Culture

Why is it that some chronic inflammatory bowel diseases, such as Crohn's, affect both the small intestine and the colon, while others, like ulcerative colitis, are restricted to the colon? In order to solve clinical puzzles such as this one, among others, researchers from the University of Würzburg created miniature versions of the digestive tract in the lab. One of their discoveries: the digestive tract contains an inherent segmentation that could shed new light onto these common inflammatory conditions.

Scientists are now able to generate miniature versions of practically any organ of our bodies - including skin, brain and intestine. These three-dimensional structures are generated from stem cells and are called "organoids".

With a diameter of around 0.5 millimeter, organoids may only be the size of a grain of mustard, but they show a remarkable similarity to the real organs. "Despite their miniscule size, organoids simulate the organ they are derived from extremely well" says Dr. Sina Bartfeld, who led the study at the Research Center for Infectious Diseases at the Institute for Molecular Infection Biology. "Organoids contain the same types of cells as the real organ. The stem cells from which the organoids are generated contain a kind of pre-programmed tissue identity. The stem cell "knows" which organ it comes from and even in culture it produces the kinds of cells that are present in this organ in our bodies." In collaboration with surgeon Armin Wiegering from the University Hospital of Würzburg, Dr. Bartfeld's team generated organoids from stomach, small intestine and colon. They discovered an unexpectedly large molecular complexity, as revealed by RNA sequencing, which reflects the gene activity of the cells.

One of their findings was that organoids from the different segments of the digestive tract switch on specific gene-programs, depending on their tissue identity. "It's intuitive that gastric and intestinal cells have to produce different digestive enzymes - but we were surprised to discover that particular binding sites of the immune system are also part of this tissue identity", says Bartfeld.

The particular organization of the immune binding sites may play a role in the organ-specific inflammatory diseases. It could even be relevant for the development of cancer, where chronic inflammation has also been implicated. Whether this is the case and how inflammation could contribute to carcinogenesis requires further research, for which organoids form a novel basis.

Not only can organoids be generated rapidly and in large numbers in the laboratory, they have the added advantage that they consist of human tissue and form an approximate representation of a human organ. Since there are substantial differences between humans and animals, organoids can help to reduce animal experiments and illuminate uniquely human diseases. They also play an increasingly important role in drug development.

Organoids demonstrate the amazing organization of the gut - also regarding the recognition of bacteria and viruses

In addition, organoids open up entirely new ways of investigating basic molecular processes in a biologically realistic model - such as the digestive system, which is also the focus of Dr. Bartfeld's research team in Würzburg. The epithelial cells that line our digestive tract have an important barrier function, which prevents bacteria from entering our bodies. These could be pathogens, such as disease-causing bacteria or viruses.

At the same time, the intestine is colonized by billions of beneficial bacteria, the so-called microbiota, which help us to digest food. The epithelial cells thus have to be able to sense both friendly and hostile bacteria or viruses and respond appropriately. This is accomplished via special immune binding sites, called pattern recognition receptors.

These receptors recognize specific molecules produced by the different bacteria in the intestine. If the epithelial cells recognize molecules produced by dangerous pathogens, as opposed to beneficial bacteria, they have to raise the alarm and induce an immune response. So far it was unclear how the epithelium is able to differentiate between friend and foe. "It is extremely difficult to untangle the complex interaction between immune cells, epithelial cells and microbes" so Dr. Bartfeld. "However, since our organoids contain only epithelial cells, we can use them to specifically investigate the contribution of the epithelium in this interaction."

During their study, the scientists discovered that each pattern recognition receptor has its own, segment-specific gene activity pattern. "The stomach as well as each segment of the intestine has its own specific repertoire of pattern recognition receptors" explains Özge Kayisoglu, first author of the study. "Thus, the immune response of the epithelium is location-specific. In this way, the stomach reacts to different bacterial compounds than the small intestine or the colon." These differences in the immune response may contribute to segment-specific diseases like ulcerative colitis or Crohn's disease.

What induces this differential reaction to bacterial compounds? Initially, the obvious assumption was that the immune receptors are regulated in response to colonization with beneficial bacteria. To test this hypothesis, the researchers generated organoids that had never come into contact with bacteria. "The data showed that the microbiota does have an effect - but we were surprised to find that in large part, immune recognition of the epithelium is in fact genetically determined during development and independent of the environment," says Bartfeld.

Collectively, their findings represent an important step in illuminating inflammatory processes. They show that each section of the digestive tract has its own specific combination of immune recognition receptors. Dysfunctions of this innate immunity may promote the development of inflammatory diseases.

Obese people among black and minority ethnic communities (BME) are at around two times higher the risk of contracting COVID-19 than white Europeans, a study conducted by a team of Leicester researchers has found.

Previous research has shown that ethnicity can alter the association between the body mass index (BMI) and cardiometabolic health so the researchers wanted to explore whether a person's weight could change the relative risk of COVID-19 across ethnic groups.

Emerging COVID-19 evidence has found that South Asian and black, African or Caribbean populations are at a higher risk of becoming seriously unwell with the condition. In addition, a link with obesity has also been found.

The research team drew expertise from the University of Leicester's Diabetes Research Centre, the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) and the NIHR Applied Research Collaboration (ARC) East Midlands.

The researchers accessed the UK Biobank - a national database of more than 500,000 people who had their health information recorded between March 2006 and July 2010. These individuals had their health records cross-referenced to a national COVID-19 laboratory test data bank between the period of March 16 and June 14, 2020. Of that cohort, 5,623 unique test results were available.

The information helped the research team to quantify the association of BMI with the risk of a positive test for COVID-19, broken down by ethnic group.

According to the results, the greater risk of COVID-19 in BME people relative to white Europeans was only apparent at higher BMI values. For example, at a BMI value of 25 kg/m2, there was no difference in risk, whereas at a BMI of 30 kg/m2 the risk of COVID-19 was nearly twice as high (1.75) and at 35 kg/m2 more than two and a half times higher (2.76) in BME individuals relative to white Europeans.

Cameron Razieh, a PhD student at the University of Leicester, concluded: "Although limited by non-random testing for COVID-19 within the UK, this data suggests that the association between BMI and the risk of COVID-19 may vary by ethnicity and acts as an important effect modifier for the increased risk of COVID-19 in BME populations. These results suggest that the combination of obesity and BME status may place individuals at particularly high-risk of contracting COVID-19, which is consistent with findings for associations of BMI and ethnicity with cardiometabolic dysfunction."

One of the researchers, Professor Kamlesh Khunti, Director of ARC East Midlands and Professor of Primary Care, Diabetes and Vascular Medicine at the University of Leicester, said: "COVID-19 has caused so much death and misery, devastated global economies and put unprecedented strain on clinical services, but despite the worldwide impact this virus has had, we still know very little about it.

"There's still so much we need to understand about the condition, but our latest findings suggest the association between BMI and the risk of COVID-19 may vary by ethnicity.

"That means the combination of obesity and BME status may place individuals at a significantly higher-risk of contracting COVID-19, which is consistent with other studies that have previously linked BMI and ethnicity with cardiometabolic dysfunction."

Co- lead author, Professor Thomas Yates, Professor of Physical Activity and Health at the University of Leicester, said: "The role of obesity as risk factor for chronic disease is well established, however we need more research to understand its role as a risk factor for the COVID-19 pandemic and how this affects different populations."

Another of the authors, Professor Melanie Davies CBE, Professor of Diabetes Medicine at the University of Leicester, who is also the Director of the Leicester BRC, said: "Knowledge is power and if we are to have any hope of beating this pandemic, we need to gain as much information about COVID-19 as we possibly can.

"Our research has given us more insight into who is at more risk from being infected and we now need to come together as one to help protect our BME communities, keeping them safe from this devastating virus."

ARC East Midlands funds vital work to tackle the region's health and care priorities by speeding up the adoption of research onto the frontline of health and social care. The organisation puts in place evidence-based frameworks to drive up standards of care and save time and money.

The Centre for BME Health, led by Professor Khunti, and funded by the ARC East Midlands and the University of Leicester, has led a campaign to increase the number of BME people involved in research relating to coronavirus in a bid to address the disproportionate impact on BME communities. Celebrities including Omid Dajlili and Whoopi Goldberg have got behind the campaign.

Citizen science could help track progress towards all 17 UN Sustainable Development Goals (SDGs). An IIASA-led study, for the first time, comprehensively analyzed the current and potential contribution of citizen science data to monitor the SDGs at the indicator level.

Huge amounts of accurate, timely, and comprehensive data are required to track progress towards the SDGs. The 17 goals set by the UN in 2015 currently include 169 targets and 231 unique indicators that are defined in an evolving framework. However, many of these indicators lack sufficient data to regularly track progress. Citizen science can help to close this data gap. According to new research published in Sustainability Science, citizen science has the potential to provide data to track one third of all SDG indicators. The study included a systematic review of all SDG indicators and mapped past and ongoing citizen science initiatives that could directly or indirectly provide data for SDG monitoring.

Most citizen science initiatives engage members of the public to contribute observations of nature at global, regional, national or local levels, so unsurprisingly, the greatest potential for input was shown to be for the environmental SDG indicators. This is particularly encouraging as, according to the United Nations Environment Programme (UNEP), 68% of environment-related indicators lack data.

"Without new ways of monitoring, such as citizen science, we will never be able to achieve global monitoring of the SDG framework, as traditional means of data collection are too expensive to cover all 231 indicators on a regular, geospatially representative basis," explains UNEP Statistician, Jillian Campbell.

Indicators that were shown to align well with citizen science approaches included those that could be supported by spatial data, such as monitoring of water or air quality, disease threats, post disaster damage assessment, and open spaces in cities.

"The most remarkable finding from this review process is that citizen science has the potential to contribute to all 17 SDGs, since it is already directly or indirectly contributing, or could contribute to at least one indicator per goal. For example, indicators that could be supported by self-reporting such as sexual violence or perceptions of safety, align well with data already being collected by some citizen science initiatives. These findings are generating interest and our results have been presented to the Inter-agency and Expert Group on SDG Indicators that is responsible for developing and implementing the global indicator framework for the SDGs and targets," says IIASA researcher and study lead author, Dilek Fraisl.

The researchers demonstrate that while citizen science data cannot replace, nor compensate for all the limitations of traditional data sources, there is great potential for new data sources to complement the traditional sources, such as the census, household surveys, and administrative records that are currently used to monitor progress on the SDGs. In many cases, citizen science initiatives are already established and only require varying degrees of modification, opening out, and collaboration to bring their approaches and tools to the table.

Examples from the study of how citizen science could contribute to SDG monitoring are the Picture Pile tool developed at IIASA and the Humanitarian OpenStreetMap for the SDG indicator on "direct economic loss attributed to a disaster". Picture Pile requires volunteers to classify satellite images to identify damaged buildings after a disaster. It is designed as a flexible tool that can also be used for monitoring SDG indicators related to poverty, food security, ecosystem health, and deforestation, among others. In the Humanitarian OpenStreetMap application, participants digitize the areas affected by disasters, which includes identifying damaged roads for disaster responders to reach those in need. Researchers can then apply maximum damage functions to the mapped areas to calculate some of the direct economic losses due to a disaster.

The study also showed that citizen science was introduced successfully as part of the reporting and monitoring process for the indicator on marine litter that initially had no established methodology and standards available to support it. The methodology of this indicator currently suggests citizen science as a primary source of data for monitoring marine litter.

The researchers highlight that realizing the full potential of citizen science will require demonstrating its value in the global data ecosystem, building partnerships around citizen science data to accelerate SDG progress, and encouraging investment to enhance its use and impact.

Okazaki, Japan - Human noroviruses are a major cause of gastroenteritis outbreaks worldwide. They cause approximately 200,000 deaths each year in developing countries. However, no effective vaccine or antiviral agent for noroviruses yet exists because cell culture methods to produce noroviruses are very limited and there is a lack of the viral structural knowledge about the virus.

In this study, the researchers have investigated the mouse norovirus structures using cryo-electron microscopy and discovered that the noroviruses present two alternative capsid structures (type A and type B) (Fig. 1 top). Noroviruses are covered by two layered proteinaceous domains, an outer protruding (P) domain and an inner shell (S) domain. Type A shows tight interaction between the two domains, with no space between them, while type B displays the P domain dislocated above the S domain with a space between them. This result has raised the questions, "How do these capsid structures switch?" and "Why do noroviruses need two capsid structures?".

Further investigations showed that the two structures of mouse norovirus particles switch depending on aqueous conditions. Viral particles showed the type A structure in lower pH solutions including metal ions, while type B structure was favored in higher pH solutions lacking metal ions. Type A was formed by rotation and shrinkage of the P domain and stabilized with an interaction between neighbors at the upper part, while type B was formed by the reverse rotation and extension of the P domain and stabilized with an interaction between neighbors at the lower part (Fig 1 middle).

Mouse noroviruses showing two structures were individually infected into cultured cells. Type B particles showed four hours delay of propagation comparing to type A particles (Fig. 1 bottom). Another experiment found that type B particles showed less adsorption to host cell surface than type A particles. It was concluded that mouse noroviruses change their structure from B to A before infection.

"Why do noroviruses need two structures?" This has not been clarified, but the researchers speculate that it is used to evade the host animal's immune system. Noroviruses are transmitted primarily through the oral route, and infect cells of the small intestine. Noroviruses may evade the immune system with the type B structure, and approach the small intestine. Then, they finally infect cells by changing to the type A structure (Fig. 2).

The research reveals a part of viral structural change and infection mechanism of mouse noroviruses. Two capsid structures were also identified in the human norovirus VLP, but it has not elucidated the switching mechanism of the structure yet. It is hypothesized that a similar mechanism is also used in human norovirus. Further investigation will clarify the switching mechanism of the structure and infection manner of human norovirus, hopefully assisting development of therapeutic drugs and vaccines in the future.

A surge in use of online sports betting platforms, and promotional tactics such as free bets to hook users in, pose a significant and growing public health challenge which needs urgent attention from policymakers, according to the author of a new academic study.

Writing in the Journal of Public Health, Dr Darragh McGee from the University of Bath highlights how a normalisation of online sports betting over recent years has had detrimental impacts on the lives of young adult men.

His analysis describes a 'gamblification of sports' - whereby new mobile app technologies and a liberalisation of regulations surrounding sports advertising have combined to broaden the appeal and entry-point of gambling. This has been promoted as something for sports fans to 'enjoy' alongside watching football, horse racing and an array of other sports, he explains.

Drawing on in-depth interviews carried out with 32 young men aged 18-35 engaged in online betting to some degree, four main themes emerge from his research:

* Gambling has become a normalised aspect of being a sports fan for young men, many of whom increasingly view the casual wagering of money as vital to their enjoyment of sport. For Callum (27), interviewed as part of the research:

"Gambling has ruined sport because you can't watch it without thinking 'I should put a fiver on first goal'. All my mates can't watch it without having a bet anymore. When I was younger, I couldn't wait to get home from school to see Man United playing in the Champions League ... Now, I'm sat there thinking about what I should be betting on tonight. I can't remember the last time that I just watched the game like a real fan."

* A perceived 'facelessness' of sports gambling platforms via mobile apps has increased people's inclination to engage in online betting. This represents a distinct shift from an era when individuals had to go to a bookies' / betting shop to gamble on sports. Joseph (26) explained:

"Why would you walk across the street when it's all on your phone? It was so easy to pick up my phone and get going."

* 'Free bet' incentives and in-play promotions have played a significant role in enticing more people into online sports betting. Josh (23) said:

"It entices people in, definitely. And it encourages you to think bigger. Bet 365 were doing a 100% match bonus if you deposit £200. All of a sudden you think you have £400 credit to wager with. And you have to wager a certain number of times, but the offer has drawn you in by the time you realise."

* Online sports gambling acts as a slippery slope to other gambling-related harms, including financial precarity, indebtedness, mortgage defaults, which in turn and in some cases is resulting in loss of employment, mental health struggles and family breakdowns. Tom (31) explained:

"I'm in debt to my eyeballs from payday loans. I'm blacklisted with them all. I'm in about £15,000 of debt just from them alone. All for gambling. It took over my life for a while. When my daughter was born, I used to sit on the computer continuous gambling for the day."

The study, which was carried out in Bristol (England) and Derry (Northern Ireland), comprised three phases of data collection: participatory focus groups, a 30-day gambling diary and semi-structured interviews.

Dr Darragh McGee from Bath's Department for Health explains: "This study examined how the growth of online sports gambling has impacted on perceptions of, and participation in, gambling practices among young adult men in the UK.

"It clearly highlights how the exponential growth of online sports gambling has wider social, economic and public health impacts beyond young men's leisure activities, with revealing and distressing insights from those involved in online gambling on a daily basis.

"And while the COVID-19 pandemic brought the sports gambling market to a temporary halt, the record-breaking viewing figures since the resumption of live sport in recent weeks may well have exacerbated its detrimental impacts for many young men."

"We urgently need to reframe debates around sports gambling, to recognise it as a public health issue that holds significant implications for individual, family and community wellbeing."

Reflecting on recent initiatives, including the remote gambling association's 'whistle-to-whistle' ban on adverts during coverage he adds: "It is paramount that reformatory interventions are developed independently of those companies or organisations who hold a commercial interest in the promotion of gambling products.

"Greater accountability should also be asked of key stakeholders within sport, including clubs, athletes, league associations and event organisers who benefit from revenue streams provided by gambling operators without due consideration for the public health implications on their fan base."

His conclusion highlights Luton Town FC's decision to reject gambling sponsorship and Everton FC ending of their partnership with SportPesa two years early as important ethical precedents for sporting organisations and athletes to follow in reviewing their sponsorship agreements with gambling operators.

Dr McGee, who is one of BBC Radio 3 - AHRC's New Generation Thinkers focusing on this topic, is now expanding this work by shining light on the increasingly global nature of the sports gambling market, the study inspired a new project, recently funded under the British Academy and Global Challenges Research Fund (GCRF) Youth Futures programme.

New UCLA research conducted in mice could explain why some people suffer more extensive scarring than others after a heart attack. The study, published in the journal Cell, reveals that a protein known as type 5 collagen plays a critical role in regulating the size of scar tissue in the heart.

Once formed, heart scar tissue remains for life, reducing the heart's ability to pump blood and adding strain to the remaining heart muscle. People who develop larger scars have a higher risk of heart rhythm problems, heart failure and sudden cardiac death.

"Two individuals with the same degree of heart attack can end up with different amounts of scar tissue," said Dr. Arjun Deb, the study's senior author and a member of Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "Given the clear correlation between scar size and survival rates, we set out to understand why some hearts scar more than others. If we can reduce this scarring, we can greatly improve survival."

Following a heart attack, connective tissue cells called fibroblasts secrete a variety of proteins that combine to form scar tissue. The vast majority of these proteins are collagens, of which there are 26 types, all functioning as a kind of glue that holds the body together.

Type 1 and 3 collagens are abundant in the uninjured heart and also make up about 97% of scar tissue. Interestingly, Deb's team observed that several collagens not found in the uninjured heart were abundant in scar tissue. Among this group, type 5 collagen stood out.

To determine the role this collagen plays in scarring, the researchers genetically engineered a mouse model that was incapable of producing type 5 collagen in scar tissue following a heart injury. The results were surprising.

"Normally if you delete a collagen, you would expect the scar tissue size to decrease because collagen forms scar tissue. We found, paradoxically, that the scar size actually increased by 50%," said Deb, who is a professor of medicine in the division of cardiology at the David Geffen School of Medicine at UCLA and director of the school's cardiovascular medicine research theme.

Digging deeper, Deb and his collaborators from the Geffen School of Medicine, the California NanoSystems Institute at UCLA and the UCLA Division of Life Sciences found that type 5 collagen was regulating the stiffness of scar tissue. Without it, the scar tissue was less stiff and therefore prone to expansion from the force of the blood within the heart.

"Scar tissue without type 5 collagen is compliant like rubber," Deb said. "So when the heart fills with blood, the scar tissue expands in much the same way as a rubber balloon expands when it is filled with air."

This expansion, the team observed, was only the beginning. The protein-secreting fibroblasts are alerted to the scar's expansion by their integrins, receptors found within the cell membrane that sense changes to the environment and send signals inward to adjust how the cell is behaving in response to these changes. The fibroblasts consequently secrete more proteins in an attempt to reinforce the scar and stop the expansion. But without type 5 collagen, Deb noted, the cycle of expansion and scar growth simply continues.

To stop the cycle, Deb tested a drug called Cilengitide that disrupts integrin signaling. Developed as a cancer treatment, the drug was found to be safe for use in humans in a phase 3 clinical trial. The team found that treating the type 5 collagen-deficient mice with Cilengitide disrupted this feedback cycle and reduced scar size.

Subtle expression differences in type 5 collagen could explain why some heart attack survivors form larger scars than others, said Deb, who is also a professor of molecular, cell and developmental biology.

He is now working to develop a test that would identify people whose bodies produce less type 5 collagen. It is possible that such a test could one day be used in a precision medicine approach aimed at people who may be prone to increased scarring from heart attacks and could benefit from drugs such as Cilengitide.

Deb's team is also collaborating with physicians and scientists from the division of dermatology at the Geffen School of Medicine to pursue a potential immediate clinical application for people with Ehlers-Danlos syndrome, a connective tissue disorder characterized by excessive scarring, even from minor injuries, due to mutations in the gene that produces type 5 collagen.

The use of Cilengitide has not been tested in humans as a treatment for excessive scarring and has not been approved by the Food and Drug Administration as safe and effective for this use. The newly identified method for treating dysregulated wound healing is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California.

Caecilians are limbless amphibians that, to the untrained eye, can be easily mistaken for snakes. Though caecilians are only distantly related to their reptilian cousins, researchers in a study appearing July 3 in the journal iScience describe specialized glands found along the teeth of the ringed caecilian (Siphonops annulatus), which have the same biological origin and possibly similar function to the venom glands of snakes. If further research can confirm that the glands contain venom, caecilians may represent the oldest land-dwelling vertebrate animal with oral venom glands.

Caecilians are peculiar creatures, being nearly blind and using a combination of facial tentacles and slime to navigate their underground tunnels. "These animals produce two types of secretions--one is found mostly in the tail that is poisonous, while the head produces a mucus to help with crawling through the earth," says senior author Carlos Jared, a biologist and Director of the Structural Biology Lab at the Butantan Institute in São Paulo. "Because caecilians are one of the least-studied vertebrates, their biology is a black box full of surprises."

"It is while examining the mucous glands of the ringed caecilian that I stumbled upon a never before described set of glands closer to the teeth," says first author Pedro Luiz Mailho-Fontana, a post-doctoral student in the Structural Biology Lab at the Butantan Institute.

What Mailho-Fontana found were a series of small fluid-filled glands in the upper and lower jaw, with long ducts that opened at the base of each tooth. Using embryonic analysis, he found that these oral glands originated from a different tissue than the slime and poison glands found in the caecilian's skin. "The poisonous skin glands of the ringed caecilian form from the epidermis, but these oral glands develop from the dental tissue, and this is the same developmental origin we find in the venom glands of reptiles," says Mailho-Fontana. This marks the first time glands of this kind have been found in an amphibian.

Researchers suspect that the ringed caecilian may use the secretions from these snake-like oral glands to incapacitate its prey. "Since caecilians have no arms or legs, the mouth is the only tool they have to hunt," says co-author Marta Maria Antoniazzi, an evolutionary biologist at the Butantan Institute. "We believe they activate their oral glands the moment they bite down, and specialized biomolecules are incorporated into their secretions.

A preliminary chemical analysis of the oral gland secretions of the ringed caecilian found high activity of phospholipase A2, a common protein found in the toxins of venomous animals. "The phospholipase A2 protein is uncommon in non-venomous species, but we do find it in the venom of bees, wasps, and many kinds of reptiles," says Mailho-Fontana. In fact, the biological activity of phospholipase A2 found in the ringed caecilian was higher than what is found in some rattlesnakes. Still, more biochemical analysis is needed to confirm whether the glandular secretions are toxic.

If future work can verify the secretions are toxic, caecilian oral glands could indicate an early evolutionary design of oral venom organs. "Unlike snakes which have few glands with a large bank of venom, the ringed caecilian has many small glands with minor amounts of fluid. Perhaps caecilians represent a more primitive form of venom gland evolution. Snakes appeared in the Cretaceous probably 100 million years ago, but caecilians are far older, being roughly 250 million years old," Jared says.

Very few groups of land-dwelling vertebrates have serpent-like bodies, and this research suggests there might be a connection between a limbless body plan and the evolution of a venomous bite. "For snakes and caecilians, the head is the sole unit to explore the environment, to fight, to eat, and to kill," says Antoniazzi. "One theory is that perhaps these necessities encourage the evolution of venom in limbless animals."

Figuring out how much energy permeates the center of the Milky Way--a discovery reported in the July 3 edition of the journal Science Advances--could yield new clues to the fundamental source of our galaxy's power, said L. Matthew Haffner of Embry-Riddle Aeronautical University.

The Milky Way's nucleus thrums with hydrogen that has been ionized, or stripped of its electrons so that it is highly energized, said Haffner, assistant professor of physics & astronomy at Embry-Riddle and co-author of the Science Advances paper. "Without an ongoing source of energy, free electrons usually find each other and recombine to return to a neutral state in a relatively short amount of time," he explained. "Being able to see ionized gas in new ways should help us discover the kinds of sources that could be responsible for keeping all that gas energized."

University of Wisconsin-Madison graduate student Dhanesh Krishnarao ("DK"), lead author of the Science Advances paper, collaborated with Haffner and UW-Whitewater Professor Bob Benjamin--a leading expert on the structure of stars and gas in the Milky Way. Before joining Embry-Riddle in 2018, Haffner worked as a research scientist for 20 years at UW, and he continues to serve as principal investigator for the Wisconsin H-Alpha Mapper, or WHAM, a telescope based in Chile that was used for the team's latest study.

To determine the amount of energy or radiation at the center of the Milky Way, the researchers had to peer through a kind of tattered dust cover. Packed with more than 200 billion stars, the Milky Way also harbors dark patches of interstellar dust and gas. Benjamin was taking a look at two decades' worth of WHAM data when he spotted a scientific red flag--a peculiar shape poking out of the Milky Way's dark, dusty center. The oddity was ionized hydrogen gas, which appears red when captured through the sensitive WHAM telescope, and it was moving in the direction of Earth.

The position of the feature--known to scientists as the "Tilted Disk" because it looks tilted compared with the rest of the Milky Way--couldn't be explained by known physical phenomena such as galactic rotation. The team had a rare opportunity to study the protruding Tilted Disk, liberated from its usual patchy dust cover, by using optical light. Usually, the Tilted Disk must be studied with infrared or radio light techniques, which allow researchers to make observations through the dust, but limit their ability to learn more about ionized gas.

"Being able to make these measurements in optical light allowed us to compare the nucleus of the Milky Way to other galaxies much more easily," Haffner said. "Many past studies have measured the quantity and quality of ionized gas from the centers of thousands of spiral galaxies throughout the universe. For the first time, we were able to directly compare measurements from our Galaxy to that large population."

Krishnarao leveraged an existing model to try and predict how much ionized gas should be in the emitting region that had caught Benjamin's eye. Raw data from the WHAM telescope allowed him to refine his predictions until the team had an accurate 3-D picture of the structure. Comparing other colors of visible light from hydrogen, nitrogen and oxygen within the structure gave researchers further clues to its composition and properties.

At least 48 percent of the hydrogen gas in the Tilted Disk at the center of the Milky Way has been ionized by an unknown source, the team reported. "The Milky Way can now be used to better understand its nature," Krishnarao said.

The gaseous, ionized structure changes as it moves away from the Milky Way's center, researchers reported. Previously, scientists only knew about the neutral (non-ionized) gas located in that region.

"Close to the nucleus of the Milky Way," Krishnarao explained, "gas is ionized by newly forming stars, but as you move further away from the center, things get more extreme, and the gas becomes similar to a class of galaxies called LINERs, or low ionization (nuclear) emission regions."

The structure appeared to be moving toward Earth because it was on an elliptical orbit interior to the Milky Way's spiral arms, researchers found.

LINER-type galaxies such as the Milky Way make up roughly a third of all galaxies. They have centers with more radiation than galaxies that are only forming new stars, yet less radiation than those whose supermassive black holes are actively consuming a tremendous amount of material.

"Before this discovery by WHAM, the Andromeda Galaxy was the closest LINER spiral to us," said Haffner. "But it's still millions of light-years away. With the nucleus of the Milky Way only tens of thousands of light-years away, we can now study a LINER region in more detail. Studying this extended ionized gas should help us learn more about the current and past environment in the center of our Galaxy."

Next up, researchers will need to figure out the source of the energy at the center of the Milky Way. Being able to categorize the galaxy based on its level of radiation was an important first step toward that goal.

Now that Haffner has joined Embry-Riddle's growing Astronomy & Astrophysics program, he and his colleague Edwin Mierkiewicz, associate professor of physics, have big plans. "In the next few years, we hope to build WHAM's successor, which would give us a sharper view of the gas we study," Haffner said. "Right now our map `pixels' are twice the size of the full moon. WHAM has been a great tool for producing the first all-sky survey of this gas, but we're hungry for more details now."

In separate research, Haffner and his colleagues earlier this month reported the first-ever visible-light measurements of "Fermi Bubbles" - mysterious plumes of light that bulge from the center of the Milky Way. That work was presented at the American Astronomical Society.

LOGAN, UTAH, USA - Utah State University biologist Edmund 'Butch' Brodie, Jr. and colleagues from São Paulo's Butantan Institute report the first known evidence of oral venom glands in amphibians. Their research, supported by the Brazilian National Council for Scientific and Technological Development, appears in the July 3, 2020, issue of iScience.

"We think of amphibians - frogs, toads and the like -- as basically harmless," says Brodie, emeritus professor in USU's Department of Biology. "We know a number of amphibians store nasty, poisonous secretions in their skin to deter predators. But to learn at least one can inflict injury from its mouth is extraordinary."

Brodie and his colleagues discovered the oral glands in a family of caecilians, serpent-like creatures related to frogs and salamanders. Neither snakes nor worms, caecilians are found in tropical climates of Africa, Asian and the Americas. Some are aquatic and some, like the ringed caecilian (Siphonops annulatus) studied by Brodie's team, live in burrows of their own making.

In 2018, the team reported the species secreted substances from skin glands at both ends of its snake-like body. Concentrated at the head and extending the length of the body, the creature emits a mucous-like lubricant that enables it to quickly dive underground to escape predators. At the tail, caecilians have glands armed with a toxin, which acts as a last line of chemical defense, blocking a hastily burrowed tunnel from hungry hunters.

"What we didn't know is these caecilians have tiny fluid-filled glands in the upper and lower jaw, with long ducts that open at the base of each of their spoon-shaped teeth," Brodie says.

His research colleague Pedro Luiz Mailho-Fontana, who studied with Brodie as a visiting graduate student at USU's Logan campus in 2015, noticed the never-before-described oral glands. Using embryonic analysis, Mailho-Fontana, first author of the paper, discovered the glands - called "dental glands" - originated from a different tissue than the slime and poison glands found in the caecilian's skin.

"The poisonous skin glands form from the epidermis, but these oral glands develop from the dental tissue, and this is the same developmental origin we find in the venom glands of reptiles," he says.

The researchers surmise caecilians, equipped with no limbs and only a mouth for hunting, activate their oral glands when they bite down on prey, including worms, termites, frogs and lizards.

The team doesn't yet know the biochemical composition of the fluid held in the oral glands.

"If we can verify the secretions are toxic, these glands could indicate an early evolutionary design of oral venom organs," Brodie says. "They may have evolved in caecilians earlier than in snakes."

A new approach could illuminate a critical stage in the life cycle of one of the most common malaria parasites. The approach was developed by scientists at Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) in Japan and published in the Malaria Journal.

"The Plasmodium vivax malaria parasite can stay dormant in a person's liver cells up to years following infection, leading to clinical relapses once the parasite is reactivated," says Kouichi Hasegawa, an iCeMS stem cell biologist and one of the study's corresponding authors.

P. vivax is responsible for around 7.5 million malaria cases worldwide, about half of which are in India. Currently, there is only one licensed drug to treat the liver stage of the parasite's life cycle, but it has many side effects and cannot be used in pregnant women and infants. The liver stage is also difficult to study in the lab. For example, scientists have struggled to recreate high infection rates in cultured liver cells.

Hasegawa and his colleagues in Japan, India and Switzerland developed a successful system for breeding mature malaria parasites, culturing human liver cells, and infecting the cells with P. vivax. While it doesn't solve the high infection rate problem, the system is providing new, localized insight into the parasite's liver stage.

"Our study provides a proof-of-concept for detecting P. vivax infection in liver cells and provides the first characterization of this infectious stage that we know of in an endemic region in India, home to the highest burden of vivax malaria worldwide," says Hasegawa.

The researchers bred Anopheles stephensi mosquitos in an insectarium in India. Female mosquitos were fed with blood specifically from Indian patients with P. vivax infection.

Two weeks later, mature sporozoites, the infective stage of the malaria parasite, were extracted from the mosquitos' salivary glands and added to liver cells cultured in a petri dish.

The scientists tested different types of cultured liver cells to try to find cells that would be infected by lots of parasites like in the human body. Researchers have already tried using cells taken liver biopsies and of various liver cancer cell lines. So far, none have led to large infections.

Hasegawa and his colleagues tried using three types of stem cells that were turned into liver cells in the lab. Notably, they took blood cells from malaria-infected patients, coaxed them into pluripotent stem cells, and then guided those to become liver cells. The researchers wondered if these cells would be genetically more susceptible to malaria infection. However, the cells were only mildly infected when exposed to the parasite sporozoites.

A low infection rate means the liver cells cannot be used for testing many different anti-malaria compounds at once. But the researchers found the cells could test if a specific anti-malaria compound would work for a specific patient's infection. This could improve individualized treatment for patients.

The scientists were also able to study one of the many aspects of parasite liver infection. They observed the malaria protein UIS4 interacting with the human protein LC3, which protected the parasite from destruction. This demonstrates their approach can be used to further investigate this important stage in the P. vivax life cycle.

Sophia Antipolis - 3 July 2020: Trouble sleeping after heart bypass surgery? Morning walks are the solution, according to research presented today on ACNAP Essentials 4 You, a scientific platform of the European Society of Cardiology (ESC).

"Many patients have trouble sleeping after heart bypass surgery," said study author Dr. Hady Atef of Cairo University, Egypt. "When this persists beyond six months it exacerbates the heart condition and puts patients at risk of having to repeat the surgery. It is therefore of utmost importance to find ways to improve sleep after bypass surgery."

Previous studies examining the effect of exercise on sleep after heart bypass surgery have failed to simultaneously assess the impact on functional capacity (the ability to do usual activities), which often declines after surgery.

This study investigated the effect of exercise on both sleep and functional capacity. The study enrolled 80 patients aged 45 to 65 years who had sleep disorders six weeks after heart bypass surgery and also had reduced functional capacity.

Three baseline measurements were performed. First, a six-minute walk test, which measures the distance patients are able to walk in six minutes on a hard, flat surface, and is a validated way to assess functional capacity. Second, participants completed the Pittsburgh sleep quality index (PSQI) questionnaire which asks about sleep disorders. Third, patients wore an actigraph watch for 96 hours to monitor rest and activity. Many of these patients have trouble staying awake during the day but have insomnia at night - the actigraph picks up both problems.

Patients were then randomly allocated to two exercise groups: aerobic exercise or a combination of aerobic and resistance exercise. Both groups did 30 exercise sessions in the morning over a 10-week period. During the aerobic exercise sessions, participants walked on a treadmill for 30 to 45 minutes. During the aerobic and resistance exercise sessions, participants walked on a treadmill for 30 to 45 minutes and did circuit weight training (a form of light resistance exercise).

After 10 weeks, patients completed the three assessments again: the six-minute walk test, the PSQI questionnaire, and wearing the actigraph watch for 96 hours. Changes in sleep and functional capacity were compared between the two exercise groups.

The researchers found that both exercise programmes (aerobic exercise alone and combined aerobic/resistance exercise) improved sleep and functional capacity over the 10-week period. But isolated aerobic exercise was much more beneficial on sleep and function than the combined programme.

Prior studies on sleep have used the PSQI questionnaire or an actigraph. A strength of this study was to use both methods of assessment, thereby providing a complete picture of the sleep disturbance. Together these measurements showed that exercise helped patients fall asleep, sleep continuously rather than waking up in the night, and sleep longer and more deeply.

"Our recommendation for heart bypass patients with difficulty sleeping and performing their usual activities is to do aerobic exercise only," said Dr. Atef. "We think that resistance exercise requires a high level of exertion for these patients. This may induce the release of stress hormones which negatively affect sleep."

"Aerobic exercise means physical activity that does not require a very high level of exertion," he explained. "Choose an activity you enjoy like walking, cycling, or swimming. Aim for 30 to 45 minutes and do it in the morning because research shows this releases the hormone melatonin which helps us sleep well at night."

For the first time, scientists have shown that the bacterium that causes the tick-borne disease anaplasmosis interferes with tick gene expression for its survival inside cells and to spread to a new vertebrate host. Girish Neelakanta of Old Dominion University and colleagues report these findings in a study published July 2nd in PLOS Genetics.

In the United States, new cases of tick-borne diseases, such as anaplasmosis, Lyme disease and babesiosis, are on the rise. There are few ways to prevent ticks from spreading these pathogens to humans, so researchers decided to look instead at interactions between the pathogen and the tick to find new ways to control the spread of disease. By looking at how the bacterium that causes anaplasmosis affects gene expression in the black legged tick, they discovered that the bacterium dials down the level of a regulatory molecule that normally stops the production of a protein called the Organic Anion Transporting Polypeptide (OATP). Further experiments showed that the bacterium's actions cause an increase in OATP levels, which results in higher numbers of the bacterium that helps it to spread to a new vertebrate host, in this case, mice.

Previous experiments have shown that both bacterial and viral pathogens depend on OATPs to colonize and survive inside ticks. Together, the findings suggest that OATPs may be ideal candidates for developing new vaccines to protect humans against tick-borne illnesses. The current study also represents an important advance in our understanding of the tick-pathogen relationship, as currently we know surprisingly little about the mechanisms that allow pathogens to use ticks as vectors. Understanding how pathogens manipulate gene expression in vectors for their benefit may lead to novel strategies for blocking their transmission from the vector to vertebrate hosts.

"Studies like these would provide important evidence that tick molecules, such as OATPs, play a significant role in tick-pathogen interactions," commented author Girish Neelakanta. "Current and future studies from my laboratory are addressing therapeutic potential of OATP as a candidate for the development of a strong anti-vector vaccine to block transmission of tick-borne pathogens."

In the US, dying from rabies is virtually unheard of. But around the world, rabies kills 59,000 people every year. Ninety-nine percent of those deaths are caused by dog bites; half of the people killed are children. There's a relatively simple way of preventing these deaths--vaccinating dogs against the disease--but systemic challenges make that easier said than done. In a new study in PLOS Neglected Tropical Diseases, an international team of researchers reported on a multi-year effort to vaccinate dogs in Kenya and highlighted some of the challenges scientists and public health officials face in eradicating the disease. They found that grassroots efforts helped lots of individuals--but that to stop the disease once and for all, these smaller campaigns must be coupled with large-scale efforts.

"It's important to focus on rabies because it's 100% preventable," says Adam Ferguson, a mammalogist at Chicago's Field Museum and one of the study's lead authors. "There's no reason why people should be dying from rabies. It's not like COVID in the sense that we don't have a vaccine for it or we don't know what to do with it."

Rabies is a virus, and it spreads through saliva in animal bites. It causes brain inflammation, and once a person begins showing symptoms, it's nearly always fatal. Any mammal can carry rabies, but humans are most likely to pick it up from dogs, because we spend more time in close contact with them than with wild animals like raccoons and bats. And while a rabies vaccine was first discovered in 1885, large parts of the world remain vulnerable to the disease to this day. "It disproportionately impacts low-income, rural communities," says Ferguson, who began the project as a National Science Foundation postdoctoral fellow at Kenya's Karatina University. "In the US, we have the luxury that if one person dies of rabies a year, it makes the front page news. In Kenya, an estimated 2,000 people die of the disease every year."

For the new study, Ferguson and his colleagues conducted grassroots dog vaccination campaigns in 2015, 2016, and 2017 in Kenya's Laikipia County. The Laikipia Rabies Vaccination Campaign expanded over the course of the three-year period, and 13,155 dogs were vaccinated. Across different communities, the team set up a central station for people to bring their dogs to get vaccines. "The excitement and commitments by the communities to bring their dogs in the centers was overwhelming. This for sure made the effort feel worth investing into. You could tell that rabies eradication was tending to be more communal than an individual effort," says Dedan Ngatia, a scientist at the University of Wyoming and one of the study's lead authors.

For rural areas, team members used a combination of central stations and door-to-door vaccinations, asking people if they had dogs and offering free rabies vaccines. "We found that in the pastoral communities, you definitely need more door-to-door outreach than you do in the other communities," says Ferguson, partly because of how sparsely populated those areas are, and partly because many of the dogs there are working animals used to herd goats and sheep and wouldn't be used to walking on a leash to go to one of the central vaccination stations.

As the project grew, more and more people were interested in getting their dogs vaccinated. But the project's popularity presented the researchers with a tough decision. They could focus on smaller areas where they could try to get 70% of the dogs vaccinated, the amount needed for risk of dogs spreading the disease to humans to be effectively eliminated. Alternatively, they could vaccinate as many dogs from as many places as possible, without reaching a critical mass of vaccinations necessary for herd immunity. They didn't have the resources to get to 70% immunity on the large scale.

"I think the question grassroots campaigns have to ask themselves is, is that their goal just to have local outreach and help a few individuals, or are they trying to eliminate it at the landscape-level scale, which is the bigger picture goal. I think, going forward, the answer should be, you should have both," says Ferguson. "We need massive, large-scale efforts, but the reality is that money and resources are limited. That's where these grassroots campaigns are helpful. We were able to expand from 5 to 17 communities because we partnered with the national and county government from the get-go."

"Our target of vaccinating more than 70% of dogs in Laikipia County through sustained campaigns will interrupt transmission in the reservoir population so that the disease is eliminated. LRVC does more than just vaccinating dogs against rabies, we visit schools to raise awareness amongst children--the most affected population by the disease--about rabies prevention," says Dishon Muloi, a scientist at International Livestock Research Institute and one of the study's lead authors.

"The need to eradicate rabies is both for the protection of people as well as wildlife, which includes some of the most endangered carnivores like the African wild dogs. For many years, infectious diseases have remained the main cause of endangerment for these species, with rabies playing a leading role in the endangerment of the African wild dogs. With massive vaccinations, and achieving 70% coverage, we will be able to protect both people and wildlife," says Ngatia.

This study was contributed to by scientists from the Field Museum, the Smithsonian Conservation Biology Institute, the University of Edinburgh, the International Livestock Research Institute, Karatina University, Maasai Mara University, the Kenya Agricultural and Livestock Research Organization, the Kenya Zoonotic Disease Unit, Washington State University, the Zoological Society of London, the Ministry of Agriculture, Livestock, and Fisheries, County Government of Laikipia, the University of Liverpool, and the Mpala Research Centre.

Lugano, Switzerland, 2 July 2020 - Artificial intelligence (AI) holds promise for enabling earlier detection of pancreatic cancer, which is crucial to saving lives. The potential of AI is showcased in a study to be presented at the ESMO World Congress on Gastrointestinal Cancer, 1-4 July 2020. (1, 2)

Overall, 12 in every 100,000 people develop pancreatic cancer. This means that screening everyone would be inefficient and would expose many people to unnecessary tests and potential side-effects. Between 70-80% of patients are diagnosed at an advanced stage when it is too late for curative treatment and five years after diagnosis, just 6% of patients have survived.

Screening helps identify cancer early, when treatments are most effective, thus improving survival. There are two main requirements for screening. First, a screening test that is easy to perform and has few side-effects. Second, a defined group that would benefit most from screening because they are at higher risk. For example, breast cancer screening involves mammography in women aged 50 to 71 years. AI could be the desperately needed answer to define a group of higher risk individuals that would benefit from screening, especially as recently some promising results have indicated that non-invasive tests for pancreatic cancer may soon be available.

It is known that patients who develop pancreatic cancer consult their general practitioner (GP) with non-specific symptoms such as gastrointestinal problems or back pain more frequently in the months and years prior to diagnosis compared with their peers who do not develop pancreatic cancer. Individually, these symptoms are unlikely to trigger further investigations for cancer. Researchers came up with the idea that AI could find a combination of these non-specific symptoms that is linked with higher risk of contracting the disease, which would be difficult to spot by GPs.

This preliminary study used electronic health records from GP practices in the UK. (3) The analysis included 1,378 patients aged 15-99 years diagnosed with pancreatic cancer in 2005 to 2010. Each patient was matched by age and sex to four people who did not get pancreatic cancer. Information on symptoms, diseases, and medications in the two years prior to diagnosis were used to create a model predicting who would develop pancreatic cancer. "We used AI to study a large volume of data and look for combinations that predict who will develop pancreatic cancer," said study author Dr. Ananya Malhotra, research fellow in statistics, London School of Hygiene & Tropical Medicine, London, UK. "It's not possible for the human eye to recognise these trends in such large amounts of data."

The pilot study found that in people under 60 years of age, the model could predict who was at higher risk of pancreatic cancer up to 20 months before diagnosis. "Our model has estimated that around 1,500 tests need to be performed to save one life from pancreatic cancer," explained Malhotra. "This is unlikely to be small enough to make screening viable just yet. However, it shows that AI holds potential to narrow down the number of people we need to screen. We should be able to reduce this quite a lot further by matching pancreatic cancer patients to controls from the general population, which is what we plan to do next (in the current study, the controls had other types of cancer)."

"Pairing this predictive model with a non-invasive screening test, followed by scans and biopsies, could lead to earlier diagnosis for a significant proportion of patients and a greater number of patients surviving this cancer," added Malhotra.

Using AI to identify people at high-risk of pancreatic cancer up to 20 months earlier could make the difference between life and death. "This should be enough time to screen for pancreatic cancer, then proceed with diagnosis and treatment in patients with a positive screening test," said Dr. Angela Lamarca, consultant in medical oncology, The Christie NHS Foundation Trust, Manchester, UK. "Early diagnosis in pancreatic cancer gives the highest chance of cure."

According to Lamarca, GPs could use this type of AI model on their medical records to highlight patients at higher risk. An alarm could be raised showing who should receive screening. She said: "We need bigger studies incorporating AI tools into daily clinical practice and exploring the benefit of screening the patients selected by AI. More research is also needed to find a good screening test for these high-risk patients."

In industry, gaseous hydrocarbons, such as ethane and methane, are frequently changed into molecules that can act as building blocks for pharmaceuticals and agrochemicals. Typically, these processes take place at high temperatures and pressures, and can also produce large amounts of pollutants. Researchers at Eindhoven University of Technology (TU/e) have developed a new method for the immediate conversion of gaseous, low-weight hydrocarbons to more complex molecules at room temperatures and low pressures by illuminating the molecules with light in the presence of a suitable catalyst. Notably, this new process is faster and leads to little or no material waste. This work has been published today in the journal Science.

In modern society, gaseous alkanes like propane, isobutane, and methane are regularly combusted for energy. These relatively cheap and plentiful molecules can also be used to produce complex molecules for medicines or chemical products in agriculture.

Current large-scale processes that activate these molecules for subsequent chemical reactions take place at high temperatures and pressures, which are harsh reaction conditions that can be difficult and expensive to maintain, while also leading to substantial waste generation. Also, for the specific case of methane, the high temperatures needed for activation negate the use of any resulting products in medicines as the organic molecules simply disintegrate.

A research team led by Timothy Noël from TU/e, in collaboration with researchers at the ShanghaiTech University (China), University of Pavia (Italy), and Vapourtec Ltd. (UK), have devised a new process for the activation of alkanes using light at room temperature and lower pressure.

Significant breakthrough

"This is a significant breakthrough for converting alkanes into useful building blocks for medicines and materials for other industries," says Noël. "Our approach allows for the immediate use of alkanes for more complex molecules without many unwanted by-products, while at the same time decreasing pollution and simplifying the activation process."

To realize this new process, the researchers had to contend with two main issues. First, they needed a method that could easily sunder or break C-H bonds with a bond dissociation energy (BDE) between 96.5 and 105 kcal mol-1. The C-H bonds in methane are the most difficult to break. Second, the handling of gaseous alkanes requires tailor-made technologies that can bring the alkanes in close contact with a catalyst in a carefully monitored reaction environment. The researchers solved both of these issues by exciting the alkanes with UV light (about 365 nm) in the presence of a suitable catalyst at room temperature.

"The catalyst used is decatungstate. When illuminated, the catalyst becomes highly energetic and then has sufficient energy to split C-H bonds. We find that this works for methane, ethane, propane, and isobutane," says Noël. He adds: "Our new approach is faster than traditional approaches, and we are excited to see how it develops. This study has employed microreactors given that they facilitate greater control over the reaction conditions, better confinement of the gaseous raw materials, and easier illumination of the catalyst. In the future, we will consider reactors that can allow higher production capacities." This new method paves the way for the cheaper production of some medicines given that the cost of activating the gases for their production would be lower.