Culture

TROY, N.Y. -- An innovative testing platform that more closely mimics what cancer encounters in the body may allow for more precise, personalized therapies by enabling the rapid study of multiple therapeutic combinations against tumor cells. The platform, which uses a three-dimensional environment to more closely mirror a tumor microenvironment, is demonstrated in research published in Communications Biology.

"This whole platform really gives us a way to optimize personalized immunotherapy on a rapid, high throughput scale," said Jonathan Dordick, Institute Professor of chemical and biological engineering and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute, who led this research. "You can imagine somebody having cancer, and you quickly biopsy the tumor and then you use this biochip platform to identify very quickly -- within a day or two -- what specific treatment modality might be ideally suited against a particular cancer."

Of particular interest to researchers is the behavior of a specific type of immune cell known as natural killer (NK) cells, which seek out cancer or viruses within the body, bind to their receptors, and excrete an enzyme meant to kill the unwanted cells. The platform studied in this paper allows researchers to compare what happens when the NK cells are left to fight tumor cells on their own versus how they behave when an antibody or cancer drug, or a combination of the two, is added.

The platform is a small two-piece plastic chip that's about the size of a microscope slide. One side of the sandwich chip contains 330 tiny pillars upon which researchers can place an external matrix, made of a gel-like substance, which mimics the mechanical environment of a tumor cell. When cancer cells are placed inside this gel-like structure, they're encouraged to grow into a spheroid shape, much as they would inside the body. The second piece contains 330 microwells within which NK cells can be added in suspension -- much as they would flow, untethered inside the body.

At Rensselaer, Dordick collaborated with Seok-Joon Kwon, senior research scientist in CBIS, and Sneha Gopal, who recently received her Ph.D. based, in part, on this study. The Rensselaer team collaborated with researchers from Konyang University and Medical & Bio Decision Company Ltd. To test this platform, researchers studied two types of breast cancer cells, as well as pancreatic cancer cells, with various combinations of NK cells, two monoclonal antibodies, and an anti-cancer chemotherapy drug.

"You can screen very quickly to determine what combinations of NK cells, antibodies, and chemotherapeutic drugs target the cancer cells within the spheroid geometry," Dordick said. "What really is amazing is we see very significant differences between what happens in that spheroid, within the slots of the chip, versus what would happen in a more traditional two-dimensional cell culture that's often used in the screening."

In the spheroid design, for instance, the chemotherapy drug paclitaxel had little effect on the three types of cancer cells on its own, whereas in a traditional two-dimensional system, Dordick said, the drug may appear to do well. It performed dramatically better when it was combined with both NK cells and an antibody.

"This platform moves researchers closer to personalized medicine," said Deepak Vashishth, director of CBIS. "This work conducted by Professor Dordick and his research group is an excellent example of how we, at Rensselaer, are providing a new angle to human health by developing new approaches at the intersection of engineering and life sciences to enhance cures for diseases such as cancer."

To further the potential use of this tool, Dordick said that it must be tested on a wide range of cancer types, including a tumor microenvironment that consists of multiple different types of cells. In the future, he envisions that the platform has the potential to identify combination therapies that work best against a patient's specific cancer, enabling the identification and delivery of personalized immunotherapy.

It's a favourite first-order for the day, but while a quick coffee may perk us up, new research from the University of South Australia shows that too much could be dragging us down, especially when it comes to brain health.

In the largest study of its kind, researchers have found that high coffee consumption is associated with smaller total brain volumes and an increased risk of dementia.

Conducted at UniSA's Australian Centre for Precision Health at SAHMRI and a team of international researchers*, the study assessed the effects of coffee on the brain among 17,702 UK Biobank participants (aged 37-73), finding that those who drank more than six cups of coffee a day had a 53 per cent increased risk of dementia.

Lead researcher and UniSA PhD candidate, Kitty Pham, says the research delivers important insights for public health.

"Coffee is among the most popular drinks in the world. Yet with global consumption being more than nine billion kilograms a year, it's critical that we understand any potential health implications," Pham says.

"This is the most extensive investigation into the connections between coffee, brain volume measurements, the risks of dementia, and the risks of stroke - it's also the largest study to consider volumetric brain imaging data and a wide range of confounding factors.

"Accounting for all possible permutations, we consistently found that higher coffee consumption was significantly associated with reduced brain volume - essentially, drinking more than six cups of coffee a day may be putting you at risk of brain diseases such as dementia and stroke."

Dementia is a degenerative brain condition that affects memory, thinking, behaviour and the ability to perform everyday tasks. About 50 million people are diagnosed with the syndrome worldwide. In Australia, dementia is the second leading cause of death, with an estimated 250 people diagnosed each day.

Stroke is a condition where the blood supply to the brain is disrupted, resulting in oxygen starvation, brain damage and loss of function. Globally, one in four adults over the age of 25 will have a stroke in their lifetime. Data suggests that 13.7 million people will have a stroke this year with 5.5 million dying as a result.

Senior investigator and Director of UniSA's Australian Centre for Precision Health, Professor Elina Hyppönen, says while the news may be a bitter brew for coffee lovers, it's all about finding a balance between what you drink and what's good for your health.

"This research provides vital insights about heavy coffee consumption and brain health, but as with many things in life, moderation is the key," Prof Hyppönen says.

"Together with other genetic evidence and a randomised controlled trial, these data strongly suggest that high coffee consumption can adversely affect brain health. While the exact mechanisms are not known, one simple thing we can do is to keep hydrated and remember to drink a bit of water alongside that cup of coffee.

"Typical daily coffee consumption is somewhere between one and two standard cups of coffee. Of course, while unit measures can vary, a couple of cups of coffee a day is generally fine.

"However, if you're finding that your coffee consumption is heading up toward more than six cups a day, it's about time you rethink your next drink."

This release has been removed upon request of the submitting institution. Please contact Jennifer Forbes, 732-788-8301, jenn.forbes@rwjms.rutgers.edu for more information.

HOUSTON -- (July 22, 2021) -- Researchers who want bacteria to feel right at home in the laboratory have put out a new welcome mat.

Rice University bioengineers and Baylor College of Medicine scientists looking for a better way to mimic intestinal infections that cause diarrhea and other diseases have built and tested a set of hydrogel-based platforms to see if they could make both transplanted cells and bacteria comfy.

As a mechanical model of intestinal environments, the lab's soft, medium and hard polyethylene glycol (PEG) hydrogels were far more welcoming to the cells that normally line the gut than the glass and plastic usually used by laboratories. These cells can then host bacteria like Escherichia coli that are sometimes pathogenic. The ability to study their dynamics under realistic conditions can help scientists find treatments for the maladies they cause.

The researchers found strong correlation between the stiffness of hydrogels, which mimic intestinal mucus, and how well a diarrhea-causing strain of E. coli adhered to and aggregated atop the epithelial cells that normally line the intestines. They reported that softer hydrogels promoted "significantly greater bacterial adhesion," which they attribute to mucus and other extracellular matrix components expressed by the cells.

The study led by bioengineer Jane Grande-Allen of Rice's Brown School of Engineering and Anthony Maresso at Baylor, which appears in Acta Biomaterialia, proved the gels' value in experiments involving the soft interface between organs and microbial or bacterial pathogens.

The Estes lab at Baylor built its model cultures using enteroids, constructs of intestinal cell cultures that scientists use to understand how epithelial cells respond to infectious invaders. Enteroids can incorporate a variety of cells found in the gut, but before Rice's hydrogels, they were grown on platforms that did not easily mimic the squishy tissues in host bodies.

"Tissue culture plastic is the standard for growing cells, but it's a really artificial environment because it's so rigid," Grande-Allen said. "It's hard plastic, like a glass slide. Certain cells grow just fine on tissue culture plastic, but they're not consistently easy to infect that way.

"This is the case with the cells in the jejunum, where most nutrient absorption happens in the small intestine," she said. "Our collaborators obtain human intestinal tissues from biopsies and bariatric surgeries to make enteroids, but the enteroids derived from jejunal cells had been difficult to infect with this pathogenic E. coli."

In Grande-Allen's lab, enteroid cells were grown on top of the hydrogel substrates. After a time, the researchers in Maresso's lab added bacteria and found that the enteric E. coli clustered easily on the intestinal cells grown on the medium and soft gels, but not on glass slides or stiff hydrogels.

All of the hydrogel-cultured enteroids showed significant enrichment of gene and signaling pathways related to epithelial differentiation, cell junctions and adhesions, extracellular matrix and mucins compared to those cultured on rigid surfaces.

The Rice lab reported its successful development of hydrogels for enteroid use in a previous paper with the Baylor researchers. "Getting the cells to adhere and spread on the hydrogels was tricky, which is why we wrote the methods paper," Grande-Allen said.

"But with that coating approach established, the hydrogel underneath could have a range of different stiffnesses," she said. "That was the variable in the new paper, and we were floored to find the effect that it had on bacterial adhesion.

"In general, stiffness and its effect on bacteria is rather understudied," Grande-Allen said. "Others have reported that bacteria grown directly on hydrogels prefer stiffer gels, and that finding will help to study biofilms. But here, our focus was trying to mimic the infectious disease process that actually happens in the gut, so we needed to involve the epithelial cells."

Grande-Allen said the hydrogels will be used to study other types of diarrhea-causing bacteria, including patient-specific cultivates, but in the near term said her lab will look at the combined effect of stiffness and shear stress on bacterial adhesion to enteroids.

Many people find it morally impermissible to put kidneys, children, or doctorates on the free market. But what makes a market transaction morally repugnant in the eyes of the public? And which transactions trigger the strongest collective disapproval? Researchers from the Max Planck Institute for Human Development and the Robert Koch Institute have addressed these questions. Their findings, published in Cognition, offer new entry points for policy interventions.

Would you be willing to sell a kidney or be paid to spend time on a date? If not, then you are not alone. Many people find the idea of selling and buying human organs, children, sex, or doctorates morally repugnant. But what are the psychological mechanisms behind these feelings? Which aspects of a transaction do people find most repugnant? A research team from the Max Planck Institute for Human Development and the Robert Koch Institute has investigated these questions.

"Our aim was to uncover the psychological drivers of people's feelings of repugnance towards such transactions," says Christina Leuker, lead author and researcher at the Robert Koch Institute, and associate research scientist in the Center for Adaptive Rationality at the Max Planck Institute for Human Development. "Once we know what makes a market transaction morally repugnant in the eyes of the public, we are in a better position to predict how people might respond to novel transactions, such as those arising from technological advances in the field of human genetic engineering."

To shine a light on the psychology of repugnance, the researchers conducted two online surveys, in which a total of 1,554 respondents judged 51 market transactions in terms of their repugnance and 21 other characteristics. These included the extent to which the transaction triggers anger or disgust, is harmful to society, affects the dignity of the seller, or leaves people open to exploitation.

The researchers found similar patterns of repugnance judgments across the respondents in both studies. Three transactions--selling rights to hunt endangered animals, selling brides, and selling voting rights--triggered the strongest collective disapproval. Moreover, the authors were able to identify five aspects that appear to underlie feelings of repugnance. One was moral outrage: The more moral outrage a transaction triggers, the more disgust and anger people feel, the less empathy they have for those engaged in the transaction, and the more harmful they think the transaction is to society.

The four other drivers of repugnance identified by the research team were the extent to which people want a transaction to be regulated; the extent to which a transaction's worth can or cannot be translated into a monetary value; the extent to which the transaction may exploit disadvantaged individuals; and the extent to which sellers are exposed to unknown risks or are unable to fully anticipate the consequences of the transaction.

Analyses showed that the degree of moral outrage was also a good predictor of the desire for regulation: Many transactions that triggered strong moral outrage were also characterized by a strong perceived need for regulation.

The researchers highlight that their approach can provide new entry points for policy interventions. "Transactions that prompt similar degrees of public repugnance may do so for very different reasons--and this has implications for policy interventions," says Ralph Hertwig, Director of the Center for Adaptive Rationality at the Max Planck Institute for Human Development. "For instance, if the main driver of repugnance toward a transaction is that it leaves disadvantaged individuals open to exploitation, an effective policy response may be geared toward protecting those who are vulnerable. If unknown risk is the main cause of repugnance, the policy may instead focus on reducing and clearly communicating potential risks."

The researchers also identified mismatches between the judged repugnance of a transaction and its current legal status. "For instance, UK respondents considered carbon emissions trading and selling permits to shoot rare animals highly repugnant, yet both are legal in their country," says Christina Leuker. "Such mismatches may be grounds for policy makers to reevaluate those transactions."

ITHACA, N.Y. - A new method that analyzes how individual immune cells react to the bacteria that cause tuberculosis could pave the way for new vaccine strategies against this deadly disease, and provide insights into fighting other infectious diseases around the world.

The cutting-edge technologies were developed in the lab of Dr. David Russell, the William Kaplan Professor of Infection Biology in the Department of Microbiology and Immunology in the College of Veterinary Medicine, and detailed in new research published in the Journal of Experimental Medicine on July 22.

For years, Russell's lab has sought to unravel how Mycobacterium tuberculosis (Mtb), the bacteria that cause tuberculosis, infect and persist in their host cells, which are typically immune cells called macrophages.

The lab's latest innovation combines two analytical tools that each target a different side of the pathogen-host relationship: "reporter" Mtb bacteria that glow different colors depending on how stressed they are in their environment; and single-cell RNA sequencing (scRNA-seq), which yields RNA transcripts of individual host macrophage cells.

"For the first time ever, Dr. Davide Pisu in my lab combined these two approaches to analyze Mtb-infected immune cells from an in vivo infection," Russell said.

After infecting mice with the fluorescent reporter Mtb bacteria, Russell's team was able to gather and flow-sort individual Mtb-infected macrophages from the mouse lung. The researchers then determined which macrophages promoted Mtb growth (sporting happy, red-glowing bacteria) or contained stressed Mtb unlikely to grow (unhappy, green-glowing bacteria).

Next, they took the two sorted, infected macrophage populations and ran them through single-cell RNA sequencing analysis, thereby generating transcriptional profiles of each individual host cell in both populations.

When the scientists compared the macrophage single cell sequencing data with the reporter bacteria phenotype, they found an almost perfect one-to-one correlation between the fitness status of the bacterium and the transcriptional profile in the host cell. Macrophages that housed unhappy green bacteria also expressed genes that were known to discourage bacterial growth, while those with happy red bacteria expressed genes known to promote bacterial growth.

Scientific experiments rarely play out so nicely.

"What absolutely stunned us is how well it worked," Russell said. "When Davide Pisu showed me the analysis I nearly fell off my chair."

Normally, phenotypes and transcriptional profiles are two characteristics that seldom come together in a perfect match, and this almost never happens from in vivo data.

This near-perfect matchup revealed new nuances.

"While our previous results identifying the resident alveolar macrophages (AM) as permissive and the blood monocyte-derived recruited macrophages (IM) as controlling Mtb infection was correct in a broad sense, we found, unsurprisingly, that this was an oversimplification," Russell said.

There was variation even within these two different macrophage types: Some AM cells controlled Mtb growth while some IMs were allowing bacterial expansion. The team found that comparable subsets of immune cells were present in both human and mouse lung samples.

An additional step in the study was to look at whether the responses of AM and IM cells to Mtb were epigenetically controlled--meaning that the cells' traits are due to certain genes being turned off or on by molecular switches This could explain how two sets of macrophages respond differently. Using a read-out of a cell's epigenetic landscape, they found that this was the case.

"The analysis showed that when these cells are exposed to Mtb or the vaccine strain- through infection or vaccination, respectively - their epigenetic programming has a major influence over whether their response leads to disease control or progression," Russell said.

Armed with this body of new information, the Russell lab plans to hit the ground running to identify novel therapeutics. "We're going to begin by screening libraries of known epigenetic inhibitor compounds to see which ones might be useful in modifying the immune response," Russell said.

If they do find promising compounds - ones that push macrophages towards an anti-Mtb behavior - they could potentially be used in combination with vaccines to assist a patient's immune system in protecting against tuberculosis.

The finding lays a foundation for more powerful studies on how pathogens affect individual cells, allowing for a holistic examination of the system.

"This is a roadmap that lets us look across an entire population of cells and see how a single perturbation impacts the cells across that population," Russell said. "We can test for drug efficacy in in vivo infection without any preconceived limitation on how compounds may function."

This approach is extremely flexible and could be used in the study of any intracellular pathogen, including viruses, and is readily applicable to any animal challenge model.

The rapid spread of the Alpha variant of COVID-19 resulted from biological changes in the virus and was enhanced by large numbers of infected people 'exporting' the variant to multiple parts of the UK, in what the researchers call a 'super-seeding' event.

Results of the largest phylogeographic analysis ever conducted, published today in the journal Science, maps the spread of the variant (also known as lineage B.1.1.7) from its origins in Kent and Greater London in November 2020 to all but five counties in Wales, Scotland, Northern Ireland and England by 19 January.

Dr Moritz Kraemer, lead author on the study and Branco Weiss Research Fellow in Oxford's Department of Zoology, says, 'At the beginning of December 2020 the epicentre of COVID-19 transmission in England shifted rapidly from the North West and North East to London and the South East, as the Alpha variant took hold.
'As people travelled from London and the South East to other areas of the UK they 'seeded' new transmission chains of the variant. This continued as a national 'super-seeding' event which did not start to slow until early January. Although travel was curbed, after travel restrictions were introduced on 20 December, this was compensated for by the continued exponential growth in Alpha variant cases.'

The rapid spread of the Alpha variant across the UK, led to initial reports that it could be up to 80% more transmissible than the original strain. This study, published today by researchers at universities including Oxford, Northeastern and Edinburgh, shows mobility significantly affected its spread and early growth rates. According to the researchers, this highlights the need for epidemiologists to work closely with virologists and geneticists rapidly to create accurate transmissibility estimates for new variants.

Professor Oliver Pybus, lead researcher of the Oxford Martin Programme on Pandemic Genomics, explains, 'Estimates of Alpha's transmission advantage over previous strains were initially 80%, but declined through time. We found Alpha's emergence was a combination of virus genetic changes and transient epidemiological factors. An initial wave of Alpha variant export to places in England with low rates of infection, from the massive outbreak in Kent and Greater London, explains why at first it spread so fast.

'The Alpha variant does contain genetic changes which makes it more transmissible. It is likely the Alpha variant was 30% to 40% more transmissible than the initial strain. And the early estimates were higher because we did not know how much its growth was exacerbated by human mobility and by how many contacts different groups of people have. Crucially, as more variants emerge and spread in other countries worldwide, we must be careful to account for these phenomena when evaluating the intrinsic transmissibility of new variants.'

Verity Hill, co-author and researcher from the University of Edinburgh, expands, 'The Alpha variant began by spreading mostly within London and the South East, even during the November lockdown in England. Once this was lifted, it spread rapidly across the country, as human movement increased significantly. Our ability to be able to trace the origins of the Alpha back to a point source in the South East of England has important implications for how new variants arise and how they will spread across the UK.'

Dr Samuel V. Scarpino, lead researcher from the Network Science Institute at Northeastern University and External Faculty at the Santa Fe Institute, highlights the importance of integrative pathogen surveillance systems, 'Only by integrating high-resolution genomic, case, testing, and aggregated, anonymous mobility data were we able to identify the drivers of Alpha variant emergence and spread in the UK.

'Uncovering the mechanisms of B.1.1.7 emergence allows governments to respond more effectively and advances our scientific understanding of epidemics. The challenge now is to build similar surveillance systems globally. Equitable, ethical data systems will be critical for ending this pandemic and preventing future ones.'

Dr Kraemer concludes, 'As new variants emerge we expect they will spread significantly before travel restrictions are put in place, as likely happened with the Delta variant. Given the scale of its current outbreak, it seems probably that the UK is now an important exporter of the Delta variant across Europe and some other parts of the world.

'The UK has decided to ease its restrictions because of our high vaccination rates and a confidence that we have protected the most vulnerable people in society. But that's not the case in most other countries and the Delta variant could be starting this process again elsewhere, highlighting the urgent need for faster and equitable distribution of vaccines worldwide.'

Engineers at the University of California San Diego developed a soft and stretchy ultrasound patch that can be worn on the skin to monitor blood flow through major arteries and veins deep inside a person's body.

Knowing how fast and how much blood flows through a patient's blood vessels is important because it can help clinicians diagnose various cardiovascular conditions, including blood clots; heart valve problems; poor circulation in the limbs; or blockages in the arteries that could lead to strokes or heart attacks.

The new ultrasound patch developed at UC San Diego can continuously monitor blood flow--as well as blood pressure and heart function--in real time. Wearing such a device could make it easier to identify cardiovascular problems early on.

A team led by Sheng Xu, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, reported the patch in a paper published July 16 in Nature Biomedical Engineering.

The patch can be worn on the neck or chest. What's special about the patch is that it can sense and measure cardiovascular signals as deep as 14 centimeters inside the body in a non-invasive manner. And it can do so with high accuracy.

"This type of wearable device can give you a more comprehensive, more accurate picture of what's going on in deep tissues and critical organs like the heart and the brain, all from the surface of the skin," said Xu.

"Sensing signals at such depths is extremely challenging for wearable electronics. Yet, this is where the body's most critical signals and the central organs are buried," said Chonghe Wang, a former nanoengineering graduate student in Xu's lab and co-first author of the study. "We engineered a wearable device that can penetrate such deep tissue depths and sense those vital signals far beneath the skin. This technology can provide new insights for the field of healthcare."

Another innovative feature of the patch is that the ultrasound beam can be tilted at different angles and steered to areas in the body that are not directly underneath the patch.

This is a first in the field of wearables, explained Xu, because existing wearable sensors typically only monitor areas right below them. "If you want to sense signals at a different position, you have to move the sensor to that location. With this patch, we can probe areas that are wider than the device's footprint. This can open up a lot of opportunities."

How it works

The patch is made up of a thin sheet of flexible, stretchable polymer that adheres to the skin. Embedded on the patch is an array of millimeter-sized ultrasound transducers. Each is individually controlled by a computer--this type of array is known as an ultrasound phased array. It is a key part of the technology because it gives the patch the ability to go deeper and wider.

The phased array offers two main modes of operation. In one mode, all the transducers can be synchronized to transmit ultrasound waves together, which produces a high-intensity ultrasound beam that focuses on one spot as deep as 14 centimeters in the body. In the other mode, the transducers can be programmed to transmit out of sync, which produces ultrasound beams that can be steered to different angles.

"With the phased array technology, we can manipulate the ultrasound beam in the way that we want," said Muyang Lin, a nanoengineering Ph.D. student at UC San Diego who is also a co-first author of the study. "This gives our device multiple capabilities: monitoring central organs as well as blood flow, with high resolution. This would not be possible using just one transducer."

The phased array consists of a 12 by 12 grid of ultrasound transducers. When electricity flows through the transducers, they vibrate and emit ultrasound waves that travel through the skin and deep into the body. When the ultrasound waves penetrate through a major blood vessel, they encounter movement from red blood cells flowing inside. This movement changes or shifts how the ultrasound waves echo back to the patch--an effect known as Doppler frequency shift. This shift in the reflected signals gets picked up by the patch and is used to create a visual recording of the blood flow. This same mechanism can also be used to create moving images of the heart's walls.

A potential game changer in the clinic

For many people, blood flow is not something that is measured during a regular visit to the physician. It is usually assessed after a patient shows some signs of cardiovascular problems, or if a patient is at high risk.

The standard blood flow exam itself can be time consuming and labor intensive. A trained technician presses a handheld ultrasound probe against a patient's skin and moves it from one area to another until it's directly above a major blood vessel. This may sound straightforward, but results can vary between tests and technicians.

Since the patch is simple to use, it could solve these problems, said Sai Zhou, a materials science and engineering Ph.D. student at UC San Diego and co-author of the study. "Just stick it on the skin, then read the signals. It's not operator dependent, and it poses no extra work or burden to the technicians, clinicians or patients," he said. "In the future, patients could wear something like this to do point of care or continuous at-home monitoring."

In tests, the patch performed as well as a commercial ultrasound probe used in the clinic. It accurately recorded blood flow in major blood vessels such as the carotid artery, which is an artery in the neck that supplies blood to the brain. Having the ability to monitor changes in this flow could, for example, help identify if a person is at risk for stroke well before the onset of symptoms.

The researchers point out that the patch still has a long way to go before it is ready for the clinic. Currently, it needs to be connected to a power source and benchtop machine in order to work. Xu's team is working on integrating all the electronics on the patch to make it wireless.

The University of Surrey has built an artificial intelligence (AI) model that identifies chemical compounds that promote healthy ageing - paving the way towards pharmaceutical innovations that extend a person's lifespan.

In a paper published by Nature Communication's Scientific Reports, a team of chemists from Surrey built a machine learning model based on the information from the DrugAge database to predict whether a compound can extend the life of Caenorhabditis elegans - a translucent worm that shares a similar metabolism to humans. The worm's shorter lifespan gave the researchers the opportunity to see the impact of the chemical compounds.

The AI singled out three compounds that have an 80 per cent chance of increasing the lifespan of elegans:

flavonoids (anti-oxidant pigments found in plants that promote cardiovascular health),

fatty acids (such as omega 3), and

Organooxygens (compounds that contain carbon to oxygen bonds, such as alcohol).

Sofia Kapsiani, co-author of the study and final year undergraduate student at the University of Surrey, said:

"Ageing is increasingly being recognised as a set of diseases in modern medicine, and we can apply the tools of the digital world, such as AI, to help slow down or protect against ageing and age-related diseases. Our study demonstrates the revolutionary ability of AI to aid the identification of compounds with anti-ageing properties."

Dr Brendan Howlin, lead author of the study and Senior Lecturer in Computational Chemistry at the University of Surrey, said:

"This research shows the power and potential of AI, which is a speciality of the University of Surrey, to drive significant benefits in human health."

As a fourth-generation cattle farmer, Jared Decker knows that cattle suffer from health and productivity issues when they are taken from one environment -- which the herd has spent generations adapting to -- to a place with a different climate, a different elevation or even different grass. But as a researcher at the University of Missouri, Decker also sees an opportunity to use science to solve this problem, both to improve the welfare of cattle and to plug a leak in a nearly $50 billion industry in the U.S.

"When I joined MU in 2013, I moved cattle from a family farm in New Mexico to my farm here in Missouri," said Decker, an associate professor and Wurdack Chair in Animal Genetics at the College of Agriculture, Food and Natural Resources. "New Mexico is hot and dry, and Missouri is also hot but has much more humidity. The cattle certainly didn't do as well as they did in New Mexico, and that spurred me to think about how we could give farmers more information about what their animals need to thrive."

In a new study published today in PLOS Genetics, Decker and his team have uncovered evidence showing that cattle are losing important environmental adaptations, losses the researchers attribute to a lack of genetic information available to farmers. After examining genetic material stretching back to the 1960s, they identified specific DNA variations associated with adaptations that could one day be used to create DNA tests for cattle -- tests that could tell farmers whether their cattle are suited for one environment or another.

"We can see that, for example, historically cows in Colorado are likely to have adaptations that ease the stress on their hearts at high altitudes," Decker said. "But if you bring in bulls or semen from a different environment, the frequency of those beneficial adaptations is going to decrease. Over generations, that cow herd will lose advantages that would have been very useful to a farmer in Colorado."

Decker's team, including then-doctoral student Troy Rowan, analyzed six decades worth of bovine DNA data from tests of cryo-preserved semen produced by cattle breed associations. They found that over time, while genes associated with higher productivity and fertility improved due to careful selection by farmers, many genes connected to environmental adaptations have faded.

Decker noted this is not the fault of farmers, given that there is currently no cost-effective genetic test they can use to determine whether their cattle are suitable for a particular environment. In other words, the study demonstrates a need for user-friendly cattle DNA tests that can look for the specific adaptations identified in the study. These adaptations include resistance to vasoconstriction -- a narrowing of the blood vessels that occurs at high elevations and puts undue stress on the heart -- resistance to a toxin in grass that can also cause vasoconstriction, and tolerance for high heat or humidity, all of which tend to recede over generations when cattle are removed from the associated environments.

"Sometimes, natural and artificial selection are moving in the same direction, and other times there is a tug of war between them," Decker said. "Efficiency and productivity have vastly improved in the last 60 years, but environmental stressors are never going to go away. Farmers need to know more about the genetic makeup of their herd, not only for the short-term success of their farm, but for the success of future generations."

The first broadly adopted genetic test for cattle was invented at the University of Missouri in 2007, and Decker and Rowan hope to tell the next chapter of that story. Both grew up on farms and share a passion for using research to help farmers balance America's farming traditions with the need for environmentally friendly business practices.

"As a society, we must produce food more sustainably and be good environmental stewards," Decker said. "Making sure a cow's genetics match their environment makes life better for cattle and helps farmers run efficient and productive operations. It's a win-win."

Having friends may not only be good for the health of your social life, but also for your actual health--if you're a hyena, that is. Strong social connections and greater maternal care early in life can influence molecular markers related to gene expression in DNA and future stress response, suggests a new University of Colorado Boulder study of spotted hyenas in the wild.

Researchers found that more social connection and maternal care during a hyena's cub and subadult, or "teenage," years corresponded with lower adult stress hormone levels and fewer modifications to DNA, including near genes involved in immune function, inflammation and aging. 

Published this week in Nature Communications, the study is one of the first to examine the association between early-life social environments and later effects on markers of health and stress response in wild animals.

"This study supports this idea that, yes, these early experiences do matter. They seem to have an effect at the molecular level and future stress response--and they're persistent," said lead author Zach Laubach, a postdoctoral fellow in ecology and evolutionary biology.

As far back as the 1950s and 60s, laboratory research has drawn associations between early life experiences in rodents, primates and humans and behavioral and physiological differences later in life. One landmark study published in 2004 also showed that the offspring of rats who got licked and groomed more by their mothers had less DNA methylation in a gene involved in regulating stress response. This kick-started the desire for more evidence that early life experiences could be related to patterns of modification in genes that influence stress and health.

One of the missing pieces in the past 20 years of research has been the ability to study this relationship in wild animals.

Enter the Masai Mara Hyena Project. Launched by co-authors Kay E. Holekamp and Laura Smale of Michigan State University in the 1980s, the project has collected more than 30 years of uninterrupted data on hyena populations in Maasai Mara National Reserve in Kenya. With this invaluable resource for studying animal behavior, evolution and conservation, the researchers have been able to utilize generations of data on individually known animals to draw connections between their interactions, behaviors and biological markers.

"Being able to measure behavior, physiology and molecular markers from the same population has allowed us to dig deeper into the possible mechanisms," said Laubach, who has been working with data from this project for nearly a decade.

Healthy stress response

Hyenas are ideal for such research as they are devoted mothers, have a strict social hierarchy and follow a consistent timeline for raising their cubs. Instead of giving birth to larger litters, they typically have one or two cubs at a time. Soon after birth, the cubs move into a communal den, where they are integrated into their peer group. For the next year, they still nurse and their mother licks and grooms them, but after that the cubs start to wander out of the den and, like teenagers, learn to start making their way in the world.

The researchers found that the more socially connected hyenas were during their teenage years, the lower their baseline stress hormone levels were later in life. This generally indicates a healthy stress response: Stress hormones can be elevated in an appropriate situation--like when being chased by a lion or a higher-ranking hyena--and when nothing's happening, levels of stress hormones remain low.

"So if you have more friends as a subadult, essentially, you have lower stress hormone levels as an adult," said Laubach. "This suggests that the type, timing and mechanisms that link these early life experiences with stress seem to be important not only in controlled laboratory settings but also in the wild, where animals are subject to natural variation."

In general, hyenas, like other vertebrates, benefit from the effects of stress hormones (e.g. cortisol) mobilizing energy, increasing their heart rate and shutting down non-essential functions, like digestion or reproduction, when escaping a dangerous situation. However, there are significant physical drawbacks to these processes occurring chronically, day after day in humans or other animals as the result of chronic stressors. That's why having a healthy stress response is so critical.

"We need these stress hormones because they are critical to a variety of basic biological functions," said Laubach. "And in the right context, like when escaping a predator, they can save your life. But when elevated chronically, these hormones can be detrimental to your health," said Laubach.

Time travel through DNA

The researchers also wanted to find out if the relationships between early life social experiences and how stress presents later in life is managed by molecular mechanisms.

To do this, Laubach and his co-authors measured and analyzed the level of care and interaction the animal received in early life and their associations with certain modifications to its DNA later in life. These modifications can, through a process known as DNA methylation, end up changing the expression of certain genes, which can in turn, affect an animal's physiology or behavior.

The researchers found that the maternal care hyenas received during their first year of life, as well as their social connections after den independence, corresponded to differences in DNA methylation levels.

"This echoes a growing body of epidemiological work which studies how the timing of an exposure affects a health outcome. The idea is that, as an organism develops, there are certain points in time, often referred to as sensitive periods, when an exposure has a larger and a more persistent effect than if that exposure occurred at a later point in time," said Laubach.

Most people can expect to break close to two bones in their lifetime, but those with osteogenesis imperfecta -- also known as brittle bone disease -- can break hundreds of bones before they even hit puberty. And while healthy bones can break from a hard fall or a bad car wreck, there may not be an apparent reason at all with brittle bone disease.

Classified as a rare disease, osteogenesis imperfecta, or OI, affects 6-7 people out of every 100,000 live births and can range in severity depending on the specific mutation. And while there are currently few treatment options and no cure, Meenal Mehrotra, M.D., Ph.D., and her lab recently published promising findings in the journal Stem Cells to address this knowledge gap.

Mehrotra, assistant professor in the department of pathology and laboratory medicine at MUSC Health and principal investigator on the paper, points to a mutation in the collagen gene as the major cause of the weak bones that come with OI. "Collagen is the matrix, or backbone, of our bones," said Mehrotra. "And when it's mutated, our bones become very brittle and break very easily."

In addition to building bones and holding them together, collagen is a protein found in blood vessels, organs, corneas and teeth, which means brittle bone disease can affect a person's eyesight and bone health and can even affect their hearing. Unfortunately, current treatment options focus on the symptoms of OI rather than the cause, and the medications in use can have long-term side effects.

For her study, Mehrotra went back to the beginning -- she looked at osteoblasts, the cells that produce collagen. "Mutated osteoblasts produce mutated collagen," she said. But if she can replace the osteoblasts, she can change the collagen produced and thus the bone that stems from it.

Osteoblasts and osteoclasts are critical to bone growth and remodeling. As a dynamic tissue with constant turnover, bone requires consistent communication between its cells. Osteoblasts form new bone, and osteoclasts reabsorb old or damaged bone; both functions are needed to keep bone strong. By replacing damaged or mutated osteoblasts with healthy ones, Mehrotra and her lab offer an option with a therapeutic promise. While current results show effectiveness in animal models, Mehrotra hopes to translate her results to people in the future.

Current dogma points to mesenchymal stem cells (MSCs) as the origin for osteoblasts, but MSC transplantation has not resulted in long-term success as a treatment option. Hematopoietic stem cells (HSCs) usually give rise to blood cells and osteoclasts, but Mehrotra hypothesized that they could give rise to osteoblasts too.

And that idea led her to investigate HSC transplantation in mice with brittle bone disease.

Not all biologists agree that HSCs can give rise to both blood cells and bone cells, so Mehrotra considers her hypothesis controversial. "There have been few studies on this topic in the past," she said. "It's not that people haven't speculated on this before, but so many scientists disagree each time it is discussed that it has not been studied in detail."

Mehrotra spent much of her paper detailing how she confirmed that only HSCs were responsible for the results of her study. Using a clonal population of HSCs from mice that expressed green fluorescent protein (GFP) only in their osteoblasts, Mehrotra and her lab conducted lineage tracing studies. These studies established hematopoietic stems cells as cells that can differentiate into osteoblasts, which then brought about clinical improvements in mice with OI.

This method of clonal HSC transplantation was developed by Mehrotra's mentor Makio Ogawa, M.D., Ph.D., who was a professor in the pathology department at MUSC Health before retiring. His method of ensuring that the clonal population was only of HSCs and did not contain any MSCs allowed Mehrotra to be confident in her results.

To transplant the characterized HSCs, Mehrotra's lab first irradiated the mice to remove their current bone marrow and make room for healthier cells. The new HSCs were then transplanted through an IV into the mice, where they gave rise to collagen-producing osteoblasts. Mehrotra found that this process replaced about 20 to 40% of osteoblasts in the long bones of the mice, which is higher than percentages seen with MSC transplantation and thus shows long-term success.

"We think this has potential as a curative therapy," Mehrotra said. "By replacing the abnormal osteoblasts with normal ones that can then secrete normal collagen, we're aiming for a therapy that could result in an actual cure."

More research is needed before the technique can become a therapeutic option for patients, but Mehrotra says this is a promising start. By replacing osteoblasts, she offers a therapeutic opportunity that is not dependent on a specific mutation but simply on a mutation being present, which means it could potentially be translated to other forms of OI and other bone diseases in the future.

Mehrotra hopes to study HSC transplantation as an auto-transplantation strategy moving forward. There are two significant forms of transplantation: auto-transplantation and allotransplantation. In auto-transplantation, cells or organs are removed from one person and then transplanted back into that same person. In allotransplantation, the cells or organs come from another person, which carries the risk of rejection or graft-versus-host disease. Mehrotra proposes that by using CRISPR-Cas9 technology, scientists can correct the collagen mutation in the OI patient's HSCs, before transplanting these corrected HSCs back into the same patient's system, where they can form normal, collagen-producing osteoblasts.

By performing this study, Mehrotra addresses the controversy surrounding the potential of HSCs giving rise to osteoblasts. She hopes more researchers will consider the promise of hematopoietic stem cells in bone diseases, and she hopes to continue to help patients with such debilitating bone diseases like OI lead a higher quality of life.

The research was supported by the National Institutes of Health.

Cambridge, MA ¬- Astronomers at the Center for Astrophysics | Harvard & Smithsonian have helped detect the clear presence of a moon-forming region around an exoplanet -- a planet outside of our Solar System. The new observations, published Thursday in The Astrophysical Journal Letters, may shed light on how moons and planets form in young stellar systems.

The detected region is known as a circumplanetary disk, a ring-shaped area surrounding a planet where moons and other satellites may form. The observed disk surrounds exoplanet PDS 70c, one of two giant, Jupiter-like planets orbiting a star nearly 400 light-years away. Astronomers had found hints of a "moon-forming" disk around this exoplanet before but since they could not clearly tell the disk apart from its surrounding environment, they could not confirm its detection -- until now.

"Our work presents a clear detection of a disk in which satellites could be forming," says Myriam Benisty, a researcher at the University of Grenoble and the University of Chile who led the research using the Atacama Large Millimetre/submillimetre Array (ALMA). "Our ALMA observations were obtained at such exquisite resolution that we could clearly identify that the disk is associated with the planet and we are able to constrain its size for the first time."

With the help of ALMA, Benisty and the team found the disk diameter is comparable to the Sun-to-Earth distance and has enough mass to form up to three satellites the size of the Moon.

"We used the millimeter emission from cool dust grains to estimate how much mass is in the disk and therefore, the potential reservoir for forming a satellite system around PDS 70c," says Sean Andrews, a study co-author and astronomer at the Center for Astrophysics (CfA).

The results are key to finding out how moons arise.

Planets form in dusty disks around young stars, carving out cavities as they gobble up material from this circumstellar disc to grow. In this process, a planet can acquire its own circumplanetary disk, which contributes to the growth of the planet by regulating the amount of material falling onto it. At the same time, the gas and dust in the circumplanetary disk can come together into progressively larger bodies through multiple collisions, ultimately leading to the birth of moons.

But astronomers do not yet fully understand the details of these processes. "In short, it is still unclear when, where, and how planets and moons form," explains ESO Research Fellow Stefano Facchini, also involved in the research.

"More than 4,000 exoplanets have been found until now, but all of them were detected in mature systems. PDS 70b and PDS 70c, which form a system reminiscent of the Jupiter-Saturn pair, are the only two exoplanets detected so far that are still in the process of being formed," explains Miriam Keppler, researcher at the Max Planck Institute for Astronomy in Germany and one of the co-authors of the study.

"This system therefore offers us a unique opportunity to observe and study the processes of planet and satellite formation," Facchini adds.

PDS 70b and PDS 70c, the two planets making up the system, were first discovered using ESO's Very Large Telescope (VLT) in 2018 and 2019 respectively, and their unique nature means they have been observed with other telescopes and instruments many times since.

These latest high resolution ALMA observations have now allowed astronomers to gain further insights into the system. In addition to confirming the detection of the circumplanetary disk around PDS 70c and studying its size and mass, they found that PDS 70b does not show clear evidence of such a disk, indicating that it was starved of dust material from its birth environment by PDS 70c.

An even deeper understanding of the planetary system will be achieved with ESO's Extremely Large Telescope (ELT), currently under construction on Cerro Armazones in the Chilean Atacama desert.

"The ELT will be key for this research since, with its much higher resolution, we will be able to map the system in great detail," says co-author Richard Teague, a co-author and Submillimeter Array (SMA) fellow at the CfA.

In particular, by using the ELT's Mid-infrared ELT Imager and Spectrograph (METIS), the team will be able to look at the gas motions surrounding PDS 70c to get a full 3D picture of the system.

Adults and children with COVID-19 who have a history of malnutrition may have an increased likelihood of death and the need for mechanical ventilation, according to a study published in Scientific Reports.

Malnutrition hampers the proper functioning of the immune system and is known to increase the risk of severe infections for other viruses, but the potential long-term effects of malnutrition on COVID-19 outcomes are less clear.

Louis Ehwerhemuepha and colleagues investigated associations between malnutrition diagnoses and subsequent COVID-19 severity, using medical records for 8,604 children and 94,495 adults (older than 18 years) who were hospitalised with COVID-19 in the United States between March and June 2020. Patients with a diagnosis of malnutrition between 2015 and 2019 were compared to patients without.

Of 520 (6%) children with severe COVID-19, 39 (7.5%) had a previous diagnosis of malnutrition, compared to 125 (1.5%) of 7,959 (98.45%) children with mild COVID-19. Of 11,423 (11%) adults with severe COVID-19, 453 (4%) had a previous diagnosis of malnutrition, compared to 1,557 (1.8%) of 81,515 (98.13%) adults with mild COVID-19.

Children older than five and adults aged 18 to 78 years with previous diagnoses of malnutrition were found to have higher odds of severe COVID-19 than those with no history of malnutrition in the same age groups. Children younger than five and adults aged 79 or above were found to have higher odds of severe COVID-19 if they were not malnourished compared to those of the same age who were malnourished. In children, this may be due to having less medical data for those under five, according to the authors. The risk of severe COVID-19 in adults with and without malnutrition continued to rise with age above 79 years.

The authors suggest that public health interventions for those at highest risk of malnutrition may help mitigate the higher likelihood of severe COVID-19 in this group.

Leesburg, VA, July 22, 2021--According to ARRS' American Journal of Roentgenology (AJR), the standardized non-invasive clear cell likelihood score (ccLS)--derived from MRI--correlates with the growth rate of small renal masses (cT1a,

Extracted from clinical reports, "the ccLS scores the likelihood that the small renal mass represents clear cell renal cell carcinoma, from 1 (very unlikely) to 5 (very likely)," explained corresponding author Ivan Pedrosa from the University of Texas Southwestern Medical Center at Dallas. "Small renal masses with lower ccLS may be considered for active surveillance, whereas small renal masses with higher ccLS may warrant earlier intervention."

Pedrosa and colleagues' retrospective study included consecutive small renal masses assigned a ccLS on clinical MRI examinations performed between June 2016 and November 2019 at an academic tertiary-care medical center or its affiliated safety net hospital system. Tumor size measurements were extracted from available prior and follow-up cross-sectional imaging examinations, through June 2020.

Among 389 small renal masses in 339 patients (198 men, 141 women; median age, 65 years) on active surveillance that were assigned a ccLS on clinical MRI examinations, those with ccLS4-5 grew significantly faster (9% diameter, 29% volume yearly) than those with ccLS1-2 (5% diameter, p

Noting that the lack of validated imaging markers to characterize biologic aggressiveness of small renal masses hinders medical decision making among available initial management strategies, "growth is associated with ccLS in small renal masses," the authors of this AJR article reiterated, "with higher ccLS correlating with faster growth."