Culture

Sanaria® PfSPZ-CVac" is a live vaccine consisting of infectious Plasmodium falciparum (Pf) malaria parasites that are injected into the subject at the same time as they receive an antimalarial drug. The parasites quickly enter the liver where they develop and multiply for 6 days, and then emerge into the blood As soon as the parasites leave the liver, the drug kills them immediately. Thus, the immune system of the vaccinated subject is primed against many parasite proteins and becomes highly effective at killing malaria parasites in the liver to block infection and prevent disease.

"With this study, we have reached a new important milestone in the development of an effective malaria vaccine. With only three immunizations over four weeks, we achieved very good protection against malaria," explains Prof. Peter Kremsner, who has helped to advance the malaria research field at the DZIF since its inception. His team was able to develop a new immunization regimen that significantly reduces vaccine administration compared to previous studies. The number of visits required by a subject for complete immunization has been reduced from 13 to three. Importantly, the team showed that vaccination with parasites from Africa could protect against genetically diverse parasites from South America.

Proof of efficacy was provided using the controlled human malaria infection (challenge) regimen developed by the Tübingen and Sanaria teams. Here, the test subjects were infected with parasites after immunization. If immunization against the parasites was successful, the parasites would be specifically killed by the immune system. If the immune protection is incomplete and the parasites multiply, the test subjects are treated before any symptoms of disease appear. Ten of 13 subjects vaccinated in this study were completely immune to the infection.

"The vaccine produces a high level of different antibodies and immune cells in the body that can recognize both the injected parasites and antigens of the subsequent liver stage. These antibodies and immune cells contribute to the strong protective immunity" explains Dr. Rolf Fendel.

With an estimated 229 million infections and 409,000 deaths worldwide in 2019, malaria is one of the world's most important and dangerous infectious diseases. It is caused by parasites transmitted to humans through the bites of infected female mosquitoes. Children under the age of five are the most vulnerable group affected by malaria, accounting for 67 percent (274,000) of all malaria deaths worldwide in 2019.

Daniel Redhead, from the Max Planck Institute for Evolutionary Anthropology, and Chris von Rueden, from the University of Richmond, published a new study that describes coalition formation among men in Tsimané Amerindians living in Amazonian Bolivia, over a period of eight years. In two Tsimané communities, the authors describe the inter-personal conflicts that tend to arise between men, and the individual attributes and existing relationships that predict the coalitional support men receive in the event of conflicts.

Conflicts that arise between men concern disputes over access to forest for slash-and-burn horticulture, as well as accusations of theft, laziness, negligence, domestic abuse, and sexual affairs.

Men tend to reciprocate coalitional support

Key findings are that men who are kin or who exchange food and labor are more likely to subsequently provide support to each other in the event of a conflict. Men tend to reciprocate coalitional support over time, and an ally of a man's current ally is likely to become a future ally. The authors also find evidence that men who share a common adversary become allies, though this finding did not hold consistently across the eight years of the study.

In reference to the impact of these findings, Redhead, said: "Coalition formation among men is multiply determined in the Tsimané, and likely in other human societies. Importantly, the social network analyses we used show that properties of the network, not just the individual, affect coalition formation."

Higher status men more likely to provide coalitional support

Furthermore, Tsimané men who are physically formidable or who have more informal influence in their community are more likely to provide coalitional support to others. Evidence was mixed that they receive more coalitional support. These higher status men are hubs of their community's coalitional support network, and there is little indication that this network is partitioned into clearly separable coalitions that divide the community.

"In the Tsimané, men who have higher informal status strategically deploy coalitional support to build up a diverse, community-wide following. In many cases, both disputants in a conflict will report the same higher status man as having provided coalitional support, which points to the often blurry line between coalitional support and conflict mediation", von Rueden said. "Politics is the art of persuading enough people you have their interests at heart. In less egalitarian societies where there is more privately available wealth and community sizes are larger, status is less contingent on providing direct support to a broad swath of community members, there is greater homophily by status, and coalitional divides within a community are more likely to be pronounced."

Redhead and von Rueden focus their study on men because they at present lack longitudinal data on women's coalition formation. However, there is reason to analyze coalition networks separately by gender, given evidence of gender differences in how men and women build and leverage their social relationships, particularly in societies like the Tsimané where there is a pronounced gendered division of labor.

5 May 2021, Bristol - In one of the most advanced applications of in-vitro 3D human lung models in vape research to date, a new peer-reviewed Imperial Brands study shows that, unlike combustible cigarette smoke, blu aerosol had little to no impact on numerous toxicological endpoints under the conditions of test using laboratory models.

Published in the journal Current Research in Toxicology, the experiments compared the toxicological responses of an in vitro 3D lung model (MucilAir™ from Epithelix) after repeated exposure to undiluted whole blu aerosol (1.6% tobacco flavour) or diluted whole cigarette smoke (3R4F Kentucky Reference) over a 28-day period.

After repeatedly exposing the model to smoke or aerosol from each product for four weeks, scientists assessed the biological activity of the 3D lung tissue model against five endpoints related to respiratory function:

Cytotoxic response (general toxicity to cells or tissue)

Barrier integrity (measuring the intactness of tissue structure )

Immunohistochemistry (general assessment of tissue structure)

Cilia beat frequency and active area (detecting abnormal lung cell function)

Pro-inflammatory response (identifying lung tissue inflammation)

This is the first peer-reviewed vaping study evaluating repeated whole cigarette smoke and whole aerosol exposure to a 3D lung model (at the air liquid interface) for this extended 28-day time period.

The use of a 3D lung model and extending the exposure scenario produced a more clinically relevant setup than previous applications, because the model is a closer representation of how the human lung is exposed to aerosol or smoke.

The Toxicity Testing in the Twenty-First Century (TT21C) driven study reinforces Imperial Brands commitment to using advanced 3D tissue models and cellular assays to as part of a global movement to reduce industry reliance on in-vivo (animal) experiments. (Imperial does not test any products on animals, unless formally required to do so by governments or recognised regulatory authorities. See our Position here.)

Results consistent with previous findings

Correlating with Imperial's previous published applications of using a similar method, in the previous study an acute exposure to undiluted whole vape aerosol showed similar biological impact to the lung cell model as humidified air under the experimental conditions. However, diluted combustible cigarettes smoke elicited a significant dose-dependent response in all measured endpoints listed above.

As expected, in the present repeated exposure study, cigarette smoke produced a significant and dose-dependent biological response against all endpoints as the puff number was increased. "Cytotoxicity and inflammatory markers were all elevated in cigarette smoke," said Fan Yu, Pre-Clinical Toxicologist at Imperial Brands and corresponding author. "Likewise, diluted cigarette smoke disrupted normal cilia beat function, cell barrier integrity, as well as tissue structure."

At each puff dose, undiluted blu aerosol contained at least seven times more nicotine relative to cigarette smoke, but for all endpoints elicited no statistically significant difference with the negative control exposed only to humidified air. "Our results suggest nicotine is not the driver of the model's cytotoxic response to cigarette smoke," Yu explained. "More likely it is the many toxicants created through burning tobacco causing the responses that are absent, or substantially reduced, in vape aerosol."

The study is further evidence that vaping may have significant harm reduction potential compared to combustible cigarettes for adult smokers who would otherwise continue to smoke.

"For adult smokers who are uninterested or unwilling to stop smoking, this study adds to a growing body research demonstrating Next Generation Products such as vapes offer a potentially reduced harm alternative if adult smokers choose to transition to these products," said Dr Grant O'Connell, Head of Tobacco Harm Reduction Science.

He added: "To ensure adult smokers are fully informed of the scientific evidence base underpinning NGPs , we urge regulators, policy makers and media alike to recognise and communicate the scientific evidence, such as that presented here, as well as many other findings in the literature, and support a role for high quality, scientifically substantiated products in maximising tobacco harm reduction."

Announcing a new article publication for BIO Integration journal. In this editorial the authors Hui Liu and Juan Chen from Shanxi Eye Hospital, Taiyuan, China discuss biophotonics in photomedicine.

As a cross-disciplinary field, biophotonics is a natural platform for innovation, e.g. researchers have taken advantages of the recently developed nanostructures in Photomedicine to optimize imaging signals and improve drug delivery efficiency. Active investment in healthcare also contributes to the quick clinical transitions of biophotonic innovations.

However, to genuinely and successfully improve people's lives, many gaps have to be bridged. Horizontally, the gaps are between scientists from different fields to make new fundamental breakthroughs through knowledge merging; vertically, the gaps lie in scientists, engineer medical professionals, and physicists to make innovated, reliable, and practical products. Learning another field's language is never easy; promoting this learning requires leaders to advocate communication and understanding among experts. Although it is still a relatively young field, with abundant success so far and booming innovations coming along, it is reasonable to expect giant waves of healthcare transformation involving biophotonics to continue for the next few decades.

Article reference: Hui Liu and Juan Chen, Biophotonics in Photomedicine. BIO Integration, 2021, https://doi.org/10.15212/bioi-2020-0043

BIO Integration is fully open access journal which will allow for the rapid dissemination of multidisciplinary views driving the progress of modern medicine.

As part of its mandate to help bring interesting work and knowledge from around the world to a wider audience, BIOI will actively support authors through open access publishing and through waiving author fees in its first years. Also, publication support for authors whose first language is not English will be offered in areas such as manuscript development, English language editing and artwork assistance.

BIOI is now open for submissions; articles can be submitted online at:

https://mc04.manuscriptcentral.com/bioi

Please visit http://www.bio-integration.org to learn more about the journal.

Editorial Board: https://bio-integration.org/editorial-board/

Please visit http://www.bio-integration.org to learn more about the journal.

Editorial Board: https://bio-integration.org/editorial-board/

BIOI is available on the IngentaConnect platform (https://www.ingentaconnect.com/content/cscript/bioi) and at the BIO Integration website (http://www.bio-integration.org).

Submissions may be made using ScholarOne (https://mc04.manuscriptcentral.com/bioi).

There are no author submission or article processing fees.

Follow BIOI on Twitter @JournalBio; Facebook (https://www.facebook.com/BIO-Integration-Journal-108140854107716/) and LinkedIn (https://www.linkedin.com/company/bio-integration-journal/).

ISSN 2712-0074

eISSN 2712-0082

Keywords: Biophotonics, Photomedicine.

Marine scientists are calling on the EU to adopt a comprehensive plan to protect dolphins and porpoises from fisheries bycatch in European waters.

A team of conservation experts, including Newcastle University's Professor Per Berggren, highlight limitations in EU's efforts to address and mitigate bycatch. The scientists argue this infective response is a result of scattered and complicated management responsibility for the conservation of dolphins and porpoises in Europe, and from a lack of quantitative conservation objectives, including biological reference points that will guide management action to ensure that bycatch does not exceed sustainable levels.

To help address the bycatch issue, which is the primary global threat to dolphins and porpoises, the researchers put forward a framework to reduce bycatch levels.

Publishing their recommendations in the journal Fish and Fisheries, the scientists outline a two-step approach that involves establishing a quantitative management objective for each population and implementing monitoring programmes.

To ensure an accurate estimation of bycatch levels, the experts recommend using electronic monitoring systems that allow a more comprehensive and representative sampling of the fleets.

The scientists also recommend regular formal assessments of small cetacean populations, including generation of estimates of abundance and bycatch mortality. If total bycatch has been estimated to exceed the calculated biological reference point, then a mitigation strategy needs to be put in place while monitoring is continued until levels are below the reference points.

The research team, involving experts from University College Cork, Ireland and Duke University, USA, argue that European countries outside the EU also have a responsibility to address the bycatch of dolphins and porpoises in their Exclusive Economic Zones. This includes the UK, which has an important responsibility to develop frameworks to address bycatch.

Professor Per Berggren, of Newcastle University's School of Natural and Environmental Sciences, said: "Among the most distinctive species of marine wildlife in Europe, cetaceans are vital to the history and culture of European maritime communities and generate significant revenue from ecotourism. However, bycatch of small cetaceans in European fisheries is widespread, including very large numbers of common dolphins in trawl fisheries and bycatch of the critically endangered population of harbour porpoise in the Baltic Sea."

Professor Andrew Read, of Duke University's Nicholas School of the Environment, said: "The failure to effectively conserve Europe's dolphins and porpoises is not a result of a lack of scientific knowledge or difficulties in monitoring fisheries and bycatch. Instead, it reflects a lack of political will to ensure that these iconic animals are protected from unsustainable mortality in commercial fisheries throughout European waters. We can and must do better."

Professor Emer Rogan, from University College Cork, added: "Despite a number of EU Regulations and Directives, there is no clear European framework to reduce the mortality of dolphins and porpoises in fisheries to sustainable levels. This limitation hampers the effective implementation of effective management actions."

Reflexes protect our bodies - for example when we pull our hand back from a hot stove. These protective mechanisms could also be useful for robots. In this interview, Prof. Sami Haddadin and Johannes Kühn of the Munich School of Robotics and Machine Intelligence (MSRM) of the Technical University of Munich (TUM) explain why giving test subjects a "slap on the hand" could lay the foundations for the robots of the future.

In your paper, published in Scientific Reports, you describe an experimental setup where people were actually slapped on the hand - to study their reflexes....

Kühn: Yes, you can put it that way. For our study, in cooperation with Imperial College London, the test subjects needed their reflexes to protect them against two different pain sources: first, a slap on the hand. And, while pulling their hand and arm out of harm's way, they also had to avoid an elbow obstacle. We studied the hand retraction and discovered that it is a highly coordinated motion.

We also observed that the pain anticipated by a person shapes the reflex: If I know that the object behind me will cause similar pain to the slap on my fingers, I will withdraw my hand differently than when I know that the object will cause no pain.

How can such a seemingly simple experiment contribute to the development of intelligent high-tech machines like robots?

Haddadin: Humans have fascinating abilities. One could speak of a built-in intelligence in the human body that is indispensable for survival. The protective reflex is a central part of this. Imagine the classical "hand on the hot stove" situation. Without thinking, we pull back our hand as soon as the skin senses heat. So far, robots do not have reflexes of this kind. Their reactions to impending collisions tend to be rather mindless: They just stop and don't move until a person takes action.

In some situations this might make sense. But if a robot simply stopped moving when touching a hot stove, this would obviously have fatal consequences. At the MSRM we are therefore interested in developing autonomous and intelligent reflex mechanisms as part of a central nervous system for robots, so to speak. Humans are serving as our role models. How do their reflexes work and what can we learn from them for the development of intelligent robots?

What conclusions can you draw from your experiment for the development of robots?

Kühn: We gained an insight into how the reflex motion works in detail: The way humans coordinate the reflex can be seen as throwing the shoulder forward, in a sense, in order to accelerate the withdrawal of the hand. This principle could be applied in the development of reflex motions in humanoid robots, with a signal sent to one part of a robot in order to influence the motion of another one.

This knowledge will also be helpful in the design of robot-enabled prosthetics that are expected to perform in "human-like" ways.

You mentioned that "anticipated pain" played a role in your experiment. Should robots be able to anticipate pain, too?

Kühn: That would be a big advantage. It could help to classify potential collisions based on danger levels - and to plan evasive actions if appropriate. This would not only ensure the safety of the robot.

If the robot were capable of anticipating human pain, it could intervene in a dangerous situation to save a person from experiencing this pain.

Would robots then need to learn how to feel pain in the same way as humans?

Haddadin: No. Our pain perception is highly complex and linked to emotions. So we can't compare this to a human's "pain sensation". Robots are tools and not living creatures. Artificial pain is nothing more than a technical signal based on data from various sensors. At the MSRM we have already developed an initial reflex mechanism for robots based on "artificial pain". When touching hot or sharp objects, our robot withdrew its arm in a reflexive movement.

What are your next steps on the way to a robot with a fully developed protective reflex?

Haddadin: The big challenge in our research field between humans and machines is that we still have only a rudimentary understanding of our role model: the human reflex system, working with the sensorimotoric learning mechanisms of a complex, neuromechanical motion apparatus. And that is where the exciting scientific challenge lies: with all of the unknowns, to continually improve the human-inspired abilities of our intelligent machines, while using what we learn to arrive at a better understanding of how humans function. Basically, we can say that this has continued since the days of Leonardo Da Vinci and will carry on for many years to come.

LAWRENCE -- Researchers at the University of Kansas have described a new species of fanged frog discovered in the Philippines that's nearly indistinguishable from a species on a neighboring island except for its unique mating call and key differences in its genome.

The KU-led team has just published its findings in the peer-reviewed journal Ichthyology & Herpetology.

"This is what we call a cryptic species because it was hiding in plain sight in front of biologists, for many, many years," said lead author Mark Herr, a doctoral student at the KU Biodiversity Institute and Natural History Museum and Department of Ecology & Evolutionary Biology. "Scientists for the last 100 years thought that these frogs were just the same species as frogs on a different island in the Philippines because they couldn't tell them apart physically. We ran a bunch of analyses -- and they do indeed look identical to the naked eye -- however, they are genetically isolated. We also found differences in their mating calls. They sound quite different. So, it was a case of using acoustics to determine that the species was different, as well as the new genetic information."

Genetic samples of the new frog, known scientifically as Limnonectes beloncioi (or commonly as the Mindoro Fanged Frog), were collected years ago by KU scientists working in the field on Mindoro Island in the central Philippines but weren't analyzed until recently. Because of its nearly identical physical similarity to a fanged frog on the island of Palawan, called Acanth's Fanged Frog, it was assumed to be the same species.

"You can look at two different things, but to the human eye without intensive investigation they might seem the same," Herr said. "So, we took a bunch of measurements of hundreds of these frogs -- how long their digits were specifically, how wide the tip of their toe was, the length of one specific segment of their leg, the diameter of their eye -- in order to compare populations statistically, even if we thought they look the same. We ran statistical analyses on body shape and size, including a principal component analysis which uses all the measurements at once to compare the frog morphology in multivariate space. After all that, just like the scientists before us, we found nothing to differentiate the frogs based on the shape of their bodies and their size."

However, because the fanged frogs inhabit islands separated by miles and miles of ocean, the researchers had doubts they were the same species, in part because they had different-sounding calls. They decided to analyze the frogs' genome and determined the Mindoro Fanged Frog qualified as its own distinct species.

"We ran genetic analyses of these frogs using some specific genetic markers, and we used a molecular clock model just to get a very basic estimate how long we thought that these frogs may have been separated from one another," Herr said. "We found they're related to each other, they are each other's close relatives, but we found they'd been separate for two to six million years -- it's a really long time for these frogs. And it's very interesting that they still look so similar but sound different."

The KU graduate student specializes in studying the many species of fanged frog across Southeast Asia, where he's carried out extensive fieldwork. He said the frogs' fangs likely are used in combat for access to prime mating sites and to protect themselves from predators. The Mindoro Fanged Frog, a stream frog, is sometimes hunted by people for food.

But the frog's characteristic call, different from Acanth's Fanged Frog, proved difficult for researchers to record.

"They're really wary of us when we're out there with our sound recorders trying to get recordings of these frogs -- that's a really tough aspect, and we were lucky in this project that we had people over many years that were out there and had recorded both of these frogs on Palawan and Mindoro. So, we had recordings from both islands, and that's kind of rare with this group of fanged frogs because people eat them. They call at night, but the second a flashlight or human voice wanders into the equation they're just going to take off -- because they know that they can be killed by people."

Herr's description of the Mindoro Fanged Frog continues a long tradition of KU field research into the herpetological biodiversity of the Philippines and Southeast Asia, according to his faculty adviser Rafe Brown, professor of ecology & evolutionary biology and curator-in-charge of the Herpetology Division of the Biodiversity Institute and Natural History Museum.

"Mark's discovery reinforces a lesson we've learned over and over through the years -- things we thought we knew, combined with new information, emerge to teach us something completely unexpected," Brown said. "A century ago, KU professor Edward Taylor identified the Mindoro Island population as Acanth's Fanged Frog, the same species as he had named, a few years before, from Palawan Island -- an arrangement that made very little sense. Zoom forward a hundred years, and we find with new technology, genetic information and bioacoustic data that the two islands' populations are actually very well-differentiated, as we would expect. But not morphologically; their physical characteristics have not diverged. This is a case in which the formation of species has not been accompanied by morphological differentiation -- so called 'cryptic speciation.'"

At the beginning of the COVID-19 pandemic, intense social distancing and lockdown measures were the primary weapon in the fight against the spread of SARS-CoV-2, but they came with a monumental societal burden. New research from the Center for the Ecology of Infectious Diseases and the College of Public Health at the University of Georgia explores if there could have been a better way.

Published in the journal Proceedings of the Royal Society B, the research analyzes more palatable alternatives to the kind of social distancing mandates that threw a wrench at how businesses, schools and even family gatherings work. The alternatives--widespread testing, contact tracing, quarantines, certification for non-infected people and other public health policy measures--can slow the spread when combined together, but only with significant investments and broad public compliance.

"I understand why government leaders quickly enacted strict social distancing mandates as the COVID-19 pandemic was rapidly spreading in 2020," said lead author John Drake, director of the Center for the Ecology of Infectious Diseases and Distinguished Research Professor in the Odum School of Ecology. "This was the best that we could do at the time. However, school and workplace closures, gathering limits and shelter-in-place orders have had extreme economic consequences. These are harsh, and we really need to find alternative solutions."

Drake worked with other researchers to develop two models. One targeted how to find infected people to limit transmission through active case finding (through testing of at-risk individuals), thorough contact tracing when cases arise, and quarantines for people infected and their traced contacts.

The second model focused on a strategy of limiting exposure by certifying healthy individuals.

"Each model was tested independently and in combination with general non-pharmaceutical interventions (NPIs)," said co-author Kyle Dahlin, a postdoctoral associate with the center.

For this study, those interventions were defined as behavioral or generalized interventions that can be broadly adopted, such as wearing a face mask, hand washing, enhanced sick leave, micro distancing and contactless transactions.

"When we ran the model to evaluate the effectiveness of only using social distancing measures, like workplace closures, after the onset of the first wave, approximately half of the population eventually became infected," said study co-author Andreas Handel, associate professor of biostatistics and epidemiology in UGA's College of Public Health who helped design the models. "When we combined social distancing with general interventions, SARS-CoV-2 transmission was slowed, but not enough for complete suppression."

When they tested the model that actively looked for infection, they found that active case-finding had to identify approximately 95% of infected persons to stop viral spread. When combined with NPIs, like face masks, the fraction of active cases that needed to be located dropped to 80%. Considering that during the first wave of the pandemic in 2020, only 1% to 10% of positive cases were found, such an approach by itself wouldn't work.

The researchers also determined that adding contact tracing and quarantine to active case finding and general NPIs did not drastically change the model's success.

The model that targeted healthy people to limit exposure determined that to successfully control viral spread, SARS-CoV-2 test validity had to occur within a very narrow window of seven to 10 days with a waiting time of three days or less, and NPIs had to be strictly adopted. Otherwise, a large outbreak would occur.

Pej Rohani, Regents' and Georgia Athletic Association Professor of Ecology and Infectious Diseases in the Odum School and College of Veterinary Medicine, said that the models' conclusions indicated the need for continued research.

"These models are important because infectious disease ecologists and epidemiologists need to understand how SARS-CoV-2 transmission can be reduced using measures that do not have extreme societal consequences," he said.

The CEID's research highlighted the importance of a robust and widespread testing program, the general adoption of NPIs like face masks, and targeted measures to globally control the ongoing pandemic. These approaches are still extremely important as vaccines continue to be distributed.

A study published in July 2020 hypothesized a link between the presence of bradykinin, a well-known peptide, and severe cases of COVID-19. Vardan Karamyan, Ph.D., an associate professor and vice chair for the Texas Tech University Health Sciences Center (TTUHSC) Jerry H. Hodge School of Pharmacy Department of Pharmaceutical Sciences, had not previously conducted or evaluated any research related to COVID-19. However, he found the article intriguing because it discussed bradykinin, one of three specific peptides with which his lab has much well-published experience.

The paper received a lot of attention in both the media and scientific literature, but as Karamyan read through it, he felt it failed to address an equally important part of a bigger picture: the likely involvement of two other bioactive peptides, known as substance P and neurotensin, in the same processes and mechanisms proposed by the authors.

"I decided to write a focused review article on the topic and looked for journals which announced special issues devoted to COVID-19," Karamyan recalled.

Karamyan learned that the American Physiological Society (APS) had two journals with ongoing special issues focusing on COVID-19. Because APS has a membership base of highly accomplished scientists and a wide audience, Karamyan submitted the manuscript of his focused review to Physiological Reports, one of APS's peer-reviewed journals that published Karamyan's review in its March 2021 issue.

In the original article, which included the author's data and additional information from other research, Karamyan saw that the researchers had postulated that bradykinin was the peptide at the center of many of the complications experienced by patients with severe COVID-19 cases. Peptides are short chains composed of at least two and no more than 50 amino acids, which also are the building blocks of proteins.

"What they were saying makes sense, and it is really beautifully done; they branch out quite a bit and they put things together in a very systematic way," Karamyan explained. "But what was very surprising is that if their proposed mechanism was true, then two other peptides (substance P and neurotensin) should also be next to bradykinin; yet there was not even a single word about those two peptides."

Karamyan said it was obvious the original study arrived at some important findings, but he also knew that a basic tenant of science says the better any disease is understood, the better the chances of curing or managing it.

"That was their motivation too," Karamyan asserted. "Their study tells us, 'Look, maybe this is what is happening,' and that made me think that I really need to try to bring awareness that there are these two other peptides that could be equally important."

Almost since the pandemic began, research has shown that many of the worst cases of COVID-19 are related to cytokine storms, which is when the body overproduces cytokines in an effort to fight the virus. Cytokines are substances such as proteins, peptides or glycoproteins that are released by cells within the immune system to affect other cells. For instance, cytokines help the body manage conditions such as immunity, inflammation and hematopoiesis (the production of blood cells and platelets). When they are overproduced, however, the resulting cytokine storm can have deleterious effects.

"In the beginning, it's a compensatory reaction when the cytokines are produced, but when it is overdone, this makes things much worse," Karamyan added.

Using their own data and that put forward by previous investigators, the researchers who authored the original paper concluded it was the overexpression of bradykinin, or a bradykinin storm rather than a cytokine storm that was adversely affecting COVID-19 patients.

"As I noted, it makes sense," Karamyan said. "It's not that cytokines don't do anything, but I agree with them that bradykinin could make things worse."

To make their case, the authors of the original paper showed there were mechanisms that would make bradykinin appear to be upregulated, or increased within the body, while other mechanisms meant to degrade bradykinin are downregulated, or decreased. Karamyan said those same mechanisms also would affect substance P and neurotensin in the same manner at least 80% of the time.

"Those same mechanisms, or the majority of them, would lead to elevated levels of not just bradykinin, but also substance P and neurotensin," Karamyan said. "That's one fact; the second is that if this inflammation is going on, if things are deteriorating in a COVID-19 patient, in the same way that bradykinin is making things worse, these peptides are known to do the same thing, and the number one thing is where the vasculature becomes leaky and we have edema formation and so on."

Karamyan said the third fact he pointed out in his review is from his own collaborative and preliminary study with TTUHSC colleague Abraham Al-Ahmad, Ph.D., where they showed that these three peptides together -- bradykinin, substance P and neurotensin -- make more profound changes in vascular permeability than each of them produce alone. Vascular permeability refers to a blood vessel wall's capacity to allow other molecules and cells to pass through.

"When they're together, bradykinin, substance P and neurotensin kind of have this synergetic or combined effect," Karamyan said.

If those three peptides are concurrently available, Karamyan continued, they could adversely affect COVID-19 patients and lead to some of the conditions the authors mentioned such as vascular permeability, oxidative stress, inflammation, edema and others. He coined the term "vasoactive peptide storm" to describe the process.

"It's a made-up term, yes, but all three are vasoactive peptides that would do similar things," Karamyan said. "That's why I suggested a vasoactive peptide storm."

In the original paper, the authors proposed using drugs known as receptor blockers that can prevent or reduce the impact of bradykinin. Karamyan agreed, but suggested adding receptor blockers for substance P and neurotensin to yield better results. In fact, Karamyan's lab may already have an enzyme that can inactivate all three, though he said the approach is speculative at this point.

"An enzyme that we are working with called neurolysin actually degrades all three peptides," Karamyan said. "It inactivates bradykinin, neurotensin and substance P. An alternative approach -- again highly speculative -- could perhaps be instead of using three different drugs to block all three peptides, possibly using one enzyme to get rid of all three peptides."

Whether Karamyan decides to investigate the significance and impact of the so-called vasoactive peptide storm, or leave it for others more accustomed to working with COVID-19, Karamyan believes he may have found another piece to the pandemic puzzle. He and several colleagues have discussed testing the ability of neurolysin to deactivate all three peptides.

"These reviewers were telling me this is something that makes sense and is worthy of trying experimentally," Karamyan said. "Obviously, it was very pleasant to hear this and it gave me confidence. Since then, I'm kind of on the border. It would be some deviation from what I do in regards to the disease itself. In regards to the mechanisms, no, because this is my field: peptides and enzymes. As of now I don't have anything planned yet, but it is possible that I may, or we may collectively as a group look into it."

PITTSBURGH, May 5, 2021 - Subtle differences in the shape of the brain that are present in adolescence are associated with the development of psychosis, according to an international team led by neuroscientists at the University of Pittsburgh School of Medicine and Maastricht University in the Netherlands.

In results published today in JAMA Psychiatry, the differences are too subtle to detect in an individual or use for diagnostic purposes. But the findings could contribute to ongoing efforts to develop a cumulative risk score for psychosis that would allow for earlier detection and treatment, as well as targeted therapies. The discovery was made with the largest-ever pooling of brain scans in children and young adults determined by psychiatric assessment to be at high risk of developing psychosis.

"These results were, in a sense, sobering," said Maria Jalbrzikowski, Ph.D., assistant professor of psychiatry at Pitt. "On the one hand, our data set includes 600% more high-risk youth who developed psychosis than any existing study, allowing us to see statistically significant results in brain structure. But the variance between whether or not a high-risk youth develops psychosis is so small that it would be impossible to see a difference at the individual level. More work is needed for our findings to be translated into clinical care."

Psychosis is an umbrella term for a constellation of severe mental disorders that cause people to have difficulty determining what is real and what is not. Most often, individuals have hallucinations where they see or hear things that others do not. They also may have strongly held beliefs, or delusions, even when most people do not believe them. Schizophrenia is only one disorder associated with psychosis, and psychotic symptoms can occur in other psychiatric disorders, such as bipolar disorder, depression, body dysmorphic disorder or post-traumatic stress disorder. In people who receive a diagnosis of psychosis, there is a great deal of heterogeneity in outcomes over time.

Diagnosis usually happens in later adolescence and early adulthood, but most often symptoms begin to manifest in the teen years, when clinicians can use psychological assessments to determine a person's risk of developing full-blown psychosis.

Jalbrzikowsi and Dennis Hernaus, Ph.D., assistant professor in the School of Mental Health and Neuroscience at Maastricht University, are co-chairs of the Enhancing Neuro Imaging Genetics Through Meta-Analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. This group pooled structural magnetic resonance imaging (MRI) scans from 3,169 volunteer participants at an average age of 21 who were recruited at 31 different institutions. About half--1,792 of the participants--had been determined to be at "clinical high risk for developing psychosis." Of those high-risk participants, 253 went on to develop psychosis within two years. The co-chairs emphasized that this study would not be possible without the collaborative efforts of the 100-plus researchers involved.

When looking at all the scans together, the team found that those at high risk for psychosis had widespread lower cortical thickness, a measure of the thickness of the brain's gray matter. In high-risk youth who later developed psychosis, a thinner cortex was most pronounced in several temporal and frontal regions.

Everyone goes through a cortical thinning process as they develop into an adult, but the team found that in younger participants between 12 and 16 years old who developed psychosis the thinning was already present. These high-risk youth who developed psychosis also progressed at a slower rate than in the control group.

"We don't yet know exactly what this means, but adolescence is a critical time in a child's life--it's a time of opportunity to take risks and explore, but also a period of vulnerability," Jalbrzikowski said. "We could be seeing the result of something that happened even earlier in brain development but only begins to influence behavior during this developmental stage."

Hernaus stressed that these findings underscore the importance of early detection and intervention in people who show risk factors for developing psychosis, which include hearing whispers from voices that aren't there and a family history of psychosis.

"Until now, researchers have primarily studied how the brains of people with clinical high risk for psychosis differ at a given point in time," Hernaus said. "An important next step is to better understand brain changes over time, which could provide new clues on underlying mechanisms relevant to psychosis."

Besides being underweight, babies born to women whose diet lacked sufficient protein during pregnancy tend to have kidney problems resulting from alterations that occurred while their organs were forming during the embryonic stage of their development.

In a study published in PLOS ONE, researchers affiliated with the University of Campinas (UNICAMP) in the state of São Paulo, Brazil, discovered the cause of the problem at the molecular level and its link to epigenetic phenomena (changes in gene expression due to environmental factors such as stress, exposure to toxins or malnutrition, among others).

According to the authors, between 10% and 13% of the world population suffer from chronic kidney disease, a gradual irreversible loss of renal function that is associated with high blood pressure and cardiovascular disorder.

The study, conducted at the Obesity and Comorbidities Research Center (OCRC), resulted from PhD research by first author Letícia de Barros Sene with a fellowship from FAPESP.

OCRC is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP.

In the article, the researchers describe the molecular pathways involved in the proliferation and differentiation of embryonic and fetal kidney cells. They obtained this knowledge by sequencing microRNAs (often called miRNAs) from the offspring of rats fed a low-protein diet while gestating. MirRNAs are small non-coding RNAs that regulate gene expression.

“We know low-protein intake during pregnancy tends to lead to a 28% decrease in the number of the offspring’s nephrons, the structures that filter blood in the kidneys. The resulting overloading of nephrons has several consequences. In the case of rats, pups become hypertensive only ten weeks after birth, when they are still considered young,” Patrícia Aline Boer, a member of the OCRC team and last author of the article, told Agência FAPESP. A healthy kidney has about a million nephrons.

Fetal programming

There has been a great deal of research in recent decades on the links between maternal health during pregnancy and child development, especially focusing on a field known as developmental origins of health and disease (DOHaD).

“In humans, these links were first observed after World War Two as a result of what’s known as the ‘Dutch famine’ [Hongerwinter], when the Nazis blocked food supplies to the Netherlands. Scientific studies showed that babies born to women who starved while pregnant in this period were underweight and developed high blood pressure, alterations in response to stress, heart problems, propensity to diabetes, and increased insulin resistance,” said Boer, who is president of DOHaD Brazil.

Since then, this epigenetic phenomenon has been studied in greater depth using animal experiment models. To understand at the molecular level what triggered the reduction in the number of nephrons, the OCRC researchers analyzed expression of miRNAs and target genes in fetal kidneys (metanephros) of rats at 17 days of gestation.

“We know the drop in the number of nephrons isn’t a genetic but an epigenetic effect,” Boer said. “It’s caused by something in the environment. In this case, gene expression is altered by the stress of hypoproteinemia. The DNA sequence doesn’t change. The expression of some genes in the offspring is altered, and the alteration can be heritable – it can be transmitted to future generations. We studied mirRNAs because they’re very important to genetic expression and alterations not associated with changes in DNA.”

Compared analysis between rats fed a regular protein diet (17% of daily calorie intake) and a second group fed a low-protein diet (6%) during pregnancy revealed alterations in 44 miRNAs – seven of which in genes associated with the proliferation and differentiation of cells essential to nephron development, researchers found. Genetic sequencing, immunohistochemistry and morphological analysis demonstrated that maternal protein restriction changed the expression of miRNAs and proteins involved in renal development as early as the 17th day of gestation.

“Previous research showed a 28% reduction in nephrogenesis, and in our study, there was a 28% decrease in the cells that give rise to nephrons. The proportion was the same, which means there must be some kind of signaling during the embryonic period that the organ has to adapt to a low-protein intake,” Boer said.

Other examples of fetal adaptation to malnutrition leading to alterations in organ development can be found in nature, Boer explained. “In our study, we observed that stem cells [which will become nephrons] differentiate very rapidly and that there was more differentiation and less proliferation of the cells that form nephrons,” she said.

The article “Impact of gestational low-protein intake on embryonic kidney microRNA expression and in nephron progenitor cells of the male fetus” (doi: 10.1371/journal.pone.0246289) by Letícia de Barros Sene, Wellerson Rodrigo Scarano, Adriana Zapparoli, José Antônio Rocha Gontijo and Patrícia Aline Boer is at: journals.plos.org/plosone/article?id=10.1371/journal.pone.0246289.

Journal

PLoS ONE

DOI

10.1371/journal.pone.0246289

Researchers from the University of Liverpool have shown the potential of repurposing an existing and cheap drug into a long-acting injectable therapy that could be used to treat Covid-19.

In a paper published in the journal Nanoscale, researchers from the University's Centre of Excellence for Long-acting Therapeutics (CELT) demonstrate the nanoparticle formulation of niclosamide, a highly insoluble drug compound, as a scalable long-acting injectable antiviral candidate.

The team started repurposing and reformulating identified drug compounds with the potential for COVID-19 therapy candidates within weeks of the first lockdown. Niclosamide is just one of the drug compounds identified and has been shown to be highly effective against SARS-CoV-2 in a number of laboratory studies.

Using their expertise in the fields of materials chemistry, long-acting drug delivery and pharmacology, CELT scientists used nanoprecipitation to form redispersible solid drug nanoparticle formulations of niclosamide that can be stored as solids, reconstituted with water and utilised as long acting injectables. Their research has demonstrated sustained circulating drug concentrations may be maintained for the duration of early infection after a single injection.

CELT is co-directed by pharmacologist Professor Andrew Owen and materials chemist Professor Steve Rannard at the University of Liverpool.

Professor Steve Rannard said: "Repurposing drug compounds is much more than using existing medicines for a new disease. The existing active drug compound needs to be shown to be active at a significant level, then reformulated to address new challenges. The conventional route of administration may also not be relevant and modifying the way the patient receives the drug compound is highly critical to efficacy. Niclosamide is an ideal candidate to be taken forward as a potential long acting injectable therapeutic to treat Covid-19.

"This is still in early-stage development but the CELT team are currently working with a contract manufacturing organisation to take this forward towards scale up and clinical manufacture. This work is progressing well and if successful, human trials would be next. We envisage a future `Test-and-Treat' scenario where infected people are treated at the point of diagnosis with the full course of therapy in one injection."

Professor Andrew Owen said: "Repurposing of medicines for SARS-CoV-2 has yielded mixed results, with some clear successes for immunomodulatory drugs such as dexamethasone, and work underway to repurpose drugs like favipiravir and molnupiravir that were designed for other viruses.

"The ultimate utility of our long-acting injectable can only be determined in adequately powered and well controlled randomised clinical trials but unlike other drugs that have been explored for repurposing niclosamide target concentrations may be achievable in humans. The formulation has shown great promise in preclinical studies at a time when it is increasingly evident that drugs are urgently required to compliment the vaccines.

"A global pandemic requires a global solution, and it is critical that interventions are available to everyone and not to the privileged few. Accordingly, we are currently working to remove obstacles to availability in low- and middle-income countries to ensure equitable access if clinical success is ultimately demonstrated."

This research paper builds on previous reports released from the team in April 2020 and published in Clinical Pharmacology and Therapeutics. The CELT team have strongly advocated in further publications in the British Journal of Clinical Pharmacology, that repurposing of drugs requires new strategies that encompass reformulation and specific dose optimisation that addresses the needs of SARS-CoV-2 treatment.

New Johns Hopkins University simulations offer an intriguing look into Saturn's interior, suggesting that a thick layer of helium rain influences the planet's magnetic field.

The models, published this week in AGU Advances, also indicate that Saturn's interior may feature higher temperatures at the equatorial region, with lower temperatures at the high latitudes at the top of the helium rain layer.

It is notoriously difficult to study the interior structures of large gaseous planets, and the findings advance the effort to map Saturn's hidden regions.

"By studying how Saturn formed and how it evolved over time, we can learn a lot about the formation of other planets similar to Saturn within our own solar system, as well as beyond it," said co-author Sabine Stanley, a Johns Hopkins planetary physicist.

Saturn stands out among the planets in our solar system because its magnetic field appears to be almost perfectly symmetrical around the rotation axis. Detailed measurements of the magnetic field gleaned from the last orbits of NASA's Cassini mission provide an opportunity to better understand the planet's deep interior, where the magnetic field is generated, said lead author Chi Yan, a Johns Hopkins PhD candidate.

By feeding data gathered by the Cassini mission into powerful computer simulations similar to those used to study weather and climate, Yan and Stanley explored what ingredients are necessary to produce the dynamo--the electromagnetic conversion mechanism--that could account for Saturn's magnetic field.

"One thing we discovered was how sensitive the model was to very specific things like temperature," said Stanley, who is also a Bloomberg Distinguished Professor at Johns Hopkins in the Department of Earth & Planetary Sciences and the Space Exploration Sector of the Applied Physics Lab. "And that means we have a really interesting probe of Saturn's deep interior as far as 20,000 kilometers down. It's a kind of X-ray vision."

Strikingly, Yan and Stanley's simulations suggest that a slight degree of non-axisymmetry could actually exist near Saturn's north and south poles.

"Even though the observations we have from Saturn look perfectly symmetrical, in our computer simulations we can fully interrogate the field," said Stanley.

Direct observation at the poles would be necessary to confirm it, but the finding could have implications for understanding another problem that has vexed scientists for decades: how to measure the rate at which Saturn rotates, or, in other words, the length of a day on the planet.

The incorporation of boron into polycyclic aromatic hydrocarbon systems leads to interesting chromophoric and fluorescing materials for optoelectronics, including organic light-emitting diodes (OLEDS) and field-effect transistors, as well as polymer-based sensors. In the journal Angewandte Chemie, a research team has now introduced a new anionic organoborane compound. Synthesis of the borafluorene succeeded through the use of carbenes.

Borafluorene is a particularly interesting boron-containing building block. It is a system of three carbon rings joined at the edges: two six-membered and one central five-membered ring, whose free tip is the boron atom. While neutral, radical, and cationic (positively charged) borafluorene compounds are quite easy to produce, there have been few examples of anionic (negatively charged) borafluorene compounds to date. Better understanding of their chemistry is important for advances in redox-dependent applications and could lead to new materials with unique bonding or optical properties. However, the relatively high reactivity of borafluorene anions makes their synthesis challenging. A team led by Robert J. Gilliard, Jr. at the University of Virginia Charlottesville, USA) and David J. D. Wilson at Latrobe University (Melbourne, Australia) has now succeeded in the isolation and structural characterization of these elusive anions.

The starting point for their new synthesis is 9-bromo-9-borafluorene, which has a bromine atom attached to its boron atom. This is treated with a very strong reducing agent (potassium graphite, sodium naphthalenide, or lithium naphthalenide) in the presence of special carbenes (organic compounds with a divalent carbon atom and a free electron pair). The anionic borafluorenes formed in the reduction are stabilized by the carbenes.

As the team demonstrated, the carbene-borafluorene anions can also be used as chemical building blocks. This makes it possible to produce new compounds that are not otherwise accessible with previously known starting materials. For example, compounds with bonds between boron and gold, selenium, or germanium were generated. Reaction with a diketone led to a ring closure and bonding of the boron atom to both ketone oxygens, forming what is known as a spirocyclic boron compound.

Proteins perform a vast array of functions in the cell of every living organism with critical roles in almost every biological process. Not only do they run our metabolism, manage cellular signaling and are in charge of energy production, as antibodies they are also the frontline workers of our immune system fighting human pathogens like the coronavirus. In view of these important duties, it is not surprising that the activity of proteins is tightly controlled. There are numerous chemical switches that control the structure and, therefore, the function of proteins in response to changing environmental conditions and stress. The biochemical structures and modes of operation of these switches were thought to be well understood. So a team of researchers at the University of Göttingen were surprised to discover a completely novel, but until now overlooked, on/off switch that seems to be a ubiquitous regulatory element in proteins in all domains of life. The results were published in Nature.

The researchers investigated a protein from the human pathogen Neisseria gonorrhoeae that causes gonorrhea, a bacterial infection with over 100 million cases worldwide. This disease is typically treated with antibiotics but increasing rates of antibiotic resistance pose a serious threat. In order to identify new treatments, they studied the structure and mechanism of a protein that is a key player in carbon metabolism of the pathogen. Surprisingly, the protein can be switched on and off by oxidation and reduction (known as a "redox switch). The scientists suspected this was caused by a common and well-established "disulfide switch" formed between two cysteine amino acids. When they deciphered the X-ray structures of the protein in the "on" and "off" state at the DESY particle accelerator in Hamburg, Germany, they were hit by an even bigger surprise. The chemical nature of the switch was completely unknown: it is formed between a lysine and a cysteine amino acid with a bridging oxygen atom.

"I couldn't believe my eyes," says Professor Kai Tittmann, who led the study, when he remembers seeing the structure of the novel switch for the first time. "We thought initially that this must have formed artificially as a by-product of the experimental process as this chemical entity was unknown." However, numerous repetitions of the experiments always gave the same result and an analysis of the protein structure database further disclosed that there are many other proteins that very likely possess this switch, which apparently escaped earlier detection as the resolution of the protein structure analysis was insufficient to detect it for certain. The researchers admit that good fortune was on their side because the crystals they measured allowed the protein structure to be determined at extremely high resolution, meaning the novel switch couldn't be missed. "The extensive screening for high-quality protein crystals has really paid off, I couldn't be happier," says Marie Wensien, first author of the paper.

The researchers believe the discovery of the novel protein switch will impact the life sciences in numerous ways, for instance in the field of protein design. It will also open new avenues in medical applications and drug design. Many human proteins with established roles in severe diseases are known to be redox-controlled and the newly discovered switch is likely to play a central role in regulating their biological function as well.