Culture

Tug-of-war receptors for sour taste in fruit flies sheds light on human taste biology

image: Fly taste receptor neurons (green) responsible for detecting acids in the food environment.

Image: 
Yali Zhang, Monell Chemical Senses Center

PHILADELPHIA - Sour taste does not have the nearly universal appeal that sweet taste does. Slightly sour foods or drinks such as yogurt and lemon juice are yummy to many, but such highly sour foods as spoiled milk are yucky, even dangerous. Like humans, many other animals, including insects, prefer slightly acidic over very acidic foods.

Evolutionary biologists surmise that the need for sour detection to be finely tuned is a two-sided coin: slightly acidic foods can enhance digestion and stimulate saliva production; relative sour-to-sweet taste can signal optimal ripeness of fruit; and extremely sour food, as with bitter taste, is a warning to what not to ingest. However, despite this usefulness, how do animals discern different concentrations of acid to produce contrasting feeding behaviors using the same sour-taste system?

A research group led by Yali Zhang, PhD, Principal Investigator at the Monell Chemical Senses Center, has recently addressed this long-standing question. Their work was recently published in Nature Communications.

Using the fruit fly as a research model, Zhang and his team set out to elucidate how animals tell the difference between low and high concentrations of acid. "We chose flies because they not only help us identify the genetic components involved in taste transduction, they also exhibit pronounced and distinct taste responses to a range of concentrations of acid compared to other animal models," said Zhang.

His team, including authors Tingwei Mi, John Mack, and Christopher Lee from the Monell Center and University of Pennsylvania, found that flies use two distinct types of gustatory (taste) receptor neurons (GRNs), which are analogous to taste receptor cells in mammals, to discriminate slightly from highly sour foods. One group of GRNs are maximally activated by low acidity, while the other group displayed its best responses to high acidity. When tasting an acidic food, the fly's brain evaluates the activation of both neuron populations and decides whether to choose or reject the acidic food, based on which type of neurons win.

"We were thrilled to discover that a fly's acid-taste behavior is dictated by a 'tug-of-war' between low- and high-acid-sensitive taste receptor cells," said Zhang. This binary sour-taste system can explain why many animals, including humans, are attracted to low but repulsed by high concentrations of acids.

In addition, Zhang's group identified a fly protein called Otopetrin-like (OtopLa), which has an analogous counterpart in humans, as a long sought-after sour taste receptor. OtopLa forms a proton-selective ion channel that is specifically required for attractive sour taste response. Remarkably, mutant flies lacking OtopLa are averse to low concentrations of acid as well as repulsed by higher concentrations.

"To my knowledge, OtopLa is the first taste receptor to be identified that is evolutionarily conserved between insects and mammals," said Zhang. This work overturns the established view that insects and mammals make use of different classes of taste receptors.

"I believe our research on fly acid sensation can greatly advance our understanding of sour taste coding in other animals, including humans," said Zhang.

Credit: 
Monell Chemical Senses Center

Controlling brain states with a ray of light

image: Controlling of brain state transitions using a molecule responsive to light.

Image: 
IBEC/IDIBAPS

The brain presents different states depending on the communication between billions of neurons, and this network is the basis of all our perceptions, memories, and behaviours. It is often considered a "black box", with difficult access for clinicians and researchers, as few limited tools are available to perform accurate and spaciotemporal studies on brain neuronal behaviour. Now, researchers from the Institute for Bioengineering of Catalonia (IBEC) in collaboration with August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and have added some light to the subject: they succeeded for the first time in controlling neuronal activity in the brain using a molecule responsive to light.

The study included participants from the Autonomous University of Barcelona (UAB) and was carried out in the frame of the Human Brain Project of the EU. It describes the first way to directly photomodulate brain state transitions in vivo.

The work, led by ICREA Research Professors Pau Gorostiza (IBEC-CERCA, BIST, CIBER-BBN) and Mavi Sanchez-Vives (IDIBAPS) and has been recently published in the journal Advanced Science. Results show that this new molecule, named PAI (for Phthalimide-Azo-Iper) can specifically and locally control the muscarinic cholinergic receptors, that is, the acetylcholine receptors, a brain neurotransmitter very important in several processes as learning attention or memory.

Control of brain states transitions with light

Transitions between brain states, such as going from being asleep to awake, or waking up from a coma, are based on the transmission of chemical and electrical signals among groups of neurons involved in different functions. Current techniques to modulate neuronal activity as transcranial-magnetic or ultrasound stimulation have limitations in spatiotemporal and spectral performance. Another technique with high precision that also uses light to control the neurons in the optogenetics, but it depends on genetic manipulation, making difficult its translation to humans due to safety reasons.

Here, researchers applied photopharmacology to tackle these problems. To do so they used a molecule previously developed at IBEC, PAI, that is light responsive and allows a spatiotemporally controlled modulation of brain neurons, binding and controlling the activity of muscarinic cholinergic receptors, key receptors on neuronal interaction and communication. By using this approach, the cholinergic-innervation dependent brain state transitions can be controlled by light using drugs chemically designed to be photosensitive.

"The control of neuronal activity in the brain is key to perform both basic and applied research, and to develop safe and accurate techniques to perform therapeutic brain interventions in clinical neurology" , explains Fabio Riefolo (IBEC), co-first author of the study.

Changes in brain states

Different brain states and transitions among them are associated with brain function. They are closely linked to changes in brain activation patterns, which in turn reflect the activity and parameters of specific neuronal networks. Thus, manipulation of neurons with a spatiotemporal control is fundamental to determine the relation among brain states and behaviour and to study the influence of neuronal circuits on specific behaviours. In addition, PAI is pharmacologically specific for a muscarinic receptor subtype, M2, which offers exciting prospects to study the pharmacology of brain waves.

When applying PAI to the intact brain, and subsequently white light, researchers could modulate the spontaneous emerging slow oscillations in neuronal circuits and reversibly manipulate the brain oscillatory frequency. This new chemically-engineered tool allowed to induce and investigate in detail, in a controlled and non-invasive way, the transitions of brain from sleep- to awake-like states using direct illumination.

In our brain, neuronal activity is driven by molecules known as neuromodulators, for example acetylcholine (ACh), through their binding to cholinergic receptors. However, it is not completely understood the contribution of the different cells expressing ACh receptors in the global brain behaviour. The use of selective and photoswitchable cholinergic drugs as PAI to achieve a spatiotemporal precise modulation of brain activity opens the way to perform accurate basic neuroscience research and to develop future brain therapies and stimulation.

"The photocontrol of endogenous receptors and their functions in the central nervous system, such as the transition between different brain states, is an achievement for neuromodulation technologies", explains Dr. Almudena Barbero-Castillo (IDIBAPS), co-first author of the study.

Credit: 
Institute for Bioengineering of Catalonia (IBEC)

Vaccination, previous infection, protect against gamma variant in animal model

MADISON - In early January 2021, travelers returning to Tokyo, Japan, from Amazonas, Brazil, were screened for COVID-19 at the airport. A few days later, the National Institute of Infectious Disease of Japan announced that the travelers had returned with a new variant of the SARS-CoV-2 virus.

That variant, known as gamma, or P.1, led to a deadly surge in COVID-19 cases in Brazil this spring, and has now spread across the world. More than 200 cases have been detected in Wisconsin. Whether current vaccines are as effective against the gamma variant remains unknown.

In a new study using variant virus recovered from one of the original travelers, researchers in the U.S. and Japan have found that vaccination with an mRNA vaccine induces antibody responses that would protect humans from infection with the gamma/P.1 variant. Hamsters previously infected with the virus strains first circulating in early 2020 were also protected from infection with the gamma variant nine months later.

The findings, the researchers say, suggest that previous SARS-CoV-2 infection and vaccines that are based on earlier strains of the virus still provide protection against infection with gamma. The study published in the Proceedings of the National Academy of Sciences on June 17, 2021.

"The animals were quite protected," says study lead Yoshihiro Kawaoka, a professor of virology at the University of Wisconsin-Madison School of Veterinary Medicine and the University of Tokyo. "There may be people who get infected with this variant even though they are vaccinated or were previously infected, but they shouldn't get severe disease."

However, he says, "that is not consistent with what has been happening in Brazil," where there have been reports of people reinfected with the gamma variant after recovering from infection with an earlier strain. It's possible, Kawaoka says, that COVID-19 immunity lasts longer in hamsters than in humans, or that cases documented as reinfections are actually first infections.

Kawaoka's research team established the Syrian hamster model for COVID-19 last year, after demonstrating that hamsters are highly susceptible to the SARS-CoV-2 virus and develop disease similar to humans, like ground glass opacity in their lungs. They also develop lasting antibodies that protect against reinfection.

"Animal models are great because (they allow us to) test vaccines, test drugs, test monoclonal antibodies and even do pathogenesis (studies)," says Kawaoka.

In fact, his team studied the gamma variant in hamsters because, while previous studies suggested P.1 might bind better to cells and resist antibodies created by previous infections or vaccination, little is known about the variant's ability to replicate in the body, how much illness or pathogenesis it causes, or how well immune responses react to the virus.

The researchers infected hamsters with either the P.1/gamma variant isolated from the traveler, or with one of two earlier strains of the virus from human samples -- one isolated from a patient in February 2020, and the other from a patient with a non-variant globally predominant strain. Each of the strains replicated similarly in the nose and lungs of hamsters and caused similar illness affecting the lungs.

Next, Kawaoka's team looked at whether antibodies in convalescent sera from 35 recovered COVID-19 patients or from people who'd received the Pfizer-BioNTech mRNA vaccine could neutralize each of the three viral strains.

Following a natural infection or vaccination, the body produces antibodies that learn to recognize the spike protein of the SARS-CoV-2 virus, which is responsible for binding to cells. Should people encounter the virus again, antibodies recognize the spike protein and subsequently fight off or limit the extent of infection.

Earlier studies have shown that a spike protein mutation -- E484K, found in gamma variants -- can change the spike protein's identity just enough that the variant can slip past these defenses. However, antibodies in the blood of vaccinated individuals reacted to all three strains, including gamma.

Antibodies in the blood of recovered COVID-19 patients were also effective at neutralizing each of the strains. However, of the 35 patients, one had been infected with gamma and the antibodies from this individual were less reactive to the non-variant strains.

The researchers say these findings suggest there are some important differences in the spike protein of gamma that might influence immunity, warranting further monitoring. Additionally, Kawaoka's group found that gamma, but not other strains of SARS-CoV-2, can infect and replicate in mice, suggesting that the spike protein interacts differently with cells than earlier strains.

The researchers also found that hamsters that had recovered from infection with either of the earlier strains of SARS-CoV-2 were protected against viral replication in their lungs if reinfected with either the same strain or the gamma variant, three weeks and nine months later.

However, gamma was recovered in the nasal passages of reinfected animals in both groups. The amount of virus in the nasal passages of reinfected animals was 1,000-fold lower than animals infected for the first time.

Finally, the researchers studied whether convalescent plasma from three patients infected with SARS-CoV-2 in early 2020 could protect against viral replication in the nose and lungs of hamsters. They found that convalescent plasma, but not plasma from patients who did not have COVID-19, limited virus replication in the lungs of hamsters infected with the prevailing non-variant strain and with gamma/P.1. Virus was found in their nasal passages.

Vaccination, Kawaoka says, is the best way to seek protection from SARS-CoV-2 and emerging variants, including the delta variant, also known as B.1.617.2. The Centers for Disease Control and Prevention recently designated the delta version as a variant of concern due to evidence that it transmits more readily.

Peter Halfmann, research associate professor at UW-Madison and co-leader of the study, added that the gamma and delta variants are circulating in Madison and other parts of the U.S., highlighting the importance of vaccination.

"The difference between the original strain and (delta) and the original strain and (gamma) is similar," Kawaoka adds, noting: "The (delta) variant may become prevalent but it shouldn't be extremely concerning as long as you are vaccinated."

With SARS-CoV-2 changing as it spreads, some versions of the virus will disappear as new variants emerge, as happened with a European variant in early 2020 that quickly eclipsed the original virus first found in China.

"At least in the vast majority of the population, we don't have good immunity to SARS-CoV-2, so the selective pressure on the virus at the moment is transmissibility," Kawaoka says, explaining why new variants that successfully spread tend to be more transmissible than those that came before. "But it will change. We should expect to see the selective pressure become immunity."

This is why vaccines will likely need to be modified in the coming years, he explains, in order to protect against a virus that will evolve to evade the protections we devise so long as spread of the virus remains high, or if our immune systems don't maintain defenses for long enough to prevent reinfections.

"We don't know which one is going to be the case ... it's too early to say how long immunity to this virus lasts," he says. "Hamsters look different from humans, anyway. It's difficult to predict."

Peter Halfmann, a research associate professor at UW-Madison, and Masaki Imai in the Division of Virology at the University of Tokyo, co-led the study.

It was supported by a Research Program on Emerging and Re-emerging Infectious Diseases (JP19fk0108113, JP19fk0108166, JP20fk0108412, and JP21fk0108104;, a Project Promoting Support for Drug Discovery (JP20nk0101612, JP20nk0101614, and JP20nk0101603); the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) (JP19fm0108006); the Japan Program for Infectious Diseases Research and Infrastructure (JP20wm0125002 and 20fk0108272) from the Japan Agency for Medical Research and Development (AMED); the National Institutes of Allergy and Infectious Diseases funded Center for Research on Influenza Pathogenesis (CRIP; HHSN272201400008C); the Wisconsin National Primate Research Center (P51?OD011106), and the Collaborative Influenza Vaccine Innovation Center (CIVIC; 75N93019C00051).

Credit: 
University of Wisconsin-Madison

New study finds SARS-CoV-2 can infect testes

Researchers at the University of Texas Medical Branch have observed that SARS-CoV-2, the virus that causes COVID-19, can infect the testes of infected hamsters. The findings, published in the journal Microorganisms, could help explain symptoms some men with COVID-19 have reported and have important implications for men's health.

As the pandemic goes on, clinicians continue to report their findings that COVID-19 affects more than just the lungs. Some patients have reported testicular pain and some reports have shown decreases in testosterone, a key hormone produced in the testes. Autopsies have also shown significant disruption of the testes at the cellular level, including the presence of immune cells.

"Given the magnitude of the COVID-19 pandemic, it is critical to investigate how this disease can impact the testes, and the potential consequences for disease severity, reproductive health, and sexual transmission," said Dr. Rafael Kroon Campos, the study's lead author and postdoctoral fellow in the laboratory of Dr. Shannan Rossi at UTMB.

The Rossi lab has been studying Zika virus infection in the testes for years and wondered if SARS-CoV-2 could cause a similar disease. Hamsters are commonly used to model COVID-19 in humans since they develop similar signs of disease. Virus was detected in the testes of all infected hamsters during the first week but tapered off. The authors think this may represent what could occur in men with mild to moderate COVID-19 disease.

"These findings are the first step in understanding how COVID-19 impacts the male genital tract and potentially men's reproductive health," said Rossi, an associate professor in the Departments of Pathology and Microbiology & Immunology. "We have much more to do before we have the full picture. Moving forward, we will investigate ways to blunt this impact, including using antivirals, antibody therapies and vaccines."

Future studies also include modeling conditions associated with severe COVID-19, such as pre-existing conditions like obesity and diabetes and SARS-CoV-2 variants of concern, the study authors said.

Credit: 
University of Texas Medical Branch at Galveston

After the big storm: How to supply emergency power

As demand for electricity rises and climate change brings more frequent and extreme storms, residents in rural and suburban communities must have access to the minimal electricity they need to survive a large, long-duration (LLD) power outage.

A new study in the journal Risk Analysis compared strategies for providing emergency power to residents in two hypothetical New England communities during such an event. The results suggest that cooperative strategies like sharing a higher capacity generator among multiple homes cost 10 to 40 times less than if each household used its own generator.

"Our findings provide impetus for utilities, regulators, and policy makers to make collective options readily accessible to communities," says co-author M. Granger Morgan, Hamerschlag University Professor of Engineering at Carnegie Mellon University and co-director of the National Science Foundation's Center for Climate and Energy Decision Making.

LLD-outages are defined as blackouts that extend over multiple service areas or states and last several days or longer. Over the last decade, severe storms have caused LLD-outages affecting millions of people. In 2012, Superstorm Sandy disrupted power in 21 states, affecting over 8 million customers with approximately 800,000 customers still without power after 10 days. And in 2017, Hurricane Maria devastated electrical service across Puerto Rico for months.

In their study, the researchers focused on power resilience among often-overlooked residential customers in rural and suburban communities. "Rural and suburban communities tend to be more vulnerable in long-duration outages," says Angelena Bohman, lead author and a Ph.D. candidate in Engineering and Public Policy at Carnegie Mellon University.

Most rural and suburban areas have overhead power lines, which can be taken down by high wind events like hurricanes and tornadoes. Ice storms can also weigh down and snap overhead lines. "The more spread out communities are, the harder it is for residents to access support in an emergency due to destroyed or blocked roads and limited fuel access," says Bohman. "They are also likely to have to wait longer for power to be restored as other critical infrastructures and urban communities typically get priority."

The team's analysis focuses on two hypothetical communities in New Hampshire, a region that has experienced both hurricanes and ice storms and where there is a risk of frozen pipes during a winter outage that could result in serious water damage. One of the hypothetical communities relies on a fuel mix for heating; the other uses piped natural gas. The study compares individual and cooperative strategies for providing limited amounts of power to residential customers in both communities during an LLD-outage.

To estimate how much power is needed by each household, the researchers considered only the energy needed for basic survival. In freezing temperatures, households need enough heat to prevent hypothermia and frozen pipes (a thermostat setting of 50° F). They need enough power to support minimal lighting at night and to charge mobile devices. A refrigerator is necessary during summer, but not winter. Air conditioning was not considered a necessity.

The analysis suggests that most houses require roughly 600 running watts during an outage to meet their emergency demand, regardless of the season. This "emergency load" comprises about 10 percent of normal household load.

The researchers analyzed the cost and performance of these four different strategies for providing emergency power during an LLD-outage:

Individual houses each purchase and use their own emergency generator fueled with gasoline, propane, or diesel or have installed a PV + battery system.

A 10-house "neighborhood" operates as a microgrid served by a small, single-phase generator fueled with propane, diesel, or natural gas

A 100-house "community" operates as a microgrid using a three-phase generator fueled by propane, diesel, or natural gas

A single, large, three-phase generator or microturbine capable of serving the entire feeder for a community is located at the substation.

They considered each strategy's performance during outages that lasted five, 10, and 20 days in duration. Compared to the cost of running an individual generator at each home, the results showed that the three cooperative solutions cost 10 to 40 times less per household.

Providing a gas-powered generator to each home would be problematic if an outage lasted more than a few days. A 5.5kW portable generator would require 300 gallons of gasoline during a 20-day outage as well as four to five oil changes. Keeping it running that long would only be plausible if the town made prior arrangements to keep filling stations operating and reached agreements about fuel supply priorities with emergency responders and others.

Co-author Ahmed Abdulla, assistant professor in the department of mechanical and aerospace engineering at Carleton University, points out that while collective strategies are significantly cheaper than individual strategies, they also require prior arrangements between customers and with the local township, local utility, third party suppliers, and regulators such as the state's Public Utility Commission (PUC).

All of this may be worth it to a state like Texas, which suffered devastating rolling blackouts during severe winter storms last February. More than 4.5 million homes and businesses were without power, some for more than three days. "If customers on distribution feeders in Texas had implemented any of the strategies outlined in our paper they would have had access to enough power to avoid frozen pipes, modestly heat their home, keep a few lights on, and cycle through other small loads to make the situation much more bearable," says Bohman.

Finding cost-efficient solutions to mitigate the impacts of climate change is more important than ever, adds Granger. "Unfortunately, the risk of LLD-outages is growing as climate change brings more frequent and extreme weather events. We are developing a set of strategies to assess how resilient a power system is likely to be as it strives to balance decarbonizing the power grid while also protecting it against these extreme events - two goals that are not always easily aligned."

Credit: 
Society for Risk Analysis

When tyrannosaurs dominated, medium-sized predators disappeared

image: New research from UMD shows ecology changed for tyrannosaurs as they grew up. Slender, agile young tyrannosaurs (left) hunted different prey and did so in a different fashion than the much larger, powerful jawed adults (right).

Image: 
Image Zubin Erik Dutta.

New UMD study suggests that everywhere tyrannosaurs rose to dominance, their juveniles took over the ecological role of medium-sized carnivores

A new study shows that medium-sized predators all but disappeared late in dinosaur history wherever Tyrannosaurus rex and its close relatives rose to dominance. In those areas--lands that eventually became central Asia and Western North America--juvenile tyrannosaurs stepped in to fill the missing ecological niche previously held by other carnivores.

The research conducted by Thomas Holtz, a principal lecturer in the University of Maryland's Department of Geology, verified previous anecdotal reports of a dramatic drop-off in diversity of medium-sized predator species in communities dominated by tyrannosaurs. Diversity of prey species, on the other hand, did not decline. This suggests that medium-sized predators did not disappear because of a drop off in their prey, and that something else--likely young tyrannosaurs--stepped in to fill their ecological role. The study was published online on June 17, 2021, in the Canadian Journal of Earth Sciences.

"Earlier in the history of dinosaurs, in most communities you'd have a bunch of different types of carnivores of various size ranges from small fox-sized all the way up to the occasional giants," Holtz said. "Then something happens between 95 and 80 million years ago, where we see a shift. The really big carnivores, larger than an elephant, like tyrannosaurs and their kin, become the apex predators, and the middle-sized predators, say leopard to buffalo-sized carnivores, are either missing or very rare."

Typically, such a dramatic change in predators would coincide with some change in their prey. Either the prey species would increase dramatically in the absence of predators, or the prey species would also drop off, perhaps indicating why the predators disappeared. But the fact that Holtz found no shift in prey species diversity indicates that something continued to fill the ecological role of the missing middle-sized predators.

Previous work by Holtz and others provides evidence that young tyrannosaurs were faster and more agile than their parents and likely hunted prey more similar to that eaten by the faster, more agile medium-sized dinosaurs.

It is possible that as tyrannosaurs evolved and grew to dominance, their juveniles outcompeted other carnivorous dinosaurs in the middle-size range. But it is also possible that something else eliminated the other carnivores and tyrannosaurs simply stepped in to fill the gap. The shift to tyrannosaur dominance and the disappearance of middle-sized predators happened during a long gap in the fossil record, so scientists can't say exactly what occurred.

"Ultimately resolving that is going to rely on the most basic first-level aspect of paleontology, which is boots on the ground and picks in the sediments," Holtz said. "We need more sampling sites from this interval between about 95 and 80 million years ago."

To conduct the study, Holtz surveyed the existing record of 60 dinosaur communities--assemblages of animals living in the same area at the same time--from the Jurassic and Cretaceous periods (201 to 66 million years ago). First, he counted the number of carnivorous species and sorted them into size categories, with medium-sized dinosaurs weighing in at 50 to 1,000 kilograms and large dinosaurs exceeding 1,000 kilograms.

His analysis revealed that in 31 communities tyrannosaurs were not the largest predators, and there was a wide range of predators in the 50 to 1,000 kilogram category. In Asia and North America, those communities existed from the Jurassic through the early part of the late Cretaceous period (201 to 80 million years ago). Outside of Asia and North America, they continued to exist through the end of the late Cretaceous period (80 to 66 million years ago).

In the other 29 dinosaur communities Holtz surveyed, tyrannosaurs were the largest, and presumably dominant, predator weighing in at over 1,000 kilograms. In those communities, which were all found in Asia and North America, predators ranging from 50 to 1,000 kilograms were rare or absent during the latter half of the late Cretaceous period (80 to 66 million years ago).

Next, Holtz analyzed the same communities looking for shifts in the number of prey species. He found no statistical difference in prey species diversity between the tyrannosaur-dominated and non-tyrannosaur-dominated communities.

"So, what does this mean?" Holtz asked. "In those communities where middle-sized predators are gone but the prey species are just as diverse, can we say that no one is preying upon these middle-sized prey? No. That's almost certainly not the case. It is quite likely juvenile tyrannosaurs took over the ecological role of the missing middle-sized carnivores."

Future studies will drill deeper into the composition of prey species communities to see if there were changes in prey size during the shift to tyrannosaur domination. Holtz also plans to survey the size distribution of carnivores during the Triassic period from 251 to 201 million years ago. Understanding changes in size distribution and species diversity may help paleontologists understand the influences that affect different types of predator and prey communities.

"These interactions are important for understanding what life was like during the time of the dinosaurs," Holtz said. "But in the broader sense, having more understanding of changing ecosystems, and in this case, looking at the predator and prey components of an ecosystem, gives us a better and more diverse view of how the interactions of life work in the world, even today.

Credit: 
University of Maryland

Alpine plant spins its own flavonoid wool

image: Electron microscope imaging of a Dionysia tapetodes glandular trichome head showing wool exit site.

Image: 
Matthieu Bourdon and Karin Müller

Like the movie version of Spider-Man who shoots spider webs from holes in his wrists, a little alpine plant has been found to eject cobweb-like threads from tiny holes in specialised cells on its leaves. It's these tiny holes that have taken plant scientists by surprise because puncturing the surface of a plant cell would normally cause it to explode like a water balloon.

The small perennial cushion-shaped plant with bright yellow flowers, Dionysia tapetodes, is in the primula family and naturally occurs in Turkmenistan and north-eastern Iran, and through the mountains of Afghanistan to the border of Pakistan. What makes it unusual is its leaves, which are covered in long silky fibres that resemble fine cobwebs called 'woolly farina'.

Quite a few of its primula relatives have leaves coated with a fine powder consisting almost entirely from flavone, which is a class of flavonoid. Flavonoids are small specialised molecules involved in plant metabolism and are recognised for their anti-inflammatory and antioxidant properties. But this Dionysia species does not have flavone powder on its leaves, instead it has very fine wool just 1-2 microns thick - far thinner than a human hair, which is about 75 microns.

As part of an ongoing collaboration between the University of Cambridge's plant science research institute Sainsbury Laboratory Cambridge University (SLCU) and Cambridge University Botanic Garden (CUBG), Dionysia was selected from the Botanic Garden's living collection of 8,000 cultivated plant species to be analysed at SLCU's Microscopy Core Facilities.

"The woolly farina threads seem to cover the entire leaf surface with long threads even connecting leaf-to-leaf," said Paul Aston, who is the Botanic Garden Alpine and Woodland Supervisor. "Nobody knew what this wool was or how it was made and so we thought that this would be an interesting specimen to study. There are many things that plants make that we do not yet know about - this is especially true for alpine plants where we see many unusual adaptations to the harsh high altitude environments they live in."

Samples were analysed using advanced light and electron microscopes, which revealed the micron-diameter wool had distinct parallel grooves running along their length. But the most surprising observation was how the wool was emerging from the leaves.

"The leaves are covered in tiny hairs called trichomes. Each trichome has a spherical shaped glandular cell at the end - like a stalk with a single round cell at the tip - and we could see the threads emerging straight out of the glandular cell," said Dr Raymond Wightman, who is the Microscopy Core Facility Manager in the University of Cambridge's Sainsbury Laboratory. "But we know that plant cells are surrounded by a cell wall that protects and retains pressure within the cell. Poking holes through the cell membrane and cell wall would cause the cell to burst - like puncturing a water balloon."

So how were the threads getting out without exploding the cell?

Using a powerful electron microscope at the Cambridge Advanced Imaging Centre (CAIC), they sectioned the glandular cells and when they zoomed in could see tiny gaps in the cells just large enough to thread a single woolly farina fibre through.

"The plant manufactures the fibre inside the cell and then threads it through the gaps that are just wide enough for it," said Dr Matthieu Bourdon who is a researcher at SLCU and co author of the report published in BMC Plant Biology. "There is a distinct opening in the plasma membrane, cell wall and cuticle creating a hole that forms a tight seal around the fibre - we could even see wax on the cell surface acting like a plug to seal any gaps. We observed multiple fibres being extruded from individual glandular cells at specific spots across its surface. The plant must be concentrating the flavone building blocks within the cells at these specific exit sites to be able to produce the elongating fibre."

Dr Wightman also analysed the chemistry of the fibres to find what they are made from using the Institute's Raman microscope, but the wool's complex structure required further analysis using specialist equipment and skills from the University's Yusuf Hamied Department of Chemistry.

"The analysis of the woolly farina sample was challenging because of the small size of the sample and the similarity of the chemicals that it was made up of, said Dr Josephine Gaynord, PhD graduate from the University of Cambridge's Department of Chemistry and who undertook the further analysis using advanced chromatography, mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy techniques. "It helped that we knew the majority of the sample was flavone, a chemical that we could buy and compare to the woolly farina sample. Thanks to some excellent support from the NMR team in the Department of Chemistry we were able to run bespoke analysis and provide possible structures for the modified flavones that were present. It would be very interesting to follow this work up in the future."

Wightman said they were expecting the fibres to be made up of flavonoids similar to the powdery coating on the leaves of some other primula species, but were intrigued by how this species was able to turn flavones into such stable wool-like fibres. "We found the wool produced by Dionysia tapetodes has a special chemical structure that is a mix of flavone and flavone derivatives that may use hydrogen bonding between molecules to form the elongated fibres. This means inside the cell these flavones need to be mixed precisely while being added to the end of the fibre so that they exit the gap as one continuous thread - like squeezing a continuous line of toothpaste from a tube."

"While it is not known what purpose the woolly farina serves, it is thought it could be a protective measure offering tolerance to freezing, drought and/or blocking high UV," said Simon Wallis, Alpine and Woodland Assistant at CUBG. "This latter theory is supported by observations that we have made from our alpine collection, comparing the wool-producing Dionysia tapetodes with a subset of Dionysia tapetodes that do not have woolly farina and are more susceptible to sun scorching."

The team is interested in further exploring the properties of these fibres to determine if they might be a useful biomaterial.

Credit: 
University of Cambridge

First report of dorsal navigation in a flying insect

image: Megalopta genalis, a sweat bee, is able to see in very low light conditions. This study of M. genalis is the first report of the use of dorsal navigation by a flying insect.

Image: 
Ajay Narendra

People--who get lost easily in the extraordinary darkness of a tropical forest--have much to learn from a bee that can find its way home in conditions 10 times dimmer than starlight. Researchers at the Smithsonian Tropical Research Institute's (STRI) research station on Barro Colorado Island in Panama and the University of Lund in Sweden reveal that sweat bees (Megalopta genalis), find their way home based on patterns in the canopy overhead using dorsal vision. This first report of dorsal navigation in a flying insect, published in Current Biology, may be of special interest to makers of drones and other night-flying vehicles.

"One of the pioneers of studies on homing behaviors in bees was Charles H. Turner, an African-American scientist from the University of Chicago," said William Wcislo, staff scientist at STRI, "He wrote in the Biological Bulletin in 1908: 'burrowing-bees use memory in finding the way home, and that they examine carefully the neighborhood of the nest, for the purpose of forming memory pictures of the topographical environment of the burrow.' But what we didn't understand until now, was that the cues that the bees are memorizing are overhead, as well as in front of their faces."

No one knows why the sweat bees on Barro Colorado Island prowl from flower to flower like crepuscular cats, gathering pollen only for about 70 minutes before sunrise and after sunset. Especially because it is 100 times darker on the tropical forest floor where the bees live inside dead twigs and vines, than above the forest canopy.

Since the late 1990's Eric Warrant and his team from the Vision Group at the University of Lund in Sweden has collaborated with Wcislo to learn more about Megalopta's optical superpowers. Their work showed that Megalopta's special compound eyes are 30 times more sensitive to light and concentrate photons of light in a way day-flying honeybee eyes cannot. By identifying pollen from the bees' bodies and their nests, they discovered that the bees gather pollen from more than 60 plant species: tall canopy trees like Hura crepitans, and Pseudobombax septenatum, to understory shrubs in the coffee family like Faramea occidentalis.

"For a human observer, the most obvious visual cues in the forest at night are gaps in the canopy when we look straight up because the sky is much brighter than the forest below," Warrant said, "We see a quite complex pattern of criss-crossing branches, but the bees'-eye-view is much less complex. They see broad blobs of light that vary in shape and position. We knew that ants could use canopy patterns to navigate as they walk through the forest, and we wondered if maybe bees were doing the same thing."

Honeybees can't do this, but to find out if Megalopta bees had yet another superpower, Sandra Chaib, a student at the University of Lund, moved to Barro Colorado Island to do the experiments.

To test this idea, Sandra first set up a special bee motel. Imagine the entrances to five rooms: each entrance is an identical, circular grey disc. The door is a tiny round opening at the center of the disc--the end of a stick nest.

In the first experiment, she asked if the bees could find their way home using a single landmark. She placed a black bar above the entrance to one of the nests. After the bees left to look for pollen, she changed the order of the nests, but the real nest was still marked by the black bar above the entrance. When the bees returned, they chose the right nest.

Next, she made it a bit more complicated by building a sort of awning--like the roof of a carport--above each nest entrance. Over the four empty nests she placed an awning with a pattern of black and white bars, and over the occupied nest, a different pattern. Again, when the bees went out, she changed the position of the nest, and again, they found the right nest when they came back. But she still had not ruled out the possibility that the bees were using another clue, like smell, to find their own nest. So she left the nest in the same place, but put the bee's learned pattern over an empty nest...and the bees chose the empty nest, showing that they were using the pattern as a guide, not smell or some other signal from the nest.

Her final experiment was the most elegant: this time two nests shared a common awning, a design of dark circles on a light background made to represent the patterns of light and dark in real forest canopies. The entrance to an empty nest was located under one end of the awning, and the entrance to the occupied nest under the opposite end. This time, when the bees left, Sandra flipped the awning around so that the pattern was reversed. The bees chose the wrong nest more than 80 percent of the time, showing once and for all that they were navigating based on the pattern above.

Understanding how Megalopta navigates may be of interest for military applications. Now, most drones use GPS to navigate, but GPS and satellites can be jammed or destroyed.

"Animals use a variety of different cues to navigate. Vision is obviously a very important one, but many animals have a magnetic sense and can measure properties of the Earth's magnetic field to work out where they are on the surface of the Earth and the direction they want to travel. We have already learned about insects and other animals that are able to use the stars for navigation; pigeons are able to use odors for navigation...there are lots of different cues. The canopy is one cue that a drone can use to navigate, but a really robust navigational system will be one that will use a number of different cues, like animals have, to use all of these systems at once to navigate,” Eric Warrant said.

STRI Facilities are still closed due to COVID-19 restrictions but researchers are itching to get back out "So far we only know how the bees identify which room in the bee motel is theirs when they come home," Wcislo said. "We still have no idea how they navigate through the forest after they leave their nests."

Credit: 
Smithsonian Tropical Research Institute

Mutant genes can promote genetic transfer across taxonomic kingdoms

image: Different from other type of plasmids, IncP1-type plasmid have very broad transfer range even to archaea and eukarya, and its analysis is applicable to both prevention of the spread of antibiotic resistance genes and gene introduction to various organisms.

Image: 
Kazuki Moriguchi, Hiroshima University

Bacteria do not sexually reproduce, but that does not stop them from exchanging genetic information as it evolves and adapts. During conjugal transfer, a bacterium can connect to another bacterium to pass along DNA and proteins. Escherichia coli bacteria, commonly called E. coli, can transfer at least one of these gene-containing plasmids to organisms across taxonomic kingdoms, including to fungi and protists. Now, researchers from Hiroshima University have a better understanding of this genetic hat trick, which has potential applications as a tool to promote desired characteristics or suppress harmful ones across genetic hosts.

They published their results on May 20 in Frontiers in Microbiology.

Plasmids transfer from one bacterium -- the donor -- to another -- the recipient. A particular kind of plasmid, called IncP1, can be hosted by a variety of bacteria and, seemingly as a result of its broad hosts, can transfer DNA to recipients beyond bacteria. The hypothesis is that the plasmid contains genes cultivated from different hosts and donors, resulting in this unique ability.

"Although conjugation factors encoded on plasmids have been extensively analyzed, those on the donor chromosome have not," said paper author Kazuki Moriguchi, associate professor, Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University.

There have been some studies on the various genes, according to Moriguchi, but the function of the genes was not examined, so it is not clear how they were related to the conjugation mechanism.

In this study, the researchers conducted a genome-wide survey on an extensive collection of bacteria mutants as donors to yeast. The mutants were engineered to have specific genes "knocked out" in order to study how the overall system performs without the presence of that specific gene, allowing researchers to infer information about the gene's function.

"We focused on 'up' mutants that have the ability to accelerate conjugative transfer to both prokaryotes and eukaryotes as they could be potent donor strains applicable to gene introduction tools," Moriguchi said, noting how IncP1's ability to transmit genetic material across kingdoms could be used to develop precise tools to introduce genes capable of changing how the bacteria perform certain functions or react to changes in their environments.

Out of 3,884 mutants surveyed, three were identified that could conjugate across E. coli or from E. coli to yeast without accumulating genetic material, indicating that the genes worked together. The researchers analyzed the genes but were unable to elucidate the exact target or targets of conjugation mechanism that allows for cross-kingdom transfer. However, their analysis did reveal how the genes appear to work.

Two of the genes work to repress the unknown target in the E. coli donor. Simultaneously, the third gene is inactivated, allowing another unknown target to resume activity.

"The results suggest that the unknown target factors of these three genes form a complex in order to activate or repress the conjugation, either directly or indirectly at an identical step or steps of the IncP1 conjugation machinery, although the exact mechanism beyond this phenomenon remains unknown," Moriguchi said.

According to Moriguchi, the data collected in this study can help facilitate the breeding of donor strains from various bacteria, each of which carries a high affinity with target organisms in addition to having a high conjugation ability.

Credit: 
Hiroshima University

Passing the COVID test in just five minutes

image: Operating principle of artificial intelligence nanopore for coronavirus detection.

Image: 
Osaka University

Osaka, Japan - A team of scientists headed by SANKEN (The Institute of Scientific and Industrial Research) at Osaka University demonstrated that single virus particles passing through a nanopore could be accurately identified using machine learning. The test platform they created was so sensitive that the coronaviruses responsible for the common cold, SARS, MERS, and COVID could be distinguished from each other. This work may lead to rapid, portable, and accurate screening tests for COVID and other viral diseases.

The global coronavirus pandemic has revealed the crucial need for rapid pathogen screening. However, the current gold-standard for detecting RNA viruses—including SARS-CoV-2, the virus that causes COVID—is reverse transcription-polymerase chain reaction (RT-PCR) testing. While accurate, this method is relatively slow, which hinders the timely interventions required to control an outbreak.

Now, scientists led by Osaka University have developed an intelligent nanopore system that can be used for the detection of SARS-CoV-2 virus particles. Using machine-learning methods, the platform can accurately discriminate between similarly sized coronaviruses responsible for different respiratory diseases. "Our innovative technology has high sensitivity and can even electrically identify single virus particles," first author Professor Masateru Taniguchi says. Using this platform, the researchers were able to achieve a sensitivity of 90% and a specificity of 96% for SARS-CoV-2 detection in just five minutes using clinical saliva samples.

To fabricate the device, nanopores just 300 nanometers in diameter were bored into a silicon nitride membrane. When a virus was pulled through a nanopore by the electrophoretic force, the opening became partially blocked. This temporarily decreased the ionic flow inside the nanopore, which was detected as a change in the electrical current. The current as a function of time provided information on the volume, structure, and surface charge of the target being analyzed. However, to interpret the subtle signals, which could be as small as a few nanoamps, machine learning was needed. The team used 40 PCR-positive and 40 PCR-negative saliva samples to train the algorithm.

"We expect that this research will enable rapid point-of-care and screening tests for SARS-CoV-2 without the need for RNA extraction," Professor Masateru Taniguchi explains. "A user-friendly and non-invasive method such as this is more amenable to immediate diagnosis in hospitals and screening in places where large crowds are gathered." The complete test platform consists of machine learning software on a server, a portable high-precision current measuring instrument, and cost-effective semiconducting nanopore modules. By using a machine-learning method, the researchers expect that this system can be adapted for use in the detection of emerging infectious diseases in the future. The team hopes that this approach will revolutionize public health and disease control.

Credit: 
Osaka University

Close-up look at brain uptake of omega-3

SINGAPORE, 17 June 2021 - New details on the structure and function of a transport protein could help researchers develop drugs for neurological diseases that are better able to cross the blood-brain barrier. The findings were published in the journal Nature by researchers at Columbia University Vagelos College of Physicians and Surgeons, Duke-NUS Medical School, Weill Cornell Medicine and colleagues.

Omega-3 fatty acids, like docosahexaenoic acid (DHA), are important for brain and eye development. They are derived mainly from dietary sources and converted by the liver into a lysolipid called lyso-phosphatidyl-choline (LPC) in order to cross from the blood into the brain and retina via the blood-brain and blood-retina barriers, respectively. These barriers are formed by cells lining blood vessels, or endothelial cells, that tightly regulate what enters these two vital organs.

A protein called 'Major Facilitator Superfamily Domain containing 2A' (MFSD2A) is located on the membrane of these endothelial cells, and acts as a molecular gateway that allows DHA to cross these barriers. How MFSD2A mediates uptake of lysolipids carrying omega-3 fatty acids, however, remained a mystery.

"We set out to determine the structure of MFSD2A in order to understand how it transports essential omega-3 fatty acids in the form of LPC to the brain," said Dr Chua Geok Lin, a senior research fellow with the Cardiovascular and Metabolic Diseases (CVMD) Programme, Duke-NUS, who is a co-author of the study. "This is important because MFSD2A is essential for getting omega-3 fatty acids like DHA across the blood-brain barrier."

Dr Rosemary Cater, a Simons Foundation Fellow at Columbia University's Vagelos College of Physicians and Surgeons, and first author of the paper, explained, "If we knew what MFSD2A looked like, we could solve this mystery and use the information to design neurotherapeutics that could hijack this molecular gateway, disguised as omega-3 fatty acid lysolipids--sort of like seeing what a lock looks like in order to design a key that fits."

The collaborative study, led by Dr Filippo Mancia at Columbia University, Dr David Silver at Duke-NUS, and Dr George Khelashvili at Weill Cornell Medicine, leveraged leading experts in the field from across a number of US research institutions--namely Columbia University, Weill Cornell Medicine, the New York Structural Biology Center, University of Chicago and University of Arizona--and Duke-NUS in Singapore.

To study the structure of MFSD2A, the research team used a special type of electron microscopy, which involves cooling samples to cryogenic temperatures and viewing molecules on a sub-nanomolar scale, in combination with novel biochemical assays. This allowed them to uncover atomic-level details of the protein's structure, which were then used to inform computer simulations exploring the mechanism of how it works.

According to Dr Mancia, Associate Professor of Physiology and Cellular Biophysics at Columbia University Vagelos College of Physicians and Surgeons, "It's extremely exciting to be able to view a protein's shape at such a resolution. We are talking about measurements of less than a billionth of a metre in size--and this information is critical to understand how it works at a molecular level."

"Using large-scale atomistic ensemble molecular dynamics (MD) simulations, followed by detailed analysis of the MD data with advanced methods of computational biophysics, such as Markov State Modelling, we were able to 'un-freeze' the cryo-EM structure of MFSD2A and study mechanistic details of how this transporter interacts with substrates," explained Dr Khelashvili, Assistant Professor of Physiology and Biophysics at Weill Cornell Medicine. "Combined with the functional data, the computational findings shed light on the molecular mechanisms by which this atypical MFS transporter mediates uptake of single-chain phospholipids into the brain."

"Some years ago, we discovered that human mutations in the gene that codes for MFSD2A lead to microcephaly, a birth defect in which the baby's head is very small," said Dr Silver, Professor and Deputy Director of Duke-NUS' CVMD Programme. "This underscores the importance of lysolipid transport by MFSD2A."

The study is the latest to add to the growing body of knowledge first initiated by Prof Silver in 2014, when he published on the discovery of MFSD2A and its role in transporting DHA to the brain. In 2017, he co-founded Singapore-based Travecta Therapeutics with the aim of harnessing this knowledge to develop new therapeutic agents that can be selectively delivered across the blood-brain barrier by MFSD2A for treatment of diseases of the central nervous system and eyes. Travecta is currently conducting preclinical studies for several therapeutic targets with the company's lead asset for pain, TVT-004, scheduled to begin clinical trials in the next several months.

A license agreement between Duke-NUS and Travecta was facilitated by Duke-NUS' Centre for Technology and Development, under the School's Office of Innovation and Entrepreneurship, granting the company rights to commercialise the research.

"The blood-brain barrier excludes the uptake of approximately 98 per cent of drugs, limiting the treatment of neurological diseases," Prof Silver explained. "The structural information we revealed in our study can be exploited to better design neurotherapeutics that can be transported by MFSD2A."

The authors said further research is needed to uncover more details on how MFSD2A mediates transport of lysolipids across the blood-brain barrier.

Credit: 
Duke-NUS Medical School

Hired blade: Anchoring complex in plant cells recruits its own katana sword

image: In wild-type plant cells, lattice-bound Msd1 (filled green circle) recruits cytoplasmic Wdr8 (open green circle) to form a heteromeric complex, which is translocated to and associated with a microtubule nucleation complex (orange) on a preexisting microtubule (green line). After nucleation of a daughter microtubule, Msd1-Wdr8 stabilizes the base of the Y-shaped nucleation structure and then recruit katanin (red) to sever the basal end of the daughter microtubule.

Image: 
Takashi Hashimoto

Ikoma, Japan - The katana, a Japanese sword, may be thought of solely as a weapon used by the samurai. But researchers from Japan have discovered that not only do plants wield their own katanas within their cells, they recruit them to specific locations within those cells to do their work.

In a study published in Nature Communications, researchers from Nara Institute of Science and Technology have revealed that the enzyme katanin, which is named after the katana, is used by an anchoring complex to cut microtubules at specific locations of the framework within individual plant cells.

Katanin severs microtubules in cells, which is an important step in cell division and central to the development of many organisms, including plants and animals. Microtubules form part of the cytoskeleton, a complex network of protein filaments found in all cells. The severing performed by katanin enables mobility, which is important during development, and treadmilling - a phenomenon where one end of a filament lengthens as the other shrinks, which results in a section of filament that seems to 'move' like a treadmill.

"Katanin severs microtubules at specific locations in plant and animal cells, and this leads to active reorganization of the microtubule cytoskeleton," says senior author of the study Takashi Hashimoto. "But the mechanisms for targeting this extraordinary enzyme at specific sites within the cell are not well understood - these are what we wanted to investigate."

The team's genetic and cell biology research results showed that the microtubule anchoring complex Msd1-Wdr8 is used to stabilize microtubule nucleation sites (where microtubules are formed) in plant cells to prevent early release of the new microtubules (called 'daughter microtubules'). But in a seemingly counterintuitive twist, Msd1-Wdr8 then turns around and recruits katanin to the same location to enable the efficient release of daughter microtubules.

"These 'glue-and-cut' functions performed by Msd1-Wdr8 and their effects on microtubule stability may seem confusing at first, but they probably enable strict control of microtubule release by the katanin activity," explains Hashimoto.

This study will inform future research on whether the Msd1-Wdr8 complex in animal cells also recruits katanin, and whether other sites use similar mechanisms for the stabilization and release of daughter microtubules. The results of this study will be of interest to cell biologists, especially those working on cytoskeletons, in plants and other organisms.

Credit: 
Nara Institute of Science and Technology

Red meat consumption may promote DNA damage-assoc. mutation in colorectral cancer patients

Bottom Line: Genetic mutations indicative of DNA damage were associated with high red meat consumption and increased cancer-related mortality in patients with colorectal cancer.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research

Author: Marios Giannakis, MD, PhD, an assistant professor of medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute

Background: "We have known for some time that consumption of processed meat and red meat is a risk factor for colorectal cancer," said Giannakis. The International Agency for Research on Cancer declared that processed meat was carcinogenic and that red meat was probably carcinogenic to humans in 2015.

Experiments in preclinical models have suggested that red meat consumption may promote the formation of carcinogenic compounds in the colon, but a direct molecular link to colorectal cancer development in patients has not been shown, Giannakis explained. "What is missing is a demonstration that colorectal cancers from patients have a specific pattern of mutations that can be attributed to red meat," he said. "Identifying these molecular changes in colon cells that can cause cancer would not only support the role of red meat in colorectal cancer development but would also provide novel avenues for cancer prevention and treatment."

How the Study was Conducted: To identify genetic changes associated with red meat intake, Giannakis and colleagues sequenced DNA from matched normal and colorectal tumor tissues from 900 patients with colorectal cancer who had participated in one of three nationwide prospective cohort studies, namely the Nurses' Health Studies and the Health Professionals Follow-Up Study. All patients had previously provided information on their diets, lifestyles, and other factors over the course of several years prior to their colorectal cancer diagnoses.

Results: Analysis of DNA sequencing data revealed the presence of several mutational signatures in normal and cancerous colon tissue, including a signature indicative of alkylation, a form of DNA damage. The alkylating signature was significantly associated with pre-diagnosis intake of processed or unprocessed red meat, but not with pre-diagnosis intake of poultry or fish or with other lifestyle factors. Red meat consumption was not associated with any of the other mutational signatures identified in this study. In line with prior studies linking red meat consumption with cancer incidence in the distal colon, Giannakis and colleagues found that normal and cancerous tissue from the distal colon had significantly higher alkylating damage than tissue from the proximal colon.

Using a predictive model, the researchers identified the KRAS and PIK3CA genes as potential targets of alkylation-induced mutation. Consistent with this prediction, they found that colorectal tumors harboring KRAS G12D, KRAS G13D, or PIK3CA E545K driver mutations, which are commonly observed in colorectal cancer, had greater enrichment of the alkylating signature compared to tumors without these mutations. The alkylating signature was also associated with patient survival: Patients whose tumors had the highest levels of alkylating damage had a 47 percent greater risk of colorectal cancer-specific death compared to patients with lower levels of damage.

Author's Comments: "Our study identified for the first time an alkylating mutational signature in colon cells and linked it to red meat consumption and cancer driver mutations," said Giannakis. "These findings suggest that red meat consumption may cause alkylating damage that leads to cancer-causing mutations in KRAS and PIK3CA, thereby promoting colorectal cancer development. Our data further support red meat intake as a risk factor for colorectal cancer and also provide opportunities to prevent, detect, and treat this disease."

Giannakis explained that if physicians could identify individuals who are genetically predisposed to accumulating alkylating damage, these individuals could be counseled to limit red meat intake as a form of precision prevention. In addition, the alkylating mutational signature could be used as a biomarker to identify patients at greater risk of developing colorectal cancer or to detect cancer at an early stage. Because of its association with patient survival, the alkylating signature may also have potential as a prognostic biomarker. However, future studies are needed to explore these possibilities, Giannakis noted.

Study Limitations: A limitation of the study is the potential selection bias of study participants, as tissue specimens could not be retrieved from all incident colorectal cancer cases in the cohort studies. Current studies from Giannakis and his colleagues are exploring the potential role of red meat intake and alkylating damage in diverse groups of patients.

Funding & Disclosures: The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (co-administered by the AACR), the Project P Fund, the Cancer Research UK Grand Challenge Award, the Nodal Award from the Dana-Farber Harvard Cancer Center, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance and Stand Up To Cancer.

Giannakis has received research funding from Bristol-Myers Squibb, Merck, Servier, and Janssen unrelated to this study.

Credit: 
American Association for Cancer Research

Disadvantaged neighborhoods see more COVID-19 infections and deaths

NEW YORK (June 17, 2021)--New York City neighborhoods that had higher levels of socioeconomic disadvantage experienced more COVID-19 infections and deaths, according to Mount Sinai scientists who created a neighborhood-level COVID-19 inequity index.

The index measured factors that fueled inequities in the residents' lives, such as employment and commuting patterns, population density of their neighborhood, food access, socioeconomic status, and access to health care. This allowed the scientists to compare between neighborhoods the contributions of these social factors in facilitating disease transmission during the first wave of the pandemic in a study published in Nature Communications in June.

"Much of the early rhetoric around COVID-19 disparities centered on comorbidities which, due to health disparities, may have explained why communities of color were suffering higher mortality. But we were seeing more people of color getting infected in the first place," said Daniel Carrión, PhD, MPH, first author and postdoctoral researcher in the Department of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai. "Our research team wanted to add to the literature outlining how structural racism is related to neighborhood disadvantage, and how that disadvantage is related to increased COVID-19 infections and mortality."

The COVID-19 inequity index showed that the disparities were considerably worse based on neighborhood racial and ethnic composition; Black neighborhoods had the highest average inequity index, followed by Latinx communities, while white neighborhoods had the lowest. The authors believe one of the reasons for these disparities is the diminished capacity to socially isolate based on where someone lives.

This study showed that areas with higher COVID-19 inequity indices had higher subway ridership after New York State introduced stay-at-home orders. This implies that the residents had less capacity to socially distance, the researchers said, possibly due to their jobs as essential workers or because they lived in denser housing.

The researchers believe their approach to identifying social factors that are associated with viral spread may be useful throughout the United States to pinpoint potential areas for targeted public health intervention.

"The social factors in the COVID-19 inequity index are upstream neighborhood characteristics--they were already in place before the pandemic," said Allan Just, PhD, senior author on the study and Assistant Professor of Environmental Medicine and Public Health at Icahn Mount Sinai. "In the near term, this speaks to the importance of place-based interventions in Black, Indigenous, and people of color (BIPOC) communities to reduce disease incidence and mortality, such as improved and targeted vaccine availability for these communities. This also supports the need to look at social factors in pandemic preparedness."

The team analyzed many forms of publicly available data, including census, New York City subway ridership, New York City Department of Health and Mental Hygiene infections and mortality data, and other datasets available through New York City's and New York State's open data portals.

Many neighborhood-level social variables are closely related; for example, median income can be strongly associated with education or even food access. This can be a challenge for traditional statistical approaches, so the team employed a new statistical framework designed to deal with these challenges, developed by co-author Elena Colicino, PhD, Assistant Professor of Environmental Medicine and Public Health at Icahn Mount Sinai.

The COVID-19 inequity index included neighborhood-level characteristics, but specifically excluded race and ethnicity as input variables. "Past literature shows that structural racism operates by historically sorting BIPOC people into neighborhoods that do not have the same resources and may facilitate infectious disease transmission," said Dr. Carrión. "We wanted to see if our index reconstructed those racial disparities."

Credit: 
The Mount Sinai Hospital / Mount Sinai School of Medicine

A biological blueprint for tough color

The unique mechanical and optical properties found in the exoskeleton of a humble Asian beetle has the potential to offer a fascinating new insight into how to develop new, effective bio-inspired technologies.

Pioneering new research by a team of international scientists, including Professor Pete Vukusic from the University of Exeter, has revealed a distinctive, and previously unknown property within the carapace of the flower beetle - a member of the scarab beetle family.

The study showed that the beetle has small micropillars within the carapace - or the upper section of the exoskeleton - that give the insect both strength and flexibility to withstand damage very effectively.

Crucially, these micropillars are incorporated into highly regular layering in the exoskeleton that concurrently give the beetle an intensely bright metallic colour appearance.

For this new study, the scientists used sophisticated modelling techniques to determine which of the two functions - very high mechanical strength or conspicuously bright colour - were more important to the survival of the beetle.

They found that although these micropillars do create a highly enhanced toughness of the beetle shell, they were most beneficial for optimising the scattering of coloured light that generates its conspicuous appearance.

The research is published this week in the leading journal, Proceedings of the National Academy of Sciences, PNAS.

Professor Vukusic, one of three leads of the research along with Professor Li at Virginia Tech and Professor Kolle at MIT, said: "The astonishing insights generated by this research have only been possible through close collaborative work between Virginia Tech, MIT, Harvard and Exeter, in labs that trailblaze the fields of materials, mechanics and optics. Our follow-up venture to make use of these bio-inspired principles will be an even more exciting journey.".

The seeds of the pioneering research were sown more than 16 years ago as part of a short project created by Professor Vukusic in the Exeter undergraduate Physics labs. Those early tests and measurements, made by enthusiastic undergraduate students, revealed the possibility of intriguing multifunctionality.

The original students examined the form and structure of beetles' carapce to try to understand the simple origin of their colour. They noticed for the first time, however, the presence of strength-inducing micropillars.

Professor Vukusic ultimately carried these initial findings to collaborators Professor Ling Li at Virginia Tech and Professor Mathias Kolle at Harvard and then MIT who specialise in the materials sciences and applied optics. Using much more sophisticated measurement and modelling techniques, the combined research team were also to confirm the unique role played by the micropillars in enhancing the beetles' strength and toughness without compromising its intense metallic colour.

The results from the study could also help inspire a new generation of bio-inspired materials, as well as the more traditional evolutionary research.

By understanding which of the functions provides the greater benefit to these beetles, scientists can develop new techniques to replicate and reproduce the exoskeleton structure, while ensuring that it has brilliant colour appearance with highly effective strength and toughness.

Professor Vukusic added: "Such natural systems as these never fail to impress with the way in which they perform, be it optical, mechanical or in another area of function. The way in which their optical or mechanical properties appear highly tolerant of all manner of imperfections too, continues to offer lessons to us about scientific and technological avenues we absolutely should explore. There is exciting science ahead of us on this journey."

Credit: 
University of Exeter