Technique creates highly customised structures that could be used in regenerative Medicine.
A team at Aalto University has used bacteria to produce intricately designed three-dimensional objects made of nanocellulose. With their technique, the researchers are able to guide the growth of bacterial colonies through the use of strongly water repellent – or superhydrophobic – surfaces. The objects show tremendous potential for medical use, including supporting tissue regeneration or as scaffolds to replace damaged organs. The results have been published in the journal ACS Nano.
Unlike fibrous objects made through current 3D printing methods, the new technique allows fibres, with a diameter a thousand times thinner than a human hair, to be aligned in any orientation, even across layers, and various gradients of thickness and topography, opening up new possibilities for application in tissue regeneration. These kinds of physical characteristics are crucial for support materials in the growth and regeneration of certain types of tissues found in muscles as well as in the brain.
Unlike in conventional 3D printing, the fibres can be aligned in any direction, even across layers. Image: Luiz Greca/Aalto University
‘It’s like having billions of tiny 3D printers that fit inside a bottle,’ explains Luiz Greca, a doctoral student at Aalto University. ‘We can think of the bacteria as natural microrobots that take the building blocks provided to them and, with the right input, create complex shapes and structures.’
Once in a superhydrophobic mould with water and nutrients — sugar, proteins and air — the aerobic bacteria produce nanocellulose. The superhydrophobic surface essentially traps a thin layer of air, which invites the bacteria to create a fibrous biofilm replicating the surface and shape of the mould. With time, the biofilm grows thicker and the objects become stronger.
Using the technique, the team has created 3D objects with pre-designed features, measuring from one-tenth the diameter of a single hair all the way up to 15-20 centimetres. The nano-sized fibres do not cause adverse reactions when placed in contact to human tissues. The method could also be used to grow realistic models of organs for training surgeons or improving the accuracy of in-vitro testing.
“It’s like having billions of tiny 3D printers that fit inside a bottle.” said Luiz Greca, doctoral student.
‘It’s really exciting to expand this area of biofabrication that takes advantage of strong cellulose nanofibres and the networks they form. We’re exploring applications for age-related tissue degeneration, with this method being a step forward in this and other directions,’ says research group leader Professor Orlando Rojas. He adds that the strain of bacteria used by the team, Komagataeibacter medellinensis, was discovered in a local market in the city of Medellin, Colombia, by previous collaborators from Universidad Pontificia Bolivariana.
In both nature and engineering, superhydrophobic surfaces are designed to minimise the adhesion of dust particles as well as microorganisms. This work is expected to open new possibilities for using superhydrophobic surfaces to precisely produce naturally manufactured materials.
As the bacteria can be removed or left in the final material, the 3D objects can also evolve as a living organism over time. The findings provide an important step towards harnessing full control over bacterially fabricated materials.
‘Our research really shows the need to understand both the fine details of bacteria interaction at interfaces and their ability to make sustainable materials. We hope that these results will also inspire scientists working on both bacteria-repelling surfaces and those making materials from bacteria,’ says Dr. Blaise Tardy.
POSTECH Professor Dong-Woo Cho’s research team develops bioink-loaded esophageal stents for treating radiation esophagitis.
Radiation esophagitis, characterized by the inflammation of the esophagus, is the most common acute adverse effect of radiation therapy that causes swallowing problems. This eventually causes dehydration and leaves the body unfit for further treatment. Unfortunately, no direct cure currently exists for patients suffering from such conditions. To this, a POSTECH research team has developed esophageal stents that biodegrade in the body using 3D printers, opening up the possibility of treating the condition.
A joint research team led by Professor Dong-Woo Cho and Ph.D. candidate Suhun Chae in the Department of Mechanical Engineering at POSTECH and Dr. Dong-Heon Ha of EDmicBio, Inc. has together produced biodegradable stents*1 with esophageal-derived bioink to directly treat radiation esophagitis and verified their therapeutic effects in animal models. These research findings were recently published in Biomaterials, an academic journal with international authority in the biomaterials field.
Various treatment methods are being developed to treat cancer, but radiation therapy is still one of the common treatments along with surgery and chemotherapy. If radiation esophagitis occurs during radiation therapy, treatment is limited to cataclysmic therapy that relieves the pain depending on the symptoms that appear, or inserting a stent to open the swollen esophagus to allow drinking or eating. However, these methods do not treat the damaged tissues directly.
The research team first produced bioink that removed cell components from esophageal tissues and extracted only extracellular matrix through the decellularization process. They produced a dumbbell-type stent that can carry this bioink using a 3D printing system. By inserting this stent into the inflamed esophagus of an animal, they confirmed that it promotes tissue regeneration while mitigating inflammatory reactions.
“The effectiveness of treatment is negated if proper nutrition cannot be delivered due to the pain,” explained Dong-Woo Cho who led the study. He added, “If this esophageal stent implantation is applied clinically, we expect that the patients will have better prognosis and higher quality of life.”
This research was conducted as part of the Research Leader Program the National Research Foundation of Korea and in cooperation with EDmicBio, Inc. which specializes in commercializing 3D organs-on-chips and medical devices.
Stent A structure made of metal or polymer used to expand and maintain a narrowed area into a constant volume of space.
Using NASA’s Chandra spacecraft, astronomers have discovered three new ultraviolet-bright radio-quiet quasars at high redshift and measured their basic X-ray properties. The newly found quasi-stellar object turns out to be the brightest in UV among the known high-redshift radio-quiet quasars. The finding is presented in a paper published November 2 on arXiv.org.
0.5-7 keV Chandra counts images of the three quasars studied in the paper. Credit: Li et al., 2020.
Quasars, or quasi-stellar objects (QSOs), are extremely luminous active galactic nuclei (AGN) containing supermassive central black holes with accretion disks. Their redshifts are measured from the strong spectral lines that dominate their visible and ultraviolet spectra.
Astronomers are especially interested in finding new high-redshift quasars (at redshift higher than 5.0) as they are the most luminous and most distant compact objects in the observable universe. Spectra of such QSOs can be used to estimate the mass of supermassive black holes that constrain the evolution and formation models of quasars. Therefore, high-redshift quasars could serve as a powerful tool to probe the early universe.
Recently, a team of astronomers led by Jiang-Tao Li of the University of Michigan, has used Chandra to conduct follow-up observations of very luminous radio quiet quasars. They found that three of them, designated J002526-014532, J074749+115352 and J220226+150952, are the UV brightest radio quiet ones detected at a redshift over 5.0.
“In this paper, we present new Chandra observations of three UV bright quasars at z > 5,” the astronomers wrote in the paper.
The three quasars reported in the study have a rest frame 2-10 keV luminosity of over 1 quattuordecillion erg/s and the X-ray power law photon index well constrained – in the range of 1.6 to 2.1. At a redshift of 5.26, J074749+115352 turned out to be the X-ray brightest radio-quiet high-redshift quasar, with an average observed X-ray flux at a level of 0.0349 picoergs/s/cm².
According to the study, the high X-ray flux of J074749+115352 makes it unique for timing analysis on a timescale of a few hours at such high redshift. The astronomers noted that there are two states in the X-ray variation of this quasar: a “high soft” state with an average X-ray flux of about 2.7 times greater than that of the “low hard” state. The mass of this quasar’s supermassive black hole was estimated to be about 1.82 billion solar masses.
By comparing the newfound three quasars to other high-redshift objects of this type, the researchers underlined how much unique is J074749+115352.
“We find that J074749+115352 is extraordinarily X-ray bright, with an average αOX = −1.46 ± 0.02 and 2-10 keV bolometric correction factor Lbol/L2−10keV = 42.4 ± 5.8; both significantly depart from some well defined scaling relations. This quasar also has a high Eddington ratio of λEdd = 2.25 ± 0.09,” the authors of the paper explained.
However, they added that more X-ray and infrared observations are needed to confirm the nature and better understand the properties of this QSO.
References: Jiang-Tao Li, Feige Wang, Jinyi Yang, Yuchen Zhang, Yuming Fu, Fuyan Bian, Joel N. Bregman, Xiaohui Fan, Qiong Li, Xue-Bing Wu, Xiaodi Yu, “Chandra Detection of Three X-ray Bright Quasars at z>5”, ArXiv, pp. 1-12, 2020. https://arxiv.org/abs/2011.02358
This article is republish here from Phys under common creative licenses
Biomedical researchers have come up with a novel way to use a beam of light to deliver CRISPR gene therapy molecules targeting illnesses.
Liposomes, which are spherical fat molecules found in cell membranes, can be loaded with CRISPR molecules that can then target specific areas of the body when triggered by light. Picture: Shutterstock
Light-activated liposomes could help to deliver CRISPR gene therapy – and the method could prove safer and more direct than current methods.
A multi-institutional team involving biomedical engineers and scientists from UNSW Sydney found that liposomes – commonly used in pharmacology to encapsulate drugs or genes – can be triggered by light to release the payload in a specific site of the body.
The team, which reported the findings today in ACS Applied Materials and Interfaces, demonstrated their results in cell lines and animal models, with more research needed to test and confirm their method in humans.
Up until now, CRISPR gene therapy technology, which uses a guide RNA to seek out faulty gene sequences and a Cas9 protein to cut or replace it with healthy versions, has used viruses loaded with the CRISPR molecules that then move through the body to find the targeted cells.
While the technology has proved revolutionary – only this year the Nobel Chemistry prize was awarded to researchers developing the technology – the use of viruses as the delivery vehicle is less than ideal because of the potential for adverse immune response and toxicity.
Liposomes the safer option
But in the latest research, the team demonstrated how they could use a much more benign vehicle to carry the CRISPR molecules while using a unique way to deliver them solely to the area of the body in need of them.
Lead author Dr Wei Deng says the team used liposomes – spherical nanostructures of fat molecules very similar to cell membrane material – to carry the CRISPR molecules to the target site in the body.
“Liposomes are already well established as an extremely effective drug-delivery system,” she says. “These ‘bubbles’ are relatively simple to prepare, can be filled with appropriate medication and then injected into the body.”
Dr Deng says because liposomes are the most common and well-established drug delivery vehicles, they are much safer than using viruses.
“The traditional delivery vehicle of CRISPR is based on viruses, but they create their own problems because it is difficult to predict the reaction of patients to the viruses.”
But having found a safer vehicle to deliver the CRISPR cargo, the team was faced with the challenge of how to ensure these gene-splicing molecules found the right target at the right time. The answer, they discovered, was light.
“Unlike the traditional liposome-based delivery systems, our liposomes can be ‘turned on’ under light illumination,” Dr Deng says. “When light is shone onto the liposomes, they can be disrupted at once, immediately releasing the entire payload.”
The team found in both cell lines and animal models that when the liposomes are triggered by an LED light, they eject the CRISPR contents which go to work looking for genes of interest. Dr Deng says the light can activate the liposomes up to a centimetre below the surface of the skin.
Deep tissue treatment
But what if the problem area is deep-seated tumour? Dr Deng says future studies will use X-rays to achieve the same effect.
“We fully expect that we will be able to carry out X-ray triggering of CRISPR delivery in deep tissue at depths greater than one centimetre,” she says.
“Our past research has already indicated that liposomes can be triggered by X-rays.”
Dr Deng says CRISPR technology is offering exciting possibilities in medical research, especially in treatment of cancer.
“Cancer affects millions of people worldwide, yet researchers have been working for decades to find effective treatments.
“Chemotherapy is great at destroying cancer cells, but because it is untargeted, it ends up damaging normal, healthy cells.
“CRISPR technology has created a very promising tool for developing new targeted, gene and cell-based therapies. Its outcomes would largely increase with the desired delivery system, and in this context, our findings may provide such a system.”
Looking ahead, Dr Deng said she and her colleagues are interested in carrying out research that shows X-rays can be used to deliver CRISPR gene-splicing molecules for deep cancer treatment.
“By using X-ray instead of light we also need to find a proper animal model that might translate to using this technology for something like breast cancer treatment. So we’re looking for collaborators who have this sort of expertise.”
Researchers investigating the heritage of thousands of rice varieties have identified just two distinct maternal lineages, a discovery which could help address the issue of global food security.
University of Queensland scientists studied more than 3000 rice genotypes and found diversity was inherited through two maternal genomes identified in all rice varieties.
Lead researcher UQ’s Professor Robert Henry said the finding was important in understanding how rice adapted to its environment.
“We think there were two separate domestications of virgin wild plants that diverged around a million years ago in the wild, and then in the last 7000 thousand years human domestication of rice has occurred,” Professor Henry said.
The two domesticated varieties interbred with the local wild rices throughout Asia.
“The wild rice has pollinated the domesticated rices planted nearby and the seed of the domesticated variety has then incorporated the genetics of the local wild varieties,” he said.
“The maternal lineage is preserved via the seed, and we’ve identified that because rice farmers have and still continue to collect the seed from the field, the local varieties become very much like the local wild rices.”
Image: UQ researcher Professor Robert Henry
Professor Henry said the finding had implications for domestication of rice and breeding for adaptation to climate change to address food security.
“It gives us clues as to how we might try to capture more of the diversity in the wild and bring it into the domesticated gene pool to improve rice crops,” he said.
“It also points to the need to understand the significance of the maternal genotype in terms of performance of rice because we did not previously understand there are two very distinct maternal functional types.”
Rice is the staple food of more than half of the world’s population and is the third-largest worldwide agricultural crop, with more than 630 million tonnes produced annually.
“Now we’ve got an ongoing collaboration with mathematicians to try and find a way of analysing the rice data in more detail, we want to look at relationships between lots of different subgroups,” Professor Henry said.
“This would include examining how the Basmatis and the Japonicas really relate and the various types of Indica rices.”
References: Moner, A.M., Furtado, A. & Henry, R.J. Two divergent chloroplast genome sequence clades captured in the domesticated rice gene pool may have significance for rice production. BMC Plant Biol 20, 472 (2020). https://doi.org/10.1186/s12870-020-02689-6
The protein, which acts as an ion channel, could be a target for new drugs against the SARS-CoV-2 virus.
MIT chemists have determined the molecular structure of a protein found in the SARS-CoV-2 virus. This protein, called the envelope protein E, forms a cation-selective channel and plays a key role in the virus’s ability to replicate itself and stimulate the host cell’s inflammation response.
Using nuclear magnetic resonance (NMR), MIT chemists have determined the molecular structure of a protein found in the SARS-CoV-2 virus. If researchers could devise ways to block this ion channel, they may be able to design drugs that would interfere with viral replication. The illustration on the right shows the five-helix bundle of the envelope protein E with a gray water column inside. Credits: Image courtesy of the researchers.
If researchers could devise ways to block this channel, they may be able to reduce the pathogenicity of the virus and interfere with viral replication, says Mei Hong, an MIT professor of chemistry. In this study, the researchers investigated the binding sites of two drugs that block the channel, but these drugs bind only weakly, so they would not be effective inhibitors of the E protein.
“Our findings could be useful for medicinal chemists to design alternative small molecules that target this channel with high affinity,” says Hong, who is the senior author of the new study.
MIT graduate student Venkata Mandala is the lead author of the paper, which appears in Nature Structural and Molecular Biology. Other authors include MIT postdoc Matthew McKay, MIT graduate students Alexander Shcherbakov and Aurelio Dregni, and Antonios Kolocouris, a professor of pharmaceutical chemistry at the University of Athens.
Structural challenges
Hong’s lab specializes in studying the structures of proteins that are embedded in cell membranes, which are often challenging to analyze because of the disorder of the lipid membrane. Using nuclear magnetic resonance (NMR) spectroscopy, she has previously developed several techniques that allow her to obtain accurate atomic-level structural information about these membrane-embedded proteins.
When the SARS-CoV-2 outbreak began earlier this year, Hong and her students decided to focus their efforts on one of the novel coronavirus proteins. She narrowed in on the E protein partly because it is similar to an influenza protein called the M2 proton channel, which she has previously studied. Both viral proteins are made of bundles of several helical proteins.
“We determined the influenza B M2 structure after about 1.5 years of hard work, which taught us how to clone, express, and purify a virus membrane protein from scratch, and what NMR experimental strategies to take to solve the structure of a homo-oligomeric helical bundle,” Hong says. “That experience turned out to be the perfect training ground for studying SARS-CoV-2 E.”
The researchers were able to clone and purify the E protein in two and half months. To determine its structure, the researchers embedded it into a lipid bilayer, similar to a cell membrane, and then analyzed it with NMR, which uses the magnetic properties of atomic nuclei to reveal the structures of the molecules containing those nuclei. They measured the NMR spectra for two months, nonstop, on the highest-field NMR instrument at MIT, a 900-megahertz spectrometer, as well as on 800- and 600-megahertz spectrometers.
Hong and her colleagues found that the part of the E protein that is embedded in the lipid bilayer, known as the transmembrane domain, assembles into a bundle of five helices. The helices remain largely immobile within this bundle, creating a tight channel that is much more constricted than the influenza M2 channel.
Interestingly, the SARS-CoV-2 E protein looks nothing like the ion channel proteins of influenza and HIV-1 viruses. In flu viruses, the equivalent M2 protein is much more mobile, while in HIV-1, the equivalent Vpu protein has a much shorter transmembrane helix and a wider pore. How these distinct structural features of E affect its functions in the SARS-CoV-2 virus lifecycle is one of the topics that Hong and her colleagues will study in the future.
The researchers also identified several amino acids at one end of the channel that may attract positively charged ions such as calcium into the channel. They believe that the structure they report in this paper is the closed state of the channel, and they now hope to determine the structure of the open state, which should shed light on how the channel opens and closes.
Fundamental research
The researchers also found that two drugs — amantadine, used to treat influenza, and hexamethylene amiloride, used to treat high blood pressure — can block the entrance of the E channel. However, these drugs only bind weakly to the E protein. If stronger inhibitors could be developed, they could be potential drug candidates to treat Covid-19, Hong says.
The study demonstrates that basic scientific research can make important contributions toward solving medical problems, she adds.
“Even when the pandemic is over, it is important that our society recognizes and remembers that fundamental scientific research into virus proteins or bacterial proteins must continue vigorously, so we can preempt pandemics,” Hong says. “The human cost and economic cost of not doing so are just too high.”
The research was funded by the National Institutes of Health and the MIT School of Science Sloan Fund.
“Although scientific evidence says the Earth is a sphere orbiting the Sun, there are some people around who still think our planet is flat… and social media plays a role”, said Anders Furze of University of Melbourne.
If you type ‘flat Earth’ into Google, you’d be joining a group of people that have helped to triple the search term over the last couple of years. In fact, a recent YouGov poll found that only around two-thirds of Americans aged between 18 and 24 believe that the Earth is round.
Although the idea the Earth is flat has been scientifically discredited, there seems to be a growing belief in the conspiracy theory.
And it’s getting more traction than some of the other conspiracies out there, like chemtrails (which proposes that a plane’s long-lasting condensation trail is actually made up of chemical or biological agent).
A third of Americans polled by YouGov believe the Earth is flat. Picture: Getty Images
Interest in most of these other far-fetched theories remains stable but the flat-Earth movement is growing, particularly in America. And it has some high-profile supporters.
From basketball players to musicians, rappers to TV hosts, a number of celebrities are jumping on the flat Earth bandwagon.
So what’s causing a renewed interest in something that’s been scientifically disproven for the past two thousand years or more? What does it say about social media? And how did we actually establish that the world is round in the first place?
ROUNDING OUT THE WORLD
Once upon a time, it made sense for people to believe that the Earth was flat, says University of Melbourne cartographer Chandra Jayasuriya. Ships would sail off toward the horizon and often never return, and those people left behind didn’t really have access to information outside of their communities.
“Their view was egocentric and geocentric. They lived in a village that was the centre of their existence,’’ she says. “The further away from the village they travelled, the more hostile the environment became.”
Greek philosophers established that the Earth was round as far back as the third century BC, but it wasn’t until the 15th century that it became commonly accepted.
A 15th century manuscript copy of Ptolemy world map, reconstituted from Ptolemy’s Geography. Picture: Getty Images
The first scientific estimates of the Earth’s circumference were made by the Greek mathematician and geographer Eratosthenes in 240 BC. He noted that on the 21st of June that year, in a town called Syene (near modern day Aswan), the reflection of the sun could be seen in a deep well, meaning that it was directly overhead.
But in Alexandria, around 800 kilometres away and almost directly north of Syene, at noon on the same day, the angle of the sun was about seven degrees – or one-50th of a circle.
If the Earth was actually flat, the angle would be identical in both places.
“From this, he concluded that the circumference of the Earth must be 50 times the distance between Syene and Alexandria,” Ms Jayasuriya adds. “This gave him a figure that was very close to the actual circumference as we know it now.”
In 150 AD, Ptolemy’s treatise Geographia laid out a revolutionary system of assigning co-ordinates, expressed in degrees of latitude and longitude, to locations around the world. The mathematician and astronomer assigned these coordinates to more than 8000 places across the known world.
Even though many of the measurements weren’t accurate, Ptolemy’s concept of ‘global mapping co-ordinates’ – used to this day – was based on the theory that the Earth was and is, indeed, round.
“Although Ptolemy’s original map didn’t survive, the text was rediscovered around 1300 AD and cartographers were able to recreate the map”, says Ms Jayasuriya.
A flat Earth map drawn by Orlando Ferguson in 1893. Picture: Wikimedia
As well as observations of the sun and its shadows, Ms Jayasuriya says many scientists throughout history continued to gather observations and evidence that the Earth is spherical including:
That we see the top of a ship’s mast coming into port and not the entire ship
That all other planets and celestial objects are spheres
That during a lunar eclipse, the Earth’s shadow on the moon is curved
DISTRUSTING THE EXPERTS
So why, despite overwhelming scientific evidence that the Earth is an “oblate spheroid” – a sphere that’s squashed at its poles and swollen at the equator – is the flat-Earth movement gaining traction in the 21st century?
Well, in part, according to School of Culture and Communication lecturer Dr Jennifer Beckett, it’s due to a general shift towards populism and a distrust in the views of experts and the mainstream media.
“It’s really about the power of knowledge, and that increasing distrust in what we once considered to be the gatekeepers of knowledge – like academics, scientific agencies, or the government,” Dr Beckett says.
In this kind of environment, “it becomes really easy for once-fringe views to gain traction. You get a bunch of people around you who are constantly reaffirming your belief.”
Circa 1600, A terrestrial and a celestial globe, side by side, engraved for Bankes’s New System of Geography. Picture: Getty Images
Dr Beckett also notes that the burgeoning movement speaks to how so-called social media “influencers” can now hold more sway than an expert in the field.
“That’s often because they tend to be better storytellers,” Dr Beckett says.
“And there’s an element of authenticity there – people naively think, ‘Oh, they’re a real person, so it must be true’.”
THE FLAT EARTH ECOSYSTEM
Dr Beckett notes that the flat Earth community uses various social media platforms in distinct, overlapping ways in order to create a kind of ecosystem around their beliefs.
“Youtube becomes a content hub, Facebook becomes an administrative one-stop shop for that hub, and Twitter continually pushing out the messaging,” she says, likening Youtube to a sort of alternative documentary channel for flat earthers.
“It’s a really interesting beast … they can have their daily or weekly TV show in the same way that we go to David Attenborough.”
It’s a more powerful social media tool than Facebook or Twitter because it’s a “high context” platform, Dr Beckett says, where users can stream themselves with an immediacy and intimacy that’s lacking from text or image-based platforms.
“It’s kind of like feeling like you have direct access to David Attenborough, after watching one of his documentaries. Being able to have a conversation with him then have him respond in the next episode to your concerns or your question.”
And unlike TV, on Youtube you can go searching for videos by people who agree with your view of the world. Or in this case, the Earth.
Dr Beckett says that as we increasingly rely on social media for entertainment, we are becoming “affect addicts” – looking for the next hit of anger, happiness or other intense emotions.
And it’s very easy for misinformation to circulate in this environment. Many flat earthers endorse the idea that the UN logo is actually a flat Earth map, for example.
But Ms Jayasuriya adds its appearance is the result of a way of ‘projecting’ a 3D sphere onto a 2D plane.
Because there’s “no perfect way to project a 3D sphere onto a 2D surface”, cartographers produce maps using different ‘projections’ for different uses. The UN logo is a particular projection centred on the North Pole.
GETTING THE FACTS FOR CRITICAL THINKING
So, the question remains: why is this a theory that still persists in 2018 in the face of science, and even photographic evidence?
Well, it also comes back to thinking critically about information that’s out there. Particularly online.
“Look, flat earthers’ are actually employing Cartesian doubt; this a philosophical idea that the world outside the self is subject to uncertainty,” Dr Beckett says, referring to a method of sceptical thinking popularised by René Descartes, the French philosopher, mathematician, and scientist.
“But, I’d say the best way to do your research on whether a story is correct is to actually go to the mainstream media, to go to those scientific agencies and see what they’re saying.
“Academics are academics not because they’re trying to pull the wool over people’s eyes, but because we spend a lot of time training and thinking deeply about these issues,” says Dr Beckett.
“You know, a lot of time, work and effort has gone into perpetuating the notion that the Earth is a globe… perhaps, that’s a sign that it is.”
New analysis reveals need for interventions that could improve wellbeing of communities.
Food insecurity is one of the nation’s leading health and nutrition issues—about 13.7 million (10.5 percent) of households in the United States were food insecure at some time during 2019, a trend likely to increase in light of the COVID-19 pandemic. According to preliminary research conducted by researchers at Penn Medicine, increasing rates of food insecurity in counties across the United States are independently associated with an increase in cardiovascular death rates among adults between the ages of 20 and 64.
The large-scale, national study, which will be presented at the American Heart Association’s Scientific Sessions 2020, provides evidence of the link between food insecurity and increased risk of cardiovascular death. This is one of the first national analyses to evaluate changes in both food security and cardiovascular mortality over time, and to see if changes in food insecurity impact cardiovascular health. The findings were also published today in Circulation: Cardiovascular Quality and Outcomes.
“This research gives us a better understanding of the connection between economic distress and cardiovascular disease,” said Sameed Khatana, MD, MPH, senior author of the study and instructor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania. “What’s going on outside the clinic has significant impact on patients’ health. There are many factors beyond the medications we may be prescribing that can influence their wellbeing, food insecurity being one of them.”
Researchers analyzed data from the National Center for Health Statistics and the Map the Meal Gap study, to examine county-level cardiovascular death rates and food insecurity rates from 2011 to 2017, among adults age 20 to 64, and those 65 years and older.
The researchers found that while the overall food insecurity rates for the entire country declined between 2011 and 2017, the counties that had the most increase in food insecurity levels had cardiovascular death rates that increased from 82 to 87 per 100,000 individuals. Additionally, for every 1 percent increase in food insecurity, there was a similar increase in cardiovascular mortality among non-elderly adults (0.83 percent).
“There has been a growing disparity when it comes to food insecurity, and this data demonstrates that parts of the country are being left behind. Unfortunately, this may only get worse as the country grapples with the ramifications of the COVID-19 pandemic,” Khatana said. “However, interventions that improve a community’s economic wellbeing could potentially lead to improved community cardiovascular health.”
The authors intend to study whether interventions that improve food insecurity can lead to better cardiovascular health.
Penn co-authors include, Atheendar S. Venkataramani, Christina A. Roberto, Lauren A. Eberly, and Peter W. Groeneveld, along with Yale’s Stephen Y. Wang.
Whether the signaling molecule IL-33 wakes up or turns down the immune response depends on what cell type releases it, School of Veterinary Medicine researchers found.
De’Broski Herbert has a philosophy that’s guided his career researching helminths, or parasitic worms, and their interaction with their hosts’ immune systems: “Follow the worm.”
Samples of nasal polyps removed from patients with chronic rhinosinusitis revealed the perforin-2 protein (labeled in green) in the cellular plasma membrane. A pore protein, perforin-2 may be how IL-33, a key immune signaling molecule, is able to exit these cells to trigger an immune response, according to new work led by a Penn Vet-led team. (Image: Courtesy of De’Broski Herbert)
“The mantra of my lab since its inception has been that parasitic worms manipulate their hosts in very interesting ways to maintain their survival,” says Herbert, an associate professor of pathobiology in Penn’s School of Veterinary Medicine. “SARS-CoV-2 doesn’t care about staying in your body very long because it is transmitted so easily. Worms aren’t spread so easily, so they have to figure out how to persist.”
That focus has revealed a key insight about an immune signaling molecule, the cytokine IL-33, that is important not only in parasite infections, but in a range of other health conditions, such as asthma, obesity, and eczema. In a new study published in Science Immunology, Herbert and colleagues made insights that explain how IL-33 can both help defend the body against parasite infection, but also suppress chronic inflammation in diseases where the immune system is activated inappropriately and causes harmful pathology. A key discovery was that the activity of IL-33 depends upon which cell type is releasing it.
“Lots of people have been interested in IL-33 ever since two big genomic association studies implicated it and its receptor in the pathogenesis of asthma,” Herbert says. “Other researchers have looked at it in the context of infections and others in the context of the brain and development. And everyone knew this protein was in the nucleus, but no one understood how it got out of the cell to accomplish all of these things.
“I’m excited for this work because not only do we find this cytokine in a cell type that nobody was expecting, but we also present a mechanism that no one was expecting for how it could come out.”
IL-33 has been of major interest to immunologists focused on what are known as type 2 immune responses, typically associated with parasite infections or asthma and allergies. On the parasite front, researchers knew that IL-33 acted in part to “wake up” the immune system to the presence of a worm infection. In a mouse model, animals lacking IL-33 sustain worm infections much longer than those with IL-33 intact.
To find out whether it mattered which cell type was releasing the IL-33 signaling molecule, Herbert and colleagues used special mouse model in which only myeloid antigen-presenting cells (immune cells), or epithelial cells (those that line mucosal surfaces), failed to release IL-33.
“Sure enough, we found that when animals lacking the myeloid-derived IL-33 experienced a hookworm infection, they eliminated those hookworms quite fast,” Herbert says. Mice lacking IL-33 in the epithelial cells, however, were not able to readily clear the infection. The same results held up in another rodent model, this one of roundworm infection.
Dendritic cells, a type of myeloid antigen-presenting cell, produce IL-33, and further experiments showed that the cytokine produced by these cells supported a specific population of regulatory T cells (Tregs), which are cells “whose whole purpose is to suppress the immune response,” Herbert says.
Now understanding that dendritic cells were key to supporting Tregs, the researchers wanted to understand how the dendritic cells were delivering the IL-33. The team screened dendritic cells from mice with and without IL-33, identifying a protein called perforin-2 to be suppressed in expression from myeloid cells lacking IL-33.
Perforin-2, as its name suggests, forms a pore that spans the cell membrane, like a tunnel in a hillside, allowing the transport of proteins in and out. The find made complete sense to the researchers, providing an explanation for how dendritic cells could promote the release of IL-33 into the tissues to interact with Tregs. And when Herbert and colleagues experimentally eliminated perforin-2 from dendritic cells, they saw a subsequent lack of Treg growth.
To connect the findings in their animal model and lab dishes to humans, the team utilized patient samples from Penn otolaryngologist Noam Cohen. They found perforin-2 at the plasma membrane of cells from polyps removed from patients with chronic rhinosinusitis, suggesting that the significance of the findings extends to human health.
The study paves the way for even more translational work in immunology—and worms are to thank. “It’s kind of the missing link,” Herbert says. “It opens up a whole new direction for understanding how this cytokine could be involved in obesty, inflammatory bowel disease, Crohn’s, asthma, and development.”
De’Broski Herbert is an associate professor of pathobiology in the University of Pennsylvania School of Veterinary Medicine.
Herbert’s coauthors on the paper were Penn Vet’s Li-Yun Hung, Karl Herbine, Christopher Pastore, Annabel Ferguson, Nisha Vora, Bonnie Douglas, and Kelly Zullo; Brenal Singh, Tiffany Li Hui Tan, Michael A. Kohanski, Taku Kambayashi, and Noam A. Cohen of Penn’s Perelman School of Medicine; the Children’s Hospital of Philadelphia’s Ed Behrens; Tohoku University Hospital’s Yukinori Tanaka; Sanofi US’s Paul Bryce; the Monell Chemical Senses Center’s Cailu, and Danielle R. Reed; and Vanderbilt University’s Breann L. Brown.
The study was funded by the Burroughs Wellcome Fund and the National Institutes of Health (grants AI144572, AI125940, and GM083204).
