Earth

Morris Animal Foundation-funded researchers at Texas A&M University and the University of Georgia may have discovered a way to treat deadly foal pneumonia without promoting multi-drug resistant bacteria. In a clinical trial, they found that gallium maltolate (GaM), a semi-metal compound with antimicrobial and anti-inflammatory properties, could be a viable alternative to overprescribed antibiotics. The team published their findings in the Nature journal Scientific Reports.

Pneumonia is one of the leading causes of disease and death in foals and there is currently no effective vaccine licensed. The bacterium Rhodococcus equi (R. equi), a naturally occurring bacterium in soil, is implicated in the most severe cases in horses. Unfortunately, current methods to screen for R. equi are imprecise and many foals are treated with antibiotics, such as the combination of a macrolide antimicrobial (e.g. azithromycin, the antibiotic in the commonly prescribed Z-pack for human use) with rifampin (MaR), even though they would not have developed pneumonia.

"While that treatment strategy saves lives in the short term, it's really driving this resistance problem because for every one foal that needs treatment, you treat several foals that don't need treatment," said Dr. Noah Cohen, the Patsy Link Chair in Equine Research at Texas A&M University, a primary investigator of the study, along with his colleague Steeve Giguère (deceased). "For the sake of foals, we want to offer veterinarians a better, nontraditional option."

For the study, the team screened 57 foals from four farms in central Kentucky for subclinical pneumonia, then divided the foals into three equal groups. Two groups contained foals with subclinical pneumonia, meaning ultrasounds found lesions on their lungs but the foals had no clinical signs. The foals also all lived on farms with positive cases of R. equi pneumonia that year. Those groups were given either MaR or GaM for two weeks.

The third group served as a control group and was made up of foals that were the same age as the subclinical foals, but were healthy. They were monitored and not given any treatment.

After two weeks, researchers analyzed fecal samples from each foal. DNA tests revealed that the MaR treated group had an increase in both the number and diversity of antibiotic-resistant genes in the bacteria. Most alarming was the discovery that the bacteria were resistant to multiple drugs and antibiotics. The GaM treated and control groups showed no change in the number or diversity of resistance genes, a positive finding.

The team also experimentally infected soil plots with resistant and nonresistant strains of R. equi to see how foals might contaminate their environment with their excrement that can contain unabsorbed and metabolized antibiotics. MaR tended to reduce the number of bacteria in a plot's soil but increase the proportion that were resistant.

Dr. Cohen said one of his team's next steps is to test the effectiveness of GaM on foals that are clinically infected with R. equi.

"The widespread use of antibiotics has consequences and we really need to be prudent in prescribing them," said Dr. Janet Patterson-Kane, Morris Animal Foundation Chief Scientific Officer. "Gallium maltonate may be an excellent alternative and we hope, if proven fully effective, that it could be put into regular use."

NASA's Terra satellite passed over the Southern Indian Ocean and provided forecasters with a visible image of newly formed Tropical Storm 22S, located near northeastern Madagascar.

The Moderate Resolution Imaging Spectroradiometer or MODIS instrument aboard Terra provided a visible image of Tropical Cyclone 22S that revealed strong thunderstorms had circled the center of circulation and western quadrant. A banding of thunderstorms on the western side were bringing rainfall and gusty winds to northeastern Madagascar. Satellite imagery also shows the storm consolidating.

At 0900 UTC, (5 a.m. EDT) Tropical Cyclone 22S was located near latitude 14.3 degrees south and longitude 52.4 degrees east, about 447 nautical miles north-northwest of Port Louis, Mauritius. 22S was moving to the west-southwest and had maximum sustained winds near 35 knots (40 mph/65 kph).

The Joint Typhoon Warning Center (JTWC) expects 22S to curve to the southeast and pass between Mauritius and Rodrigues. The storm will strengthen to 90 knots (104 mph/167 kph) before becoming subtropical.

Skin is our body's most ardent defender against pathogens and other external threats. Its outermost layer is maintained through a remarkable transformation in which skin cells swiftly convert into squames--flat, dead cells that provide a tight seal between the living portion of the skin and the world outside.

"Throughout our lifetime, squames are continually being shed from the skin surface and replaced by inner cells moving outward," says Elaine Fuchs, Rockefeller's Rebecca C. Lancefield Professor, whose lab recently shed new light onto this process. "We've identified the mechanism that allows skin cells to sense new changes in their environment and very quickly deploy instructions to drive squame formation."

Conducted in mice and described in Science, the research also provides insight into how errors in this mechanism might lead to skin conditions like atopic dermatitis and psoriasis.

Like oil and vinegar

The skin's epidermis consists of an inner layer of stem cells that periodically stop dividing and move outward, toward the body surface. As the cells transit through subsequent layers, they face the increasingly harsh extremes of our environment, like variations in temperature. In the very last step, as they approach the surface, the cells' nuclei and organelles are suddenly lost in the dramatic transformation into squames.

Felipe Garcia Quiroz, a former postdoctoral fellow in Fuchs' lab, noticed something odd in the skin cells just before they turn into squames: darkly-stained protein deposits resembling the droplets you would see if you poured oil into vinegar and gave the mixture a good shake.

This phenomenon, called phase separation, occurs when liquids with mismatched properties come together: The oil prefers to be in the company of other oil, so it separates from the water-based vinegar. Phase separation is also thought to take place inside cells, where the equivalent of oil droplets are poorly understood structures that, unlike many other cellular organelles, are not bound by lipid membranes. Quiroz and his colleagues suspected that in skin cells, the dark protein deposits observed, known as keratohyalin granules, form through phase separation and carry molecular messages that, when released, prompt the cells to quickly flatten and die.

To test this idea directly in skin, Quiroz and his colleagues developed a technique to visualize phase separation dynamics without disrupting a cell's normal processes. They created mice with a phase separation sensor, a biomolecule that emits green light under the microscope when keratohyalin granules form, and then dissipates when the granules disassemble.

With this method, the researchers were able to show that a protein called filaggrin, which is known to be mutated in some skin conditions, plays a key role in granule formation. "If filaggrin is not functioning properly, phase separation fails to occur, skin lacks keratohyalin granules, and the cells can no longer transform in response to environmental triggers," says Quiroz.

Barrier breakdown

The findings also shed light on the underlying causes of skin conditions linked to mutations in filaggrin. For example, when Quiroz engineered filaggrin proteins mimicking mutations associated with atopic dermatitis, skin cells could no longer form normal granules. "We suspect that this lack of phase separation contributes to defects in building the skin barrier, resulting in the inflamed, cracked skin that is seen in these conditions," he says.

Fuchs adds that the work might open up entirely new avenues for developing treatments for this and other filaggrin-linked skin diseases.

"Most treatments developed thus far have been focused on suppressing the immune system, but our findings suggest that we should be looking more closely into the barrier itself," she says.

Research conducted in recent decades has shown how the destruction of forests brings about a decline in species diversity. A research group in Brazil led by scientists at São Paulo State University (UNESP) has now reported the findings of an investigation into how landscape changes caused by deforestation, habitat loss and fragmentation lead directly to the loss not only of species but also of their ecological interactions. The report is published in Biotropica and features on the journal's cover. The study was supported by São Paulo Research Foundation - FAPESP.

"In ecology, we know a lot about species-area relationships but little or almost nothing about the relationship between species interactions and loss of area. Our study used ecological networks to find out how seed dispersal interactions respond to loss of area and landscape fragmentation. Shrinkage of forest fragments leads to a loss of ecological interactions that are important to the functioning of forests and the maintenance of biodiversity," said Carine Emer, first author of the article, produced while she was a postdoctoral fellow in the Conservation Biology Laboratory (LABIC) of the Bioscience Institute (IB-UNESP) in Rio Claro, with funding from FAPESP.

The study was part of the project "Ecological consequences of defaunation in the Atlantic Rainforest", supported by FAPESP and led by Mauro Galetti, a professor at IB-UNESP.

The researchers compiled data from 16 studies of plant-frugivore interactions in different fragments of the Atlantic Rainforest biome selected to form a gradient of human disturbance inferred from the size of each forest remnant. They focused on the interactions between plants and seed-dispersing birds because these animals are considered essential to constant forest regeneration. They concluded that the smaller the forest fragment the smaller the number of species living there and the fewer the interactions that are able to persist.

Forests and interactions

The largest and best conserved forest in the study was in Intervales State Park in the south of São Paulo State, with 42,000 hectares. It had the highest species diversity (81 frugivores and 185 fruit-bearing plants) and the most plant-seed disperser interactions (1,100 or 3.65 per species).

At the opposite end of the gradient was a six-hectare fragment that has been regenerating for a little over eight years in Piracicaba, with a far smaller number of frugivorous birds (28 species) interacting with only a few fruit-bearing plant species (6). Thus 169 seed disperser interactions were recorded, corresponding to only 1.47 per species.

In the former area, one bird species dispersed the seeds of three to four plant species. In the latter, it dispersed no more than two.

"The first to disappear are the larger birds, which are essential to disperse plant species with large seeds. This loss isn't just numerical. It's also functional, directly influencing the forest regeneration process," Emer said. "In the medium to long term, plants with large seeds that lose their main dispersers tend to disappear from the landscape and become limited to larger, better conserved areas. The fragmented forest becomes poorer numerically and functionally. The only birds that remain are small species whose functional role is to disperse plant species with small seeds. In other words, we lose the ecological function of large seed dispersal. This can change our forests forever."

Another article published previously by the group, also with Emer as lead author, showed that interactions involving large species are lost in forest fragments of less than 10,000 hectares. It also highlighted the importance of small generalist bird species that disperse the small seeds of equally generalist plants, maintaining connectivity in a fragmented landscape. In other words, Emer noted, "the Atlantic Rainforest is currently connected by interactions involving generalist birds that disperse plant species adapted to disturbed environments."

Besides larger species, fragmentation also has an adverse effect on what are known as specific interactions. Thus a plant species dispersed by one or only a few bird species, for example, is more at risk of extinction than another species whose fruit is eaten by several different bird species.

The research line also includes a study published last year in the prestigious journal Science Advances, in which the group estimated in millions of years the loss to the evolutionary history of seed dispersal in the Atlantic Rainforest due to the disappearance of large birds.

"The Atlantic Rainforest has dwindled to only about 12% of its original area, and most of this is small forest fragments," Emer said. "There is great diversity of seed dispersal interactions in the fragments we analyzed, with most occurring in only one or two fragments. These interactions correspond to millions of years of evolution. Species with different evolutionary trajectories interact in the present and are increasingly restricted to a few areas. In sum, we've reached a threshold beyond which we can't afford any more losses. Each and every fragment of Atlantic Rainforest corresponds to millions of years of unique evolutionary history that must be conserved."

New University of Melbourne research has revealed that ice ages over the last million years ended when the tilt angle of the Earth's axis was approaching high values.

During these times, longer and stronger summers melted the large Northern Hemisphere ice sheets, propelling the Earth's climate into a warm 'interglacial' state, like the one we've experienced over the last 11,000 years.

The study by PhD candidate, Petra Bajo, and colleagues also showed that summer energy levels at the time these 'ice-age terminations' were triggered controlled how long it took for the ice sheets to collapse, with higher energy levels producing fast collapse.

Researchers are still trying to understand how often these periods happen and how soon we can expect another one.

Since the mid 1800s, scientists have long suspected that changes in the geometry of Earth's orbit are responsible for the coming and going of ice ages - the uncertainty has been over which orbital property is most important.

Petra Bajo's paperPersistent influence of obliquity on ice age terminations since the Middle Pleistocene transition, published today in Science, moves closer to resolving some of the mystery of why ice ages end by establishing when they end.

The team combined data from Italian stalagmites with information from ocean sediments drilled off the coast of Portugal.

"Colleagues from the University of Cambridge and Portugal's Instituto Português do Mar e da Atmosfera compiled detailed records of the North Atlantic's response to ice-sheet collapse," said Associate Professor Russell Drysdale, from the research team.

"We could identify in the stalagmite growth layers the same changes that were being recorded in the ocean sediments. This allowed us to apply the age information from the stalagmite to the ocean sediment record, which cannot be dated for this time period."

Using the latest techniques in radiometric dating, the international team determined the age of two terminations that occurred about 960,000 and 875,000 years ago.

The ages suggest that the initiation of both terminations is more consistent with increases in Earth's tilt angle. These increases produce warmer summers over the regions where the Northern Hemisphere ice sheets are situated, causing melting.

"Both terminations then progressed to completion at a time when Northern Hemisphere summer energy over the ice sheets approached peak values," said Dr Drysdale. "A comparison of these findings with previously published data from younger terminations shows this pattern has been a recurring feature of the last million years."

The team plan to have a closer look next at the Middle Pleistocene Transition when the average length of ice-age cycles suddenly doubled in length.

A study led by researchers at Baylor College of Medicine reports that a hyperactive variant of enzyme ACOX1 produces elevated levels of toxic reactive oxygen species (ROS) and causes a previously unidentified late-onset neurodegenerative disorder. The team named this new syndrome "Mitchell disease" in reference to the first patient to be diagnosed with this disorder.

Experiments using fruit flies revealed that Mitchell disease caused by a hyperactive ACOX1 enzyme and ACOX1 gene deficiency are molecularly very distinct disorders. The study also identified therapeutic strategies to successfully reverse the damages specific to each condition.

In flies, bezafibrate, a commonly prescribed cholesterol-lowering drug, suppressed the symptoms of ACOX1 deficiency while N-acetylcysteine amide (NACA), an improved derivative of a widely available antioxidant supplement, N-acetyl cysteine (NAC), strongly reversed the toxic effects of hyperactive ACOX1 enzyme in Mitchell's disease. The study appears in the journal Neuron.

"The brain has large amounts of lipids, which are critical for the proper functioning of the nervous system. Abnormal breakdown of lipids in the brain and peripheral nervous system is associated with several neurodegenerative diseases," said corresponding author Hugo J. Bellen, professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and also a Howard Hughes Medical Institute investigator.

In higher vertebrates and insects, very-long-chain-fatty acids (VLCFA) are exclusively broken down in small intracellular organelles called peroxisomes by a series of reactions initiated by an enzyme called Acyl-CoA oxidase 1 (ACOX1). Loss of ACOX1 in humans results in ACOX1 deficiency, which causes an early-onset fatal neuro-inflammatory disease and death at a young age.

A medical mystery

This study began when a patient with puzzling neurological symptoms enrolled in the Undiagnosed Diseases Network (UDN) at the suggestion of Drs. Tiphanie Vogel, Soe Mar and Robert Buccelli, his healthcare providers and co-authors of this study. On comparing the patient's and his parents' DNA, the team identified a mutation in the patient that resulted in a single amino acid substitution (N237S) in the ACOX1 protein. This change was seen only in the patient and was not present in either of his parents' DNA, indicating that the patient had a de novo, or new, mutation on this gene. With the help of an online gene-matching tool, GeneMatcher, the team found two more patients who had the same new mutation in the ACOX1 gene.

All three patients, who ranged from 3 to 12 years old at the time of disease onset, had remarkably similar clinical features, including degeneration of peripheral nerves that caused a progressive loss of mobility and hearing. The three individuals had identical variants, a clear indication that ACOX1 dysfunction likely was the cause of the symptoms.

However, this finding initially baffled the researchers - the only known ACOX1-related disorder described in the medical literature at that time presented earlier in infancy with seizures, severe cognitive decline, neuro-inflammation and accumulation of VLCFA in plasma and, more importantly, was caused by the lack of the protein - none of which was true for these three patients.

Fruit flies solve the medical mystery

To resolve this conundrum, the Bellen team turned to fruit flies. The first surprising discovery made by the lead author, Hyunglok Chung, was that the ACOX1 protein is abundant and is critical for the maintenance of glia, cells that support neurons. This uncovered a previously unknown role of peroxisomes in glial cells and paved the way for further experiments.

To understand how ACOX1 variants affect the function of glia, they generated two mutant fly lines, the first one lacked both the copies of ACOX1 gene and the second, carried the substitution mutation (ACOX1 p.N237S) found in the patients in one of the copies.

"Flies lacking ACOX1 mimicked the symptoms of ACOX1 deficiency in humans, including elevated levels of VLCFA along with dramatic loss of glia and neurons and progressively impaired neuronal function. When we reduced VLCFA synthesis in these flies by administering bezafibrate, we observed significant improvements in lifespan, vision, motor coordination and neuronal function, implicating elevated levels of VLCFA and their excessive accumulation in glia as an important contributor," said Chung, postdoctoral fellow in the Bellen lab.

"It is remarkable how well bezafibrate suppressed the symptoms of ACOX1 deficiency, suggesting a new therapeutic avenue for patients with this condition," Bellen said.

In contrast to the loss of ACOX1, a hyperactive ACOX1 resulting from the introduction of a single amino acid substitution results in Mitchell's disease. Typically, breakdown of VLCFA by the enzymatic action of ACOX1 produces small amounts of highly reactive oxygen species, but glial cells quickly neutralize them. However, in Mitchell's disease, hyperactive ACOX1 produces copious amounts of toxic ROS leading to the destruction of glia and their neighboring neurons.

The harmful effects due to hyperactive ACOX1 were potently reversed with the antioxidant, N-acetyl cysteine amide (NACA). However, NACA did not suppress the lethality or toxic effects in flies that lack ACOX1, a clear indication that the two diseases act via entirely different pathways and have to be treated with two distinct therapeutic strategies.

"This study is a prime example of how combining UDN's unique team science approach with power of fruit fly genetics is facilitating rapid and phenomenal progress in rare diseases research. We are able to take on cases of patient(s) with mystery conditions, uncover new diseases and find definitive molecular diagnosis for them, make significant progress in unraveling pathogenesis of these novel diseases and rapidly identify and test promising new treatment options," Bellen said. "We have successfully identified more than 25 disease-causing genes within the past three years - a task that typically takes many years."

A major international study has shed new light on the mechanisms through which earthquakes are triggered up to 40km beneath the earth's surface.

While such earthquakes are unusual, because rocks at those depth are expected to creep slowly and aseismically, they account for around 30 per cent of intracontinental seismic activity. Recent examples include a significant proportion of seismicity in the Himalaya as well as aftershocks associated with the 2001 Bhuj earthquake in India.

However, very little is presently known about what causes them, in large part due to the fact that any effects are normally hidden deep underground.

The current study, published in Nature Communications and funded by the Natural Environment Research Council, sought to understand how such deep earthquakes may be generated.

They showed that earthquake ruptures may be encouraged by the interaction of different shear zones that are creeping slowly and aseismically. This interaction loads the adjacent blocks of stiff rocks in the deep crust, until they cannot sustain the rising stress anymore, and snap - generating earthquakes.

Emphasising observations of quite complex networks created by earthquake-generated faults, they suggest that this context is characterised by repeating cycles of deformation, with long-term slow creep on the shear zones punctuated by episodic earthquakes.

Although only a transient component of such deformation cycles, the earthquakes release a significant proportion of the accumulated stress across the region.

The research was led by the University of Plymouth (UK) and University of Oslo (Norway), with scientists conducting geological observations of seismic structures in exhumed lower crustal rocks on the Lofoten Islands.

The region is home to one of the few well-exposed large sections of exhumed continental lower crust in the world, exposed during the opening of the North Atlantic Ocean.

Scientists spent several months in the region, conducting a detailed analysis of the exposed rock and in particular pristine pseudotachylytes (solidified melt produced during seismic slip regarded as 'fossil earthquakes') which decorate fault sets linking adjacent or intersecting shear zones.

They also collected samples from the region which were then analysed using cutting edge technology in the University's Plymouth Electron Microscopy Centre.

Lead author Dr Lucy Campbell, Post-Doctoral Research Fellow at the University of Plymouth, said: "The Lofoten Islands provide an almost unique location in which to examine the impact of earthquakes in the lower crust. But by looking at sections of exposed rock less than 15 metres wide, we were able to see examples of slow-forming rock deformation working to trigger earthquakes generated up to 30km beneath the surface. The model we have now developed provides a novel explanation of the causes and effects of such earthquakes that could be applied at many locations where they occur."

Project lead Dr Luca Menegon, Associate Professor at the University of Plymouth and the University of Oslo, added: "Deep earthquakes can be as destructive as those nucleating closer to the Earth's surface. They often occur in highly populated areas in the interior of the continents, like in Central Asia for example. But while a lot is known about what causes seismic activity in the upper crust, we know far less about those which occur lower. This study gives us a fascinating insight into what is happening deep below the Earth's surface, and our challenge is now to take this research forward and see if we can use it to make at-risk communities more aware of the dangers posed by such activity."

As part of the study, scientists also worked with University of Plymouth filmmaker Heidi Morstang to produce a 60-minute documentary film about their work. Pseudotachylyte premiered at the 2019 Bergen International Film Festival, and will be distributed internationally once it has screened at various other festivals globally.

University of Iowa neuroscientists have identified a specific area of the brain involved in the loss of breathing that occurs during a seizure. The findings, published in JCI Insight on March 12, could have important implications for predicting, or even treating and preventing sudden unexpected death due to epilepsy (SUDEP).

Although it has been known for more than a century that seizures can cause people to stop breathing, for much of that time this transient effect has not been taken very seriously. More recently, evidence has been building, though studies done at the UI and elsewhere, suggesting that seizure-induced loss of breathing plays a critical role in SUDEP, which is the leading cause of death in people who have uncontrolled epilepsy.

In the new study, the UI team led by neurosurgeon Brian Dlouhy, MD, studied eight pediatric patients with epilepsy, ranging in age from 3 to 17, who were undergoing seizure mapping with implanted, intracranial electrodes. Previous studies in adults from UI and elsewhere have shown that the amygdala is important for seizure-induced loss of breathing (apnea), but no one has looked at the role of the amygdala and loss of breathing in children with epilepsy.

Using brain recordings from the implanted electrodes and continuous monitoring of breathing, the researchers showed that a specific (medial) subregion of the amygdala was the critical site in the children's brains. In two patients they observed loss of breathing when the seizure reached the amygdala; and electrically stimulating the amygdala, but not other parts of the brain, produced apnea in all eight patients. These effects did not depend on the age of the child or type of epilepsy affecting the children.

Remarkably, none of the children were aware that they had stopped breathing during the stimulation trials, and none of them had any of the normal feelings of stress or discomfort that usually happen if a person stops breathing.

"We think the patient's lack of awareness or alarm that they have stopped breathing, which we also see in adult patients, may be critical in SUDEP," says Dlouhy, an assistant professor of neurosurgery with UI Health Care and member of the Iowa Neuroscience Institute.

Finally, because the new study involved a relatively large number of patients and brain sites, the team was able to collect data from many brain recordings. Using a machine-based learning algorithm (artificial intelligence) based on data from 45 stimulation sites in the children's brains and 210 stimulation trials, the team identified a focused region in the amygdala that consistently inhibited respiration and caused loss of breathing during electrical stimulation and seizures. The researchers dubbed this area the Amygdala Inhibition of Respiration (AIR) site, which includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.

"Pinpointing exactly which part of the amygdala is responsible for loss of breathing during seizures could be key to preventing SUDEP." Dlouhy says. "A more complete understanding of the AIR site may prove valuable for determining which patients are at greatest risk for SUDEP and may even provide a therapeutic target for preventing seizure-induced apnea and SUDEP."

More than 35 million Americans take statin drugs daily to lower their blood cholesterol levels. Now, in experiments with human cells in the laboratory, researchers at Johns Hopkins Medicine have added to growing evidence that the ubiquitous drug may kill cancer cells and have uncovered clues to how they do it.

The findings, say the researchers, enhance previous evidence that statins could be valuable in combating some forms of cancer. In unrelated studies, other Johns Hopkins Medicine researchers have studied how statins may cut the risk for aggressive prostate cancer.

"There have been epidemiological indications that people who take statins long term have fewer and less aggressive cancers, and that statins can kill cancer cells in the laboratory, but our research was not initially designed to investigate possible biological causes of these observations," says Peter Devreotes, Ph.D., Issac Morris and Lucille Elizabeth Hay Professor of Cell Biology.

Results of the new research appeared Feb. 12 in the Proceedings of the National Academy of Sciences.

Devreotes and his team began the new study with an unbiased screen of about 2,500 drugs approved by the U.S. Food and Drug Administration (FDA) to see which ones had the best kill rate of cells genetically engineered to have a mutation in a cancer gene called PTEN. The gene codes for an enzyme that suppresses tumor growth. Among the thousands of drugs, statins and in particular pitavastatin, emerged as a top contender in cancer-killing ability. Most of the other drugs had no effect or killed normal and engineered cells at the same rate. Equal concentrations of pitavastatin caused cell death in nearly all of the engineered cells, but very in few normal cells.

Devreotes and his team then looked at the molecular pathways that statins were likely to affect. It's well known, for example, that statins block a liver enzyme that makes cholesterol, but the drug also blocks the creation of a small molecule called geranylgeranyl pyrophosphate, or GGPP, which is responsible for connecting cellular proteins to cellular membranes.

When the researchers added pitavastatin and GGPP to human cancer cells with PTEN mutations, the researchers found that GGPP prevented the statin's killing effects and the cancer cells survived, suggesting that GGPP may be a key ingredient to cancer cell survival.

Next, looking under a microscope at cells engineered to lack the enzyme that makes GGPP, Devreotes and his team saw that as the cells began to die, they stopped moving. Under normal circumstances, cancer cells are a bundle of moving energy, consuming massive amounts of nutrients to maintain their unchecked growth. They maintain this breakneck pace by creating straw-like protrusions from their surface to drink up nutrients from the surrounding environment.

Suspecting that the non-moving cancer cells were literally "starving to death," Devreotes says, the scientists then measured the statin-treated cells' intake by adding a fluorescent tag to proteins in the cells' environment.

Normal human cells glowed brightly with the fluorescent tag, suggesting that these cells ingested protein from their surroundings regardless of whether the scientists added statins to the mix of nutrients and cells. However, human cancer cells with PTEN mutations took in almost no glowing proteins after the scientists added statins. The inability of the statin-treated cancer cells to make the protrusions needed take up proteins leads to their starvation.

Devreotes says his team plans further research on the effects of statins in people with cancer and compounds that block GGPP.

How does the immune system act to limit tumor development? Using in vivo imaging tools, scientists from the Institut Pasteur and Inserm described the spatiotemporal activity of tumor-infiltrating T lymphocytes, both locally and remotely. Their research was published in the journal Nature Cancer on March 9, 2020.

Some cells in the immune system, like T lymphocytes, are capable of attacking cancer cells. Promising new therapies known as immunotherapies, recognized by the 2018 Nobel Prize in Medicine, attempt to boost the immune system's response to cancer.

But how exactly do T lymphocytes act in tumors? T lymphocytes are killer cells that are capable of infiltrating a tumor and destroying cancer cells, one by one, through direct contact. This destruction of cancer cells is a highly local phenomenon that only occurs in the immediate vicinity of killer cells. But during these contacts, T lymphocytes also produce soluble molecules known as cytokines. Scientists from the Institut Pasteur and Inserm set out to understand the effect of one of these cytokines, known as interferon-gamma (IFN-γ), on the tumor microenvironment.

They used highly powerful imaging techniques to visualize, in real time and in vivo in mice, both the behavior of T lymphocytes and also the effect of IFN-γ within the tumor. The scientists observed that rather than acting locally, the cytokines spread rapidly within the tumor and affect cancer cells that may be distant from the T cells. "This remote action within the tumor is very interesting because it enables T lymphocytes to act on a large number of cancer cells, especially those that may have developed mechanisms to escape the immune system," explains lead author Philippe Bousso, an Inserm researcher and Head of the Dynamics of Immune Responses Unit at the Institut Pasteur.

In their research, the scientists also demonstrated that the number of T lymphocytes that successfully infiltrate the tumor is correlated with the quantity of cytokine produced and determines the extent of tumor cell response. A study of melanoma patient cells supports this model of remote action by immune cells. Stimulating this collective response could therefore represent a key target for future immunotherapy approaches.

When large earthquakes occur, seismologists are well aware that subsequent, smaller tremors are likely to take place afterwards in the surrounding geographical region. So far, however, few studies have explored how the similarity between these inter-earthquake times and distances is related to their separation from initial events. In a new study published in EPJ B, researchers led by Min Lin at the Ocean University of China in Qingdao show for the first time that the two values become increasingly correlated the closer they are in time and space to previous, larger earthquakes.

As one of Earth's most familiar natural disasters, this new mathematical insight into the occurrence of earthquakes could better inform policymakers about how they should prepare for the disasters. The team's work leads on from previous models, which were developed to understand the mechanisms and dynamics underlying earthquake occurrence following large, initial seismic events. Over a wide range of time and distance scales, Lin and colleagues revealed a strong 'cross-correlation' between inter-earthquake distances and times - a quantity describing the similarity between the two values as a function of their relative separation in time and space from an original event.

The researchers achieved their results through 'detrended cross-correlation analysis', performed on data gathered in the earthquake-prone regions of California and Sumatra between 1990 and 2013. Lin's team also accounted for the evolution in cross-correlation over time, revealing that the relationship remains strong in the time following large earthquakes but weakens both before and after this period. Their insights could help seismologists to better understand the patterns which unfold after large initial earthquakes. In turn, this could enable governments and local communities to better safeguard their populations against the worst effects of large seismic events.

DURHAM, N.C. -- Biomedical engineers at Duke University have devised a method for making small particles that are safe for living tissues that will allow them to create new shapes attractive for drug delivery, diagnostics and tissue engineering.

The results appear online on March 12 in the journal Nature Communications.

"With nothing more than some heat and light, we can make some pretty bizarre microparticles," said Stefan Roberts, a biomedical engineering research scientist at Duke. "The technique is simple enough that it could be scaled up to make billions of microparticles in a matter of minutes."

In the world of biocompatible microparticles, shape, size, internal microstructure and type of material dictate their intrinsic properties. Although companies and research labs can already fabricate many complex microparticles, the process usually involves sophisticated manufacturing techniques such as multiple-emulsion microfluidics or flow lithography. Both have their disadvantages.

Multiple-emulsion microfluidics tediously controls a series of individual oil droplets, but struggles to keep materials completely separate from one another and cannot be used for large-scale production. Flow lithography shines light through a patterned mask to etch shapes in soft materials and can make many particles in short order, but the process is difficult to tailor to complicated shapes and internal architectures.

Working with Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke, Roberts set out to try a completely new approach -- biological materials. The research pair have a history of working with elastin-like polypeptides (ELPs), which are disordered proteins that, much like a ball of spaghetti, derive their stability from chaos and have no true shape. More recently, the team began working with partially ordered proteins (POPs), which retain many of the ELPs' biologically useful properties but have enough ordered segments to provide more stability than wet noodles.

Both types of proteins can be engineered to shift back and forth between phase states at certain temperatures. While this is a useful feature for applications such as slowly releasing drugs into the body or supporting tissue growth in wounds, the researchers soon discovered that they could also create various particle shapes by putting ELPs and POPs together.

"Disordered proteins are a hot topic in biology, with many researchers trying to discover how proteins without shape can still have a biological purpose," said Roberts. "An undercurrent of our work is to instead think of these proteins as a materials scientist would and see if we can engineer them for our own biological functions in ways that can't be achieved with current materials."

In the paper, Roberts and Chilkoti demonstrate some new microparticles made with these two types of proteins. By tweaking the temperatures at which they assemble and disassemble, and sweeping back and forth through a range of temperatures at various rates, the researchers show that they are able to create a suite of shapes such as a shell with a solid core, a shell with no core, and a tangle of cords dotted with shells that they dubbed "fruits on a vine." Then, by incorporating photosensitive amino acids, they show that they can freeze these shapes into solid microparticles with a flash of light.

The researchers say that the ability to create microparticles with precisely separated regions is relevant for applications such as drug delivery and tissue engineering.

Each set of parameters simultaneously creates millions of solid, biocompatible microparticles slightly larger than an average cell. It only takes a few minutes, and it all happens in a volume of liquid about the size of a drop of water.

"This is a test case for a type of material that is flexible and simple enough to create both commonly used shapes and architectures that aren't seen using current techniques," said Roberts. "We're using new biocompatible materials to create never-before-seen shapes simply by heating, cooling and shining a light on them."

Even before uttering their first words, babies master the grammar basics of their mother tongue. Thus eight-month-old French infants can distinguish function words, or functors--e.g. articles (the), personal pronouns (she), or prepositions (on)--from content words--e.g. nouns (rainbow), verbs (to drive), or adjectives (green). Functors are frequently encountered because there are fewer of them, and they are placed before content words in languages such as English and French. In contrast, there is a much greater diversity of content words, which are also longer. Experiments conducted by three researchers from the Integrative Neuroscience and Cognition Center (CNRS/Université de Paris) with 175 eight-month-old babies, using a simple artificial language, demonstrated that these infants understood functors were more frequent and came before content words in their mother tongue (French). The young participants quickly adapted to new content words but showed little interest for newly introduced functors--as though already aware there were only a limited number of prepositions, determiners, and other words in this category. Babies' preferences were evaluated by observing how long they looked at visual displays associated with the grammar words. This study appears in Current Biology, 12 March 2020.

Heat stress from extreme heat and humidity will annually affect areas now home to 1.2 billion people by 2100, assuming current greenhouse gas emissions, according to a Rutgers study.

That's more than four times the number of people affected today, and more than 12 times the number who would have been affected without industrial era global warming.

The research is published in the journal Environmental Research Letters.

Rising global temperatures are increasing exposure to heat stress, which harms human health, agriculture, the economy and the environment. Most climate studies on projected heat stress have focused on heat extremes but not considered the role of humidity, another key driver.

"When we look at the risks of a warmer planet, we need to pay particular attention to combined extremes of heat and humidity, which are especially dangerous to human health," said senior author Robert E. Kopp, director of the Rutgers Institute of Earth, Ocean, and Atmospheric Sciences and a professor in the Department of Earth and Planetary Sciences in the School of Arts and Sciences at Rutgers University-New Brunswick.

"Every bit of global warming makes hot, humid days more frequent and intense. In New York City, for example, the hottest, most humid day in a typical year already occurs about 11 times more frequently than it would have in the 19th century," said lead author Dawei Li, a former Rutgers post-doctoral associate now at the University of Massachusetts.

Heat stress is caused by the body's inability to cool down properly through sweating. Body temperature can rise rapidly, and high temperatures may damage the brain and other vital organs. Heat stress ranges from milder conditions like heat rash and heat cramps to heat exhaustion, the most common type. Heat stroke, the most serious heat-related illness, can kill or cause permanent disability without emergency treatment, according to the U.S. Centers for Disease Control and Prevention.

The study looked at how combined extremes of heat and humidity increase on a warming Earth, using 40 climate simulations to get statistics on rare events. The study focused on a measure of heat stress that accounts for temperature, humidity and other environmental factors, including wind speed, sun angle and solar and infrared radiation.

Annual exposure to extreme heat and humidity in excess of safety guidelines is projected to affect areas currently home to about 500 million people if the planet warms by 1.5 degrees Celsius (2.7 degrees Fahrenheit) and nearly 800 million at 2 degrees Celsius (3.6 degrees Fahrenheit). The planet has already warmed by about 1.2 degrees (2.2 degrees Fahrenheit) above late 19th century levels.

An estimated 1.2 billion people would be affected with 3 degrees Celsius (5.4 degrees Fahrenheit) of warming, as expected by the end of this century under current global policies.

In New York City, extreme heat and humidity, comparable to the worst day in a typical year today, is projected to occur on four days in a typical year with global warming of 1.5 degrees Celsius (2.7 degrees Fahrenheit) and about eight days per year with warming of 2 degrees Celsius (3.6 degrees Fahrenheit). With 3 degrees Celsius (5.4 degrees Fahrenheit) of warming, extreme heat and humidity are projected to occur for about 24 days in a typical year.

One of the characteristics of Alzheimer's disease is the presence of knot-like structures between brain cells. These are called "amyloid fibrils" and are formed by the notorious amyloid beta peptide and Tau protein, which are two of the most sought-after targets for the development of therapies to treat Alzheimer's and similar diseases.

Both amyloid beta and Tau are normally produced in the brain. However, these proteins can begin to get tangled up with each other to form bulky fibril structures. When this happens, they give rise to disorders like Alzheimer's disease and other neurodegenerative diseases.

The fibril structures spread throughout the brain by moving from one cell to another. This is thought to lead to degeneration of neurons, causing brain damage and cognitive impairments like memory loss, and research efforts have generally focused on blocking these processes to slow the progression of the disease.

We now know that these amyloid fibrils can exist in multiple shapes and structures that exhibit different distinct properties which may explain why Alzheimer's and Parkinson's disease patients show different clinical symptoms. Therefore, capturing this diversity and correlating with disease symptoms in humans or the biological activity of these species in disease models has important implications for understanding disease mechanisms and developing novel therapies and diagnostics.

Given the importance of amyloid fibrils, there have been many efforts to visualize them in as much detail as possible in order to gain insights about their structure. Unraveling their structural details could possibly lead to detection of weak spots that could be targeted for treatment and pave the way for developing more reliable diagnostic tools. Despite much work, however, imaging and capturing the diversity of fibrils in biological samples has proven to be very difficult due to their complex nature and heterogeneity.

The way of gold (nanoparticles)

Now, scientists from the groups of Francesco Stellacci and Hilal Lashuel at EPFL have found a solution. In a breakthrough paper published in PNAS, the researchers show that gold amphiphilic anionic nanoparticles with a diameter around 3 nm, have a unique ability to efficiently label the edge of amyloid fibrils in a hydrated state. This makes the visualization of the diverse amyloid fibrils easier.

The research project was led by PhD student Urszula Cendrowska and Dr Paulo J. Silva.

This was possible by imaging the nanoparticles-decorated fibrils using a specialized form of TEM called "cryogenic transmission electron microscopy" (cryo-EM). The main difference here is that in cryo-EM the sample - here the fibrils - is first rapidly frozen to a very low temperature and can be visualized in its "natural" state without having to be fixed or stained beforehand.

Between the highly efficient binding of gold nanoparticles and the capabilities of cryo-EM, the scientists were able to obtain images of fibrils and unmask their diversity with unprecedented clarity. This included fibrils grown in the lab as well as from actual postmortem tissues of patients.

"Our findings reveal a striking morphological difference between the fibrils produced in cell-free systems and those isolated from patients," says Stellacci. "This supports the current view that the physiologic environment plays a major role in determining different types of amyloid fibrils."

"These advances pave the way for elucidating the structural basis of amyloid strains and toxicity," says Lashuel. "The nanoparticles are powerful and desperately needed tools for rapid imaging and profiling of amyloid morphological polymorphism in different types of samples under cryo-conditions, especially complex samples isolated from human-derived pathological aggregates."

Cryo-EM will be the focus of the upcoming Dubochet Center for Imaging, which will be created by EPFL and the University of Lausanne (UNIL) to fully harness this technology in the biomedical field, and to take this technology to the next level by combining the two schools' expertise. The facility will be named after Jacques Dubochet, a Swiss researcher who played a pioneering role in developing cryo-EM technology in the 1980s - for which he won the 2017 Nobel Prize in Chemistry. Read more here: https://www.epfl.ch/about/philanthropy/the-dubochet-center-for-imaging/