This did not happen in mice without chronic NF-kappaB activation. "Using a special microscopy technique, we observed that the lymphoma cells enter the brain from the blood vessels in normal mice too. However, in these animals, they do not remain in the brain; instead, they go back into the peripheral blood vessels. In the genetically modified rodents, the lymphoma cells that have entered the brain remain there. So we wanted to know what keeps them there," Heikenwälder continued.

In a healthy brain without inflammation, a messenger substance ensures that both white blood cells and lymphoma cells leave the brain tissue and go back into the blood vessels. The DKFZ scientists have now identified an important antagonist of this messenger substance in their experiments: the signaling molecule CCL19, the production of which is stimulated by NF-kappaB. "The two messenger substances fight so to speak over where the lymphoma cells go," Heikenwälder explained. "In the event of inflammation with increased NF-kappaB activity, there is also more CCL19, which means it gains the upper hand and keeps the lymphoma cells in the brain." There, they multiply and develop into tumors.

The researchers found a similar situation in human brains. In people affected by primary or secondary brain lymphomas, the NF-kappaB signaling pathway is also activated, so there is more CCL19. As in the mice, the messenger substance is released by special brain cells known as astrocytes.

The DKFZ researchers have thus not only provided the first explanation of how secondary CNS lymphomas arise. "We have also identified inflammatory processes in the brain as potential risk factors for CNS lymphomas," Heikenwälder continued.

In their experiment, lymphoma cells in older animals that were not genetically modified behaved exactly like those in young genetically modified animals with chronic inflammation. "Now we can think about whether and how inflammation in the brains of lymphoma patients can be treated to prevent the development of secondary CNS lymphomas."

New Haven, Conn. - A key question for climate scientists in recent years has been whether the Atlantic Ocean's main circulation system is slowing down, a development that could have dramatic consequences for Europe and other parts of the Atlantic rim. But a new study suggests help may be on the way from an unexpected source -- the Indian Ocean.

Think of it as ocean-to-ocean altruism in the age of climate change.

The new study, from Shineng Hu of the Scripps Institution of Oceanography at the University of California-San Diego and Alexey Fedorov of Yale University, appears Sept. 16 in the journal Nature Climate Change. It is the latest in a growing body of research that explores how global warming may alter global climate components such as the Atlantic meridional overturning circulation (AMOC).

AMOC is one of the planet's largest water circulation systems. It operates like a liquid escalator, delivering warm water to the North Atlantic via an upper limb and sending colder water south via a deeper limb.

Although AMOC has been stable for thousands of years, data from the past 15 years, as well as computer model projections, have given some scientists cause for concern. AMOC has showed signs of slowing during that period, but whether it is a result of global warming or only a short-term anomaly related to natural ocean variability is not known.

"There is no consensus yet," Fedorov said, "but I think the issue of AMOC stability should not be ignored. The mere possibility that the AMOC could collapse should be a strong reason for concern in an era when human activity is forcing significant changes to the Earth's systems.

"We know that the last time AMOC weakened substantially was 15,000 to 17,000 years ago, and it had global impacts," Fedorov added. "We would be talking about harsh winters in Europe, with more storms or a drier Sahel in Africa due to the downward shift of the tropical rain belt, for example."

Much of Fedorov and Hu's work focuses on specific climate mechanisms and features that may be shifting due to global warming. Using a combination of observational data and sophisticated computer modeling, they plot out what effects such shifts might have over time. For example, Fedorov has looked previously at the role melting Arctic sea ice might have on AMOC.

For the new study, they looked at warming in the Indian Ocean.

"The Indian Ocean is one of the fingerprints of global warming," said Hu, who is first author of the new work. "Warming of the Indian Ocean is considered one of the most robust aspects of global warming."

The researchers said their modeling indicates a series of cascading effects that stretch from the Indian Ocean all way over to the Atlantic: As the Indian Ocean warms faster and faster, it generates additional precipitation. This, in turn, draws more air from other parts of the world, including the Atlantic, to the Indian Ocean.

With so much precipitation in the Indian Ocean, there will be less precipitation in the Atlantic Ocean, the researchers said. Less precipitation will lead to higher salinity in the waters of the tropical portion of the Atlantic -- because there won't be as much rainwater to dilute it. This saltier water in the Atlantic, as it comes north via AMOC, will get cold much quicker than usual and sink faster.

"This would act as a jump-start for AMOC, intensifying the circulation," Fedorov said. "On the other hand, we don't know how long this enhanced Indian Ocean warming will continue. If other tropical oceans' warming, especially the Pacific, catches up with the Indian Ocean, the advantage for AMOC will stop."

The researchers said this latest finding illustrates the intricate, interconnected nature of global climate. As scientists try to understand the unfolding effects of climate change, they must attempt to identify all of the climate variables and mechanisms that are likely to play a role, they added.

"There are undoubtedly many other connections that we don't know about yet," Fedorov said. "Which mechanisms are most dominant? We're interested in that interplay."

The intensity of brain activity during the day, notwithstanding how long we've been awake, appears to increase our need for sleep, according to a new UCL study in zebrafish.

The research, published in Neuron, found a gene that responds to brain activity in order to coordinate the need for sleep. It helps shed new light on how sleep is regulated in the brain.

"There are two systems regulating sleep: the circadian and homeostatic systems. We understand the circadian system pretty well - our built-in 24-hour clock that times our biological rhythms, including sleep cycles, and we know where in the brain this rhythm is generated," explained lead author Dr Jason Rihel (UCL Cell & Developmental Biology).

"But the homeostatic system, which causes us to feel increasingly tired after a very long day or sleepless night, is not well understood. What we've found is that it appears to be driven not just by how long you've been awake for, but how intensive your brain activity has been since you last slept."

To understand what processes in the brain drive homeostatic sleep regulation - independent of time of day - the research team studied zebrafish larvae.

Zebrafish are commonly used in biomedical research, partly due to their near-transparent bodies that facilitate imaging, in addition to similarities to humans such as sleeping every night.

The researchers facilitated an increase in brain activity of the zebrafish using various stimulants including caffeine.

Those zebrafish which had drug-induced increased brain activity slept for longer after the drugs had worn off, confirming that the increase in brain activity contributed to a greater need for sleep.

The researchers found that one specific area of the zebrafish brain was central to the effect on sleep pressure: a brain area that is comparable to a human brain area found in the hypothalamus, known to be active during sleep. In the zebrafish brain area, one specific brain signalling molecule called galanin was particularly active during recovery sleep, but did not play as big a role in regular overnight sleep.

To confirm that the drug-induced findings were relevant to actual sleep deprivation, the researchers conducted a test where they kept the young zebrafish awake all night on a 'treadmill' where the fish were shown moving stripes - by imitating fast-flowing water, this gives the fish the impression that they need to keep swimming. The zebrafish that were kept awake slept more the next day, and their brains showed an increase in galanin activity during recovery sleep.

The findings suggest that galanin neurons may be tracking total brain activity, but further research is needed to clarify how they detect what's going on across the whole brain.

The researchers say their finding that excess brain activity can increase the need for sleep might explain why people often feel exhausted after a seizure.

"Our findings may also shed light on how some animals can avoid sleep under certain conditions such as starvation or mating season - it may be that their brains are able to minimise brain activity to limit the need for sleep," said the study's first author, Dr Sabine Reichert (UCL Cell & Developmental Biology).

The researchers say that by discovering a gene that plays a central role in homeostatic sleep regulation, their findings may help to understand sleep disorders and conditions that impair sleep, such as Alzheimer's disease.

"We may have identified a good drug target for sleep disorders, as it may be possible to develop therapies that act on galanin," added Dr Reichert.

The conductivity of Graphene has made it a target for many researchers seeking to exploit it to create molecular scale devices and now a research team jointly led by University of Warwick and EMPA have found a way past a frustrating catch 22 issue of stability and reproducibility that meant that graphene based junctions were either mechanically stable or electrically stable but not both at the same time.

Graphene and graphene like molecules are attractive choice as an electronic component in molecular devices but up till now it has proven very challenging to use them in large scale production of molecular devices that will work and be robust at room temperatures. In a joint effort research teams from the University of Warwick, EMPA and Lancaster and Bern Universities have reached both electrical and mechanical stability in graphene based junctions million times smaller than diameter of human hair. They have today (Monday 16 September 2019) published their findings in a paper entitled "Robust graphene-based molecular devices" in the journal Nature Nanotechnology.

Simple mechanically stable structures such as graphene-like molecules are easy to produce by chemical synthesis but at this very small scale these are subject to a range of limits when they placed in a junction to form an electronic device such as variations in molecule electrode interface. The researchers overcome these limits by separating the requirements for mechanical and electronic stability at the molecular level.

They produced an electrically effective structure by building a graphene-like molecule stack to form a electron path through the graphene-like molecules P orbitals (these are dumbbell shaped electron clouds within which an electron can be found, within a certain degree of probability) This would open new avenues to use fascinating molecular properties such as quantum interference which occurs at such a small scale provided a sufficiently mechanical robust structures achieved. For this, the research team also created bonds between each molecule and a silicon-oxide substrate. This gave the structure significant mechanical stability by effectively anchoring the graphene-like molecule stack to the substrate using a silanization reaction. This is illustrated in the simplified diagram accompanying this press release.

Dr Hatef Sadeghi from the University of Warwick's School of Engineering who led the theoretical modelling of this work said:

"This method allowed us to design and produce graphene-based molecular devices that are electronically and mechanically stable over a large temperature range. This was achieved by decoupling the mechanical anchoring from the electronic pathways by combining a covalent binding of the molecules to the substrate and large π-conjugated head groups.

"The junctions were reproducible over several devices and operated from 20 Kelvin up to room temperature. Our approach represents a simple but powerful strategy for the future integration of molecule-based functions into stable and controllable nanoelectronic devices."

A study carried out with a new human stem cell-derived model reveals that the most prevalent genetic risk factor of Alzheimer's disease (AD), apolipoprotein E4 (APOE4), impairs the function of human brain immune cells, microglia. These findings pave the way for new, effective treatment approaches for AD. The results were published in Stem Cell Reports.

The study of human microglia has been hindered by the considerable challenges of isolating sufficient numbers of viable microglia from human brain tissue. The new study presents a protocol to differentiate patient-derived stem cells to produce large numbers of human microglia that closely resemble their in vivo counterparts and that can be studied under controlled laboratory conditions. The study was carried out at the University of Eastern Finland in collaboration with the University of Wollongong, Australia, and the University of Helsinki.

Alzheimer's disease, the most common cause of dementia among the elderly, is thought to be caused by the abnormal build-up of amyloid protein in the brain. However, it is not known exactly what causes this process. Amyloid build-up is characterized by accompanying damage to the neurons, leading to cell death and shrinking of the brain. There is no treatment to cure or slow down the progress of the disease. Several promising compounds in animal trials have proven to be disappointing in clinical studies with humans. Most efforts to find a cure have focused on inhibiting the production of amyloid proteins.

Microglia remove amyloid from the brain using a mechanism called phagocytosis, and they take care of other inflammatory processes in the brain. The growing body of evidence shows that there are important differences between humans and animals especially in inflammatory processes. In Alzheimer's disease, the function of microglia is compromised, but it is incompletely understood why microglia are unable to remove toxic amyloid in patients. Instead, microglia either lose their normal function or activate adversely and increase the loss of neurons.

APOE4 is the strongest genetic risk factor for Alzheimer's disease. Apolipoprotein, APOE, plays a critical role in the metabolism of lipids, such as cholesterol, and contributes to repairing neuronal damage in the brain. APOE is present in humans in three isoforms, and genetics determines which forms an individual carries. Only the APOE4 form predisposes for Alzheimer's disease, and over half of patients carry this form. In humans, the APOE gene is abundantly expressed in microglia, but its role specifically in these cells is poorly understood.

In the present study, researchers showed that APOE4 increases the inflammatory response of human microglia, but at the same time reduces the ability of the cells to migrate and phagocytose pathogenic material. These functions are important for maintaining the brain homeostasis, to protect from pathogens and control the normal cell death that comes with aging. Moreover, the researchers were able to identify for the first time that APOE4 impairs the metabolic activity of human microglia. Together, these findings demonstrate that APOE4 has a profound impact on the basic functions of human microglia. The metabolism of microglia may open up new avenues for targeted treatment and prevention of Alzheimer's disease.

The present study reveals a new, interesting observation for treatment: microglia may have a significant role in the progression of Alzheimer's disease, independent from their ability to remove toxic amyloid build-up. Patient stem cell-derived microglia offer an exciting new tool enabling studies of molecular mechanisms in other brain diseases, too, as well as controlled studies of new targeted therapies.

For years, astronomers have looked up at the sky and speculated about the strange dimming behavior of Tabby's Star.

First identified more than a century ago, the star dips in brightness over days or weeks before recovering to its previous luminosity. At the same time, the star appears to be slowly losing its luster overall, leaving researchers scratching their heads.

Now, astronomers at Columbia University believe they've developed an explanation for this oddity.

In a new paper published in the Monthly Notices of the Royal Astronomical Society, astrophysicists Brian Metzger, Miguel Martinez and Nicholas Stone propose that the long-term dimming is the result of a disk of debris - torn from a melting exomoon - that is accumulating and orbiting the star, blocking its light as the material passes between the star and Earth.

"The exomoon is like a comet of ice that is evaporating and spewing off these rocks into space," said Metzger, associate professor of astrophysics at Columbia University and principal investigator on the study. "Eventually the exomoon will completely evaporate, but it will take millions of years for the moon to be melted and consumed by the star. We're so lucky to see this evaporation event happen."

Tabby's Star, also known as KIC 8462852 or Boyajian's Star, is named after Tabetha Boyajian, the Louisiana State University (LSU) astrophysicist who discovered the star's unusual dimming behavior in 2015. Boyajian found that Tabby's Star occasionally dips in brightness - sometimes by just 1 percent and other times by as much as 22 percent - over days or weeks before recovering its luster. A year later, LSU astronomer Bradley Schaefer discovered that the star's brightness is also becoming fainter overall with time, dimming by 14 percent between 1890 and 1989.

Scientists around the world have proposed a variety of theories, ranging from comet storms to alien "megastructures," to explain the short-term dips in brightness, but very recently agreed on a much more mundane culprit - dust.

As an exoplanet is destroyed by strong interactions or collisions with its parent star, Metzger explained, the exomoon orbiting the exoplanet can become vulnerable to the pull of the system's central star. The force can be so great that the star rips the exomoon away from its planet, causing the exomoon to either collide with a star or otherwise be ejected from the system.

In a small percentage of cases, however, the star steals the exomoon and places it into a new orbit around itself. In this new orbit, the icy, dusty exomoon is exposed to radiation from the star that rips apart its outer layers, creating dust clouds that are eventually blown out to the solar system. When those clouds of dust pass between the star and Earth, intermittent dips in brightness are observed.

This explains the short-term, inconsistent dimming of Tabby's Star, but researchers have had a harder time explaining the long-term overall fading.

The Columbia team suggests that Tabby's Star abducted an exomoon from a now long-gone, nearby planet and pulled it into orbit around itself, where it has been getting torn apart by stronger stellar radiation than existed in its former orbit. Chunks of the exomoon's dusty outer layers of ice, gas, and carbonaceous rock have been able to withstand the radiation blow-out pressure that ejects smaller-grain dust clouds, and the volatile, large-grain material has inherited the exomoon's new orbit around Tabby's Star, where it forms a disk that persistently blocks the star's light. The opaqueness of the disk can change slowly, as smaller-grain clouds pass through and larger particles stuck in orbit move from the disk toward Tabby's Star, eventually getting so hot that they melt and fall onto the star's surface.

Ultimately, after millions of years, the exomoon orbiting Tabby's Star will completely evaporate, the researchers suggest.

Martinez, a Columbia College alumnus (CC'19) and researcher working with Metzger, said the team's model is unique in its hypothesis of what drives the original planet toward the star in the first place. "It naturally results in the orphaned exomoons ending up on (highly eccentric) orbits with precisely the properties previous research had shown were needed to explain the dimming of Tabby's star," Martinez said. "No other previous model was able to put all these pieces together."

There are other stellar systems that demonstrate unusual brightness dips, Martinez said, and there may be other explanations for the flux that are equally compelling. Tabby's Star is unusual because it is very similar to Earth's sun but is exhibiting drastically different behavior. It is the only star like it among the one million stars observed by Kepler, but there are many million times more stars in the universe that have yet to be observed.

The challenge now is finding other stars like Tabby's that have abducted exomoons and have not yet finished annihilating them. If the team's explanation is correct, Metzger said, it indicates that moons are a common feature of exoplanetary systems, thereby providing a way to probe the existence of exomoons.

"We don't really have any evidence that moons exist outside of our solar system, but a moon being thrown off into its host star can't be that uncommon," he said. "This is a contribution to the broadening of our knowledge of the exotic happenings in other solar systems that we wouldn't have known 20 or 30 years ago."

Communities across the United States are working with scientists to respond to climate change impacts, shows a new report and multimedia resources developed by the American Association for the Advancement of Science (AAAS). How We Respond shares details and perspectives from 18 communities using scientific information to adapt to climate change impacts and/or reduce greenhouse gas emissions.

Community-based solutions discussed in the report and associated multimedia include using wetlands to limit flooding and emissions, updating transportation, water, food and/or waste systems, and deploying sea level sensors and monitoring.

The How We Respond report summarizes the robust science on climate change, citing impacts being felt in communities throughout the United States. Through a series of profiles, the report shows how scientific information can be used in multiple stages of community response, from understanding the risks and analyzing possible options to implementing a plan and monitoring progress. For example, many communities in the United States are working with scientists to conduct vulnerability assessments that evaluate local climate risks and can help inform responses.

The impacts of climate change vary across the nation and the globe, and how communities respond depends on their needs, values and resources.

"We want to shine a light on how communities are taking action on climate change," said Emily Therese Cloyd, director of the AAAS Center for Public Engagement with Science and Technology. "We hope How We Respond gives communities ideas for how they can respond to climate change locally and ways that scientists and community members can work together to build stronger, more resilient communities."

Initiatives involving local governments, nonprofits and businesses detailed in the How We Respond report demonstrate a range of climate responses at the community level, and present solutions and approaches that could be adapted for other communities. They include:

Austin, Texas - improve energy efficiency for churches

California and New Jersey - build regional climate alliances

Cambridge, Massachusetts - climate adaptation planning with the most vulnerable communities

Dane County, Wisconsin - capture methane and develop cleaner energy

Davenport, Iowa - use wetlands to moderate river flooding and protect communities along the river

Fort Hood, Texas - transition to renewable energy sources

Herring River, Massachusetts - restore wetlands to reduce methane emissions and prepare for storm surge and sea level rise

Homer and Napakiak, Alaska - relocate buildings due to shoreline erosion

Laramie, Wyoming - develop and use biochar, an agricultural product that can improve farming and prevent the release of carbon into the atmosphere

Marquette, Michigan - address the public health impacts of climate change

Netarts Bay, Oregon - adapt shellfish hatcheries to ocean acidification and launch an ocean-monitoring network

New Orleans, Louisiana - community data collection to monitor flooding and heat waves

Phoenix, Arizona - community planning to help citizens respond to extreme heat

Savannah, Georgia - use sea-level sensors to provide real-time data on flooding

Sheridan County, Kansas - improve water use and efficiency in farming

Washington, DC - improve urban transportation

Whitefish, Montana - address climate risks and benefits to local tourism and become a resilient "fire-adapted community"

Yurok Territory, California - restore salmon stocks and manage forests and rivers

To learn more about community response to climate impacts, visit howwerespond.aaas.org.

The way immune cells pick friends from foes can be described by a classic maths puzzle known as the "narrow escape problem".

That's a key finding arising from an international collaboration between biologists, immunologists and mathematicians, published in the journal Proceedings of the National Academy of Sciences.

The narrow escape problem is a framework often applied in cellular biology. It posits randomly moving particles trapped in a space with only a tiny exit, and calculates the average time required for each one to escape.

"This is a new application for some familiar equations," says co-author Justin Tzou from Macquarie University's Department of Mathematics and Statistics.

Tzou worked with colleagues at the universities of Oxford and Cambridge in the UK, the University of British Columbia in Canada, and the University of Skövde in Sweden to analyse how potential pathogens are probed by T cells, which identify and attack invaders. The researchers discovered that the equations used in the narrow escape problem play a key role in determining whether an immune response is triggered.

"The narrow escape problem turns out to be a close cousin of the situation with T cell receptors," Justin says. "It is about determining how long a diffusing particle remains in a certain region before escaping."

The unique shape of T cells creates what has been termed a "close-contact zone" for triggering molecules called T cell receptors. Unlike most cells, which have relatively smooth surfaces, T cells are covered in ruffles, bumps and other protrusions.

Scientists have known for a long time that T cell receptor molecules sit on the surface of the cells to recognise enemies and trigger a hostile response.

The receptors contain molecular patterns that mirror those found on the surfaces of bacteria, tumours, and other dangerous interlopers. But exactly how the process of recognition and triggering works - and particularly how it works so quickly and accurately - has been a mystery.

The researchers believe the unusually lumpy shape of the T cell plays a vital role.

The protrusions on the surface mean that its area of contact with a potential enemy cell is very small - only a couple of hundred nanometres across, or a thousand times smaller than the width of a human hair.

And according to the new theory, T cell receptors follow a two-second rule: if they spend more than two seconds in the small contact zone, a chemical process begins to sound the alarm and trigger an attack.

The size of the contact zone depends on the size of the bumps on the surface of the T cell.

"The smaller the zone, the less likely the T cell receptor is able to stay in that zone by chance, triggering an attack," Justin says. "It looks like the size of these protrusions keeps the process sensitive to the presence of the invader."

The researchers hope their work will provide new insights into immune deficiencies and auto-immune conditions, in which the immune system turns against the body's own cells.

A team of scientists from Ural Federal University (Yekaterinburg), Bangladesh University of Engineering and Technology and other collaborator have published an article about a new method for the synthesis of magnetic nanoparticles. Today nanoparticles are used in various fields, from biomedicine to magnetic resonance imaging, data storage systems, environmental reclamation technologies, magnetically controlled liquids, various sensors, and immunoassay systems.

The manufacture of nanomaterials is a popular area today, and like any other industry, it is wanted to be eco-friendly. Scientists work on the so-called green synthesis - environmentally-friendly methods for producing nanomaterials from plant extracts. However, many substances contained in natural materials are unstable and quickly enter into oxidation-reduction reactions with certain components of the environment. Stabilizer is very important substance for newly synthesized nanoparticles which was one of the goals of the study conducted by the team of scientist.

To synthesize iron oxide nanoparticles, the team used inorganic substances such as iron chloride and sodium hydroxide. The scientists also used an extract made of the leaves of Ipomoea aquatica (a plant from the bindweed family) as a stabilizing and reducing agent. It helped prevent the agglutination of the particles and supported their small size.

Besides the green nature of the process, the team paid attention to different properties of the obtained nanoparticles. The ratio between the surface of the particle and its volume played an important role in the reactivity of a magnetic nanoparticles. All these leads to tune the properties that are important for biology and medicine. They also studied the magnetic properties of the nanoparticles stabilized with the Ipomoea aquatica extract. To do so, they placed the particles into an external magnetic field at room temperature and monitored their behavior. The experiments showed certain manifestations of the particles' superparamagnetic nature. This is a special form of magnetism that is observed specifically in nanosized ferromagnetic or ferrimagnetic particles.

According to several studies, it is established that magnetic nature of the nanoparticles enhances the activity of medicines. The team also conducted an experiment to confirm that the new nanoparticles suppressed the growth of bacteria. Thus, the authors claimed that the superparamagnetic nanoparticles at room temperature and their antibacterial properties would make them potential material for biomedical applications.

"Our study of different properties of the new nanoparticles confirmed they met all existing standards. The new methodology is based on plant raw materials and therefore it is eco-friendly", said Hossain Aslam, a research engineer of Ural Federal University.

Magnetite (Fe3O4) nanoparticles (MNPs) have been synthesized through a facile green synthesis route using naturally available Ipomoea aquatica leaf aqueous extract where biomolecules of leaf extract acted as a stabilizer as well as reducing agent. The synthesized MNPs has pronounced antibacterial activity against both Gram-negative and Gram-positive bacteria. The room temperature superparamagnetic nature and antibacterial activity of MNPs demonstrate that it could be potential materials for biomedical applications.

When it comes to the impact of climate change on ecosystems, we still have large knowledge gaps. Most experiments are unrealistic because they do not correspond to projected climate scenarios for a specific region. As a result, we lack reliable data on what ecosystems might look like in the future, as a team of biodiversity researchers from Central Germany show in the journal "Global Change Biology". The team reviewed all experimental studies on the topic. The researchers are now calling for the introduction of common protocols for future experiments.

The facts that climate change is man-made and that it will alter ecosystems are indisputable. However, there is debate about its extent and its consequences. "In order to predict how plant communities will react to climate change and what ecosystems of the future will look like, we need realistic field experiments worldwide," says Humboldt Professor Tiffany M. Knight from Martin Luther University Halle-Wittenberg (MLU) and the Helmholtz Centre for Environmental Research (UFZ). She heads the group "Spatial Interaction Ecology" at the German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig. According to Knight, field experiments are a necessary tool for understanding the effects of climate on plant communities. "Nature is complex and plant communities are structured by many interacting environmental factors. Experiments can specifically isolate the role of climate factors, such as precipitation and temperature," says Knight.

The researchers conducted an extensive literature review on the subject, searching for field experiments on the relationship between climate factors and plant communities. "In these experiments, temperature and precipitation are altered to investigate their effects on the plant community," explains Dr Lotte Korell, a member of Knight's research group and lead author of the study. The team was able to identify a total of 76 studies that manipulated either precipitation, temperature or both.

"We were surprised to find that most of the studies were not based on the actual climate forecasts for the specific geographical regions. In many cases they were not even close," says Korell. According to her, this mismatch between the climate manipulations in field experiments and climate projections for the regions is due to many factors. Many of the experiments were set up to address questions unrelated to climate change, or were set up before more precise climate projections were available for some regions. "There's nothing wrong with the science in those experiments. They are just not suited to answer the questions we are now asking", says Tiffany Knight.

Depending on the region, current climate models project changes in precipitation of up to 25 per cent and higher temperatures of up to 5 degrees Celsius. However, almost all of the studies the team looked at manipulated much more extreme changes in precipitation, with values ranging from -100 and +300 percent. The temperature experiments, on the other hand, underestimated the climate forecasts for the worst-case scenario. "This is why we don't have the data we need to forecast and plan for our future," says Lotte Korell. "There is too little known about how ecosystems will react to climate change and how we can best manage our natural ecosystems to maintain the functions that are critical to humanity", she continues. For example, it is unclear whether ecosystems react consistently to a changing climate or whether there are thresholds at which ecosystems react in a dramatic or even unexpected way. The team is therefore suggesting the establishment of global protocols that can be used to conduct climate experiments based on realistic projections.

BINGHAMTON, N.Y. -- A team of researchers, including faculty at Binghamton University, have developed machine learning algorithms which can successfully identify bullies and aggressors on Twitter with 90 percent accuracy.

Effective tools for detecting harmful actions on social media are scarce, as this type of behavior is often ambiguous in nature and/or exhibited via seemingly superficial comments and criticisms. Aiming to address this gap, a research team featuring Binghamton University computer scientist Jeremy Blackburn analyzed the behavioral patterns exhibited by abusive Twitter users and their differences from other Twitter users.

"We built crawlers -- programs that collect data from Twitter via variety of mechanisms," said Blackburn. "We gathered tweets of Twitter users, their profiles, as well as (social) network-related things, like who they follow and who follows them."

The researchers then performed natural language processing and sentiment analysis on the tweets themselves, as well as a variety of social network analyses on the connections between users. The researchers developed algorithms to automatically classify two specific types of offensive online behavior, i.e., cyberbullying and cyberaggression. The algorithms were able to identify abusive users on Twitter with 90 percent accuracy. These are users who engage in harassing behavior, e.g. those who send death threats or make racist remarks to users.

"In a nutshell, the algorithms 'learn' how to tell the difference between bullies and typical users by weighing certain features as they are shown more examples," said Blackburn.

While this research can help mitigate cyberbullying, it is only a first step, said Blackburn.

"One of the biggest issues with cyber safety problems is the damage being done is to humans, and is very difficult to 'undo,'" Said Blackburn. "For example, our research indicates that machine learning can be used to automatically detect users that are cyberbullies, and thus could help Twitter and other social media platforms remove problematic users. However, such a system is ultimately reactive: it does not inherently prevent bullying actions, it just identifies them taking place at scale. And the unfortunate truth is that even if bullying accounts are deleted, even if all their previous attacks are deleted, the victims still saw and were potentially affected by them."

Blackburn and his team are currently exploring pro-active mitigation techniques to deal with harassment campaigns.