Neighbourhood Watch: What The Mission to Map the Milky Way is Revealing About Satellite Galaxies (Astronomy)

Our Milky Way is not alone in the universe. Surrounding us are numerous satellite galaxies, taking part in a continuous grand dance. But how do these neighbouring galaxies behave, how do they interact with our galaxy, and what does the future hold for them?

Researchers are trying to determine if the Large Magallenic Cloud – the largest of our satellite galaxies – is orbiting the Milky Way or not. Image credit – Skatebiker/Wikimedia, licenced under CC BY-SA 3.0

To find out, scientists are making use of a vast new trove of data from the European Space Agency’s (ESA) Gaia space observatory. This telescope, launched in 2013, has been busy mapping more than a billion stars inside and outside our galaxy – and its latest batch of data has just been released.

On 3 December, the first part of the third batch of data from Gaia – called the Gaia Early Data Release 3 – was made available to scientists. It revealed new positional and velocity data for many stars already in its database, a small portion of which were in these satellite galaxies.

Using this new data, which includes more precise measurements for hundreds of millions of these stars, scientists are planning to probe our galaxy and its surroundings in exquisite detail. And in so doing, we’re about to learn more about our satellite galaxies than ever before.

The Milky Way has at least 50 to 60 satellite galaxies, although the exact number is unknown – some are simply too faint to see. The most populated of these contain billions of stars, compared to hundreds of billions in our own galaxy, while the least populated have just hundreds. They range in distances from about 26,000 to a million light years away.

Plane

While they come in different shapes and sizes, most share an odd trait. ‘Many of the satellites move in a plane, akin to how the planets move around the sun in our solar system,’ said Dr Marius Cautun from Leiden University in the Netherlands. ‘This is quite puzzling, because (based on current theoretical models) we would expect more random motion.’

Dr Cautun and his team made this discovery as part of a project called DancingGalaxies. Using Gaia’s unprecedented and vast data, they have been able to monitor the motion of stars inside these satellite galaxies, and thus track their overall movements.

‘Most of the data from Gaia is about stars in the (Milky Way),’ said Dr Cautun. ‘But you can measure the motion of bright stars as far as 100,000 light years, and maybe even farther, away. And we can average the motion of those stars and obtain the motion of the satellite galaxies.’

This revealed the odd motion of these satellite galaxies – and it could provide an insight into the evolution of the Milky Way. ‘Typically, galaxies grow by accreting (gathering) matter from outside,’ said Dr Cautun. ‘What we think happened in the case of our own Milky Way is the matter, instead of being accreted spherically, was accreted in a plane – including the satellite galaxies. If this is the case, the Milky Way is an extreme example of accretion in a plane.’ This might make the Milky Way a bit unusual, as other galaxies are thought to have accreted spherically.

‘Many of the satellites move in a plane, akin to how the planets move around the sun in our solar system.’, said Dr Marius Cautun, Leiden University, the Netherlands.

Dark matter

Studying the motion of these galaxies has also allowed astronomers like Dr Cautun to probe dark matter, specifically a halo of dark matter known to surround our galaxy. The atypical motion of our satellites has suggested that, rather than being spherical, the dark matter halo is more shaped like a rugby ball and twisted.

‘The puzzling thing is that at some distance, maybe 40,000 to 100,000 light years away from the centre of our own galaxy, the halo undergoes a sudden flip,’ said Dr Cautun, a feature that again might mean the Milky Way is unique, as less than one percent of galaxies are thought to have such a flip. ‘It’s like rugby balls on top of each other, but at some point the rugby ball gets flipped by 90 degrees, a twist in the dark matter halo. This is a weird feature that only happens in very, very few galaxies.’

In the future it should be possible to use Gaia data to probe some of our faintest satellite galaxies in greater detail than before. ‘We are going to have more precise measurements for the motion of the faintest satellites,’ said Dr Cautun, with at least a factor of ten improvement expected on the known motion of such galaxies. ‘It will make a big difference.’

Two satellite galaxies in particular are of keen interest to astronomers, because they are in the process of interacting both with each other and with our Milky Way. These are known as the Small and Large Magellanic Clouds, or SMC and LMC, located about 200,000 and 163,000 light years away respectively.

Professor Maria-Rosa Cioni at the Leibniz Institute for Astrophysics Potsdam in Germany is the lead on a project called Interclouds that is using the LMC and SMC, the former being the largest of our satellite galaxies, to understand more about how galaxies behave. ‘(Our) idea is to use these two galaxies to learn about galaxy interactions,’ she said. Their close proximity to Earth makes them easy candidates to study as even individual stars can be seen.

Pass

To study them, Prof. Cioni and her team have been analysing the populations and motions of the stars in each cloud. Currently, both clouds are moving away from the Milky Way at about 320 kilometres per second, with this being the end of a close pass that began recently in astronomical terms within the last two billion years. A major unanswered question, however, is whether this was their first or second pass.

‘It appears they’re moving too fast to be on a bound orbit, so we think they just made the first passage to the Milky Way,’ said Prof. Cioni. ‘But there are other people that think they are on their second passage, which (would mean) they are already bound to the Milky Way.’

If the former is true, it’s possible the Magellanic Clouds may continue to move away – and thus might not actually be satellites. To find out we will need to know exactly how their mass compares to the Milky Way to discern if there is a strong enough gravitational pull to bring them back or not, and Gaia’s data is vital to come up with that accurate measure of their masses.

‘If the Milky Way is not very massive, then the gravitational force that the Magellanic Clouds would feel is not very strong,’ said Prof. Cioni. ‘(But) if the mass of the Milky Way is significantly larger than the mass of the Magellanic Clouds, they will slow down tremendously such that they will remain closer.’

Prof. Cioni also hopes to probe the ages of the Magellanic Clouds, their chemical compositions, and even their structures – something simply not possible without large-scale datasets like Gaia. ‘Gaia is allowing us to do that on a level that was not possible before,’ she said.

The research in this article was funded by the EU.

Provided by Horizon: The EU Research & Innovation Magazine

What Psychology Can Tell Us About Why Some People Don’t Wear Masks – And How to Change Their Minds (Psychology)

While the world is eagerly waiting for COVID-19 vaccines to bring an end to the pandemic, wearing a mask to help prevent viral transmission has become more or less mandatory globally. Though many people embrace mask wearing and adhere to public health advice, some rebel and argue that wearing a mask has been imposed upon them against their will.

Marina Biryukova/Shutterstock

With mask wearing and social distancing, it’s down to the individual to decide whether or not to comply, yet what influences compliance isn’t straightforward. Demographic factors such as income level, political affiliation and gender have all been associated with whether people choose to wear a mask and socially distance.

However, psychology can go some way to explaining why behavioural differences occur. Past research has shown that psychological factors such as an individual’s perception of risk and tendency towards risky behaviour influence adherence to health behaviours. This is now being seen in the current pandemic.

One preprint study (yet to be peer reviewed) has shown that a greater propensity for risky decision-making goes hand in hand with being less likely to appropriately wear a mask or maintain social distancing. In another piece of research, perceptions of the risk of COVID-19 are cited as a driver of whether people decide to socially distance.

And there may also be a further psychological explanation: the phenomenon of “psychological reactance”. This is where people vehemently believe they have freedom to behave how they wish, and experience negative emotions when this freedom is threatened, and so become motivated to reinstate it.

This means that when told to wear a mask and socially distance, some people may perceive their behavioural freedom to be under threat. Anger and other negative emotions then follow. To reduce these uncomfortable feelings, these individuals may then attempt to restore their freedom by not complying with the advice.

Some people have pushed back against mask wearing by protesting against it publicly. Ilyas Tayfun Salci/Shutterstock

The potential problem of psychological reactance has been discussed since early on in the pandemic, and is now being investigated specifically regarding masks.

How to encourage mask wearing

Just as psychology can help explain why people may reject masks, it can also offer guidance on how to get people to accept them. A variety of techniques from social psychology can be used to persuade people to comply with health advice such as mask wearing, social distancing and self-isolating.

One key persuasion method is portraying consensus. When you show people that an attitude is shared (or not) by others, they are more likely to adopt it. Seeing someone wearing a mask makes it more likely that others will do the same. Persuasion strategies could therefore focus on making sure that people perceive mask wearing as widespread – perhaps by depicting it frequently in the media or by making it mandatory in certain places.

We also know from previous studies that people are more likely to comply with public health guidelines if they are clear, precise, simple and consistent – and if they trust the source from which they come.

But the effectiveness of these sorts of “one-size-fits-all” approaches to persuasion and behavioural change are likely to be limited. Initial findings in the area of personalised persuasion suggest it might be more effective to try bespoke approaches for people, based on combinations of their key characteristics (their “psychographic profiles”).

For example, in a recent piece of non-COVID research we identified three main personality profiles. Those who are more shy, socially inhibited and anxious tend to report being more likely to be persuaded by those in authority, whereas those who are more self-oriented and manipulative tend to feel the opposite; they report being less likely to be influenced by authority figures.

Moreover, those in the third group – who are agreeable, extroverted and conscientious – report being more likely to be persuaded to do something if it is consistent with what they have done before, and less likely if it requires them to change their position. This means if they have decided in the past that wearing masks is a bad thing, they’re more likely to resist any subsequent efforts to make them wear one.

A recent article concluded that shouting at people to wear masks won’t help, and this research into personalised persuasion backs this up. Only those in the shy and anxious group would be likely to respond well to such a direct and heavy-handed tactic. A far better strategy would be to try an empathetic approach that seeks to understand the varying motivations of different groups of people – including whether there is psychological reactance at play – and then tailor messages to individuals accordingly.

This article is republished here from the conversation under common creative licenses. To read original click here.

Research Finds Promising Treatment to Protect Kidney Function in Diabetes (Medicine)

A clinical trial involving researchers at University of Limerick, Ireland has demonstrated the potential benefits of new drugs in protecting kidney function in diabetes.

© Paras Hospitals

The new study has found that combining two treatments that lower uric acid concentrations in the blood reduces the leakage of albumin in the urine, one of the earliest signs of kidney damage in diabetes.

The discovery could help to prevent kidney failure in diabetes patients, the UL researchers believe.

Researchers from the University of Limerick School of Medicine and University Hospital Limerick, working with investigators from the University of California San Diego, USA and AstraZeneca, found that the combination of Verinurad and Febuxostat reduced albuminuria in the urine by 39.4% in patients with Type 2 diabetes after 12 weeks of treatment compared to placebo.

The results of this AstraZeneca sponsored Phase 2a clinical trial were recently published in the American Journal of Kidney Disease.

Verinurad is a novel inhibitor of the uric acid transporter (URAT1) and is currently under investigation for the treatment of hyperuricaemia and kidney disease. Febuxostat is a potent, selective xanthine oxidase inhibitor used to lower urate levels in patients with gout and hyperuricaemia.

The CITRINE clinical trial results show that the combination of drugs reduces the leaking of protein through the kidney.

“This is exciting news as leaking of protein is the earliest clinical sign of kidney damage,” said Professor Austin Stack, Foundation Chair of Medicine at UL’s School of Medicine and Consultant Nephrologist at University Hospital Limerick, who was lead author of the study.

“The results are very promising as they demonstrate an important reduction in albuminuria and hyperuricaemia in patients with type 2 diabetes when treated with a combination of Verinurad and Febuxostat.

“If we can intervene early on then we are more likely to prevent patients from going into kidney failure. The findings raise hope for the 350 million people with type 2 diabetes globally who are at increased risk of kidney failure,” added Professor Stack, director of the National Kidney Disease Surveillance System (NKDSS).

In the multicentre randomized clinical trial, 60 patients with type 2 diabetes with albuminuria and elevated uric acid levels were randomized to receive either Verinurad 9mg, and Febuxostat 80mg or placebo. The patients were followed up for 24 weeks.

The primary endpoint of the study was met and showed a 39% reduction in albuminuria, after 12 weeks with combined treatment of Verinurad and Febuxostat versus placebo. This effect persisted at 24 weeks with an overall 49% reduction in albuminuria. Treated patients also experienced a 57% reduction in uric acid levels at 12 weeks. Both Verinurad and Febuxostat were well tolerated by patients, according to the study.

“One of the earliest signals of kidney disease is development of albuminuria (leaking of albumin into the urine) and recent studies have shown that this can be associated with high levels of uric acid,” said Professor Stack, a HRB-funded principal investigator whose work in this area has raised the profile of uric acid as a potential risk factor for kidney and heart disease.

“A key goal in protecting kidney function is the lowering of albuminuria in the urine, as patients with high levels are at risk of progressing to kidney failure. This clinical trial was designed to examine the effects of an intensive uric acid lowering strategy on albuminuria by combining Verinurad with Febuxostat in patients with type 2 diabetes mellitus with pre-existing albuminuria.

“Although these are early clinical findings, our results show that combined treatment with Verinurad and Febuxostat in patients with diabetes results in a rapid reduction in albuminuria that was sustained through week 24,” Professor Stack added.

A larger clinical trial, the SAPPHIRE study, is currently underway to determine whether an intensive uric acid lowering strategy combining Verinurad with a xanthine oxidase inhibitor will slow the progression of chronic kidney disease.

“Diabetes is the greatest contributor to the 850 million globally with chronic kidney disease,” explained Professor Stack.

“More than 40% of patients with diabetes are at risk for developing kidney disease and significant number of these will progress to kidney failure. Preventing kidney failure is a key goal in all healthcare systems to reduce morbidity of diabetes and improve patient outcomes,” he added.

Reference: Austin G. Stack et al, Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial, American Journal of Kidney Diseases (2020). DOI: 10.1053/j.ajkd.2020.09.009

Provided by University of Limerick

Social Media Messages Help Reduce Meat Consumption (Psychology)

Sending direct messages on social media informing people of the negative health and environmental impacts of consuming meat has proven successful at changing eating habits, a new study from Cardiff University has shown.

The study showed that sending direct messages twice a day through Facebook Messenger led to a significant reduction in the amount of red and processed meat the participants consumed over a 14-day period.

Participants reported, on average, eating between 7 and 8 portions of red or processed meat during the previous week before the Facebook messages were sent, which then dropped to between 4 and 5 portions during the second week of the intervention and stayed at roughly the same level one month after the intervention.

Furthermore, the intervention led to an observed ‘behavioural spillover’ effect in which the participants indicated a desire to also reduce other types of meat they would consume in the future, alongside dairy products.

The study has been published in the journal Frontiers in Psychology.

The health impacts of eating too much red and processed meat are well established, with links to cardiovascular disease, stroke, and certain forms of cancer.

Meat is also a major driver of climate change, responsible for approximately 15% of global anthropogenic greenhouse gas emissions, with a growing consensus among scientists that reducing excess meat consumption will be necessary to meet climate change targets.

Yet, evidence suggests there is a lack of public awareness of the issue and that people tend to greatly underestimate the extent to which meat consumption leads to climate change.

“With Christmas approaching, it is a good time to consider how much meat we consume on a day-to-day basis and the impacts that this can have on the environment as well as our health,” said Emily Wolstenholme from the School of Psychology, who led the study.

“Our study shows that making people aware of these climate impacts makes them think about their eating habits. It also shows that people are willing to make changes to help the climate.”

A total of 320 participants were recruited for the study, who were then divided into either one of three experimental conditions, or the control group, and were sent messages through Facebook Messenger twice a day during the two-week intervention period.

Different messages were sent to participants in the experimental groups, each focussing on the environmental and/or health consequences of eating too much meat, for example: “If you eat only a small amount of red and processed meat, you will protect the environment by reducing the release of harmful greenhouse gases.”

Participants were asked to complete a food diary every day during the two-week period to keep track of their diet.

Surveys were sent to participants at the end of the two-week intervention to measure their red and processed meat consumption, as well as other environmentally friendly behaviors. The same survey was repeated a month after the end of the intervention.

Over the two-week period the researchers observed a significant reduction in the amount of red and processed meat that was consumed by the participants receiving health messages, environmental messages and combined health and environmental messages—with no significant difference between each of these approaches.

Professor Wouter Poortinga, co-author of the study from the Welsh School of Architecture, said: “The results of the research are really encouraging. It shows that we can make changes to our diet, and if we all do, it can make a big difference for climate change. “

Reference: Emily Wolstenholme et al. Two Birds, One Stone: The Effectiveness of Health and Environmental Messages to Reduce Meat Consumption and Encourage Pro-environmental Behavioral Spillover, Frontiers in Psychology (2020). DOI: 10.3389/fpsyg.2020.577111

Provided by Cardiff University

Study Reveals Distinct Genomic Landscape for Young Adults With Appendiceal Cancer (Oncology / Medicine)

The first study to compare molecular landscapes of early-onset and late-onset appendiceal cancer has revealed distinct non-silent mutations in the tumors of younger patients, setting the stage for the development of potential therapeutic advances for this rare disease.

The findings, published Dec. 9 in JAMA Network Open, were derived from an analysis of tumor genomic profiles of patients under age 50 compared to those 50 and older at diagnosis from the American Association for Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) registry.

“Appendiceal cancer among young patients harbors a distinct biology, which has potential clinical actionability,” said the study’s lead author, Andreana Holowatyj, Ph.D., MSCI, assistant professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and an epidemiologist with Vanderbilt-Ingram Cancer Center.

Patients with early-onset appendiceal cancer harbored unique mutation patterns in the genes PIK3CA, GNAS, SMAD3 and TSC2. A targeted therapy for the PIK3CA mutation when it occurs in advanced breast cancer, alpelisib, has already been approved by the U.S. Food and Drug Administration.

“There are currently no targeted therapies specifically for appendiceal cancer patients,” Holowatyj said. “After surgery, National Comprehensive Cancer Network (NCCN) guidelines recommend to treat it as a right-sided colon tumor for that reason. But the fact that one of every eight young patients diagnosed with appendiceal cancer has a PIK3CA mutation, a much higher mutation rate compared with late-onset cases, really lends for the potential and the promise to evaluate repurposing existing drugs for early-onset patients diagnosed with this rare malignancy.”

Although appendiceal cancer is rare, its incidence is on the rise. Cancer of the appendix is typically found during surgery for acute appendicitis, and even though the rate of appendectomies has been stable over the last two decades, diagnoses have increased 232% in the United States.

Holowatyj and colleagues used data from 12 of the AACR Project GENIE participating institutions contained within the registry in their analysis. The international registry offers real-world data that would otherwise be difficult to compile. The researchers were able to study the genomic profiles of appendiceal cancer in 385 patients.

“As a rare disease, appendiceal cancer is understudied, and it is challenging to garner sufficient resources and funding to study this malignancy,” Holowatyj said. “But given its increasing incidence, especially among young people, it merits further investigation. In contrast to colorectal cancer, where one out of every 10 adults are diagnosed before age 50, this study also shows that one out of every three adults with appendiceal cancer is diagnosed before age 50.”

Provided by Vanderbilt University Medical Center

Obesity Impairs Immune Cell Function, Accelerates Tumor Growth (Medicine)

Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive.

Tumors from a nonobese animal (top row) contain more CD8+ T cells (red), compared to those from an obese one (bottom row). Tumor cells are highlighted in cyan. Credit: Ringel et al, 2020.

Now, in a study in mice, Harvard Medical School researchers have uncovered a new piece of this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel.

Reporting in Cell on Dec. 9, the research team shows that a high-fat diet reduces the numbers and antitumor activity of CD8+ T cells, a critical type of immune cell, inside tumors. This occurs because cancer cells reprogram their metabolism in response to increased fat availability to better gobble up energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.

“Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet,” said Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS and co-senior author of the study. “This finding suggests that a therapy that would potentially work in one setting might not be as effective in another, which needs to be better understood given the obesity epidemic in our society.”

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results suggest new strategies for improving such therapies.

“Cancer immunotherapies are making an enormous impact on patients’ lives, but they do not benefit everyone,” said co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute.

“We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity,” Sharpe said. “Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways.”

Haigis, Sharpe and colleagues investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team gave mice normal or high-fat diets, the latter leading to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors, together called the tumor microenvironment.

Fatty paradox

The researchers found that tumors grew much more rapidly in animals on high-fat diets compared to those on normal diets. But this occurred only in cancer types that are immunogenic, which can contain high numbers of immune cells; are more easily recognized by the immune system; and are more likely to provoke an immune response.

Experiments revealed that diet-related differences in tumor growth depended specifically on the activity of CD8+ T cells, immune cells that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice.

Strikingly, high-fat diets reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. Those remaining in the tumor were less robust—they divided more slowly and had markers of decreased activity. But when these cells were isolated and grown in a lab, they had normal activity, suggesting something in the tumor impaired these cells’ function.

The team also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, a major cellular fuel source, even though the rest of the body was enriched in fats, as expected in obesity.

These clues pushed the researchers to craft a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diet conditions.

The analyses revealed that cancer cells adapted in response to changes in fat availability. Under a high-fat diet, cancer cells were able to reprogram their metabolism to increase fat uptake and utilization, while CD8+ T cells did not. This ultimately depleted the tumor microenvironment of certain fatty acids, leaving T cells starved for this essential fuel.

“The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really blew us away and it was the launch pad for our analyses,” said Ringel, a postdoctoral fellow in the Haigis lab. “That obesity and whole-body metabolism can change how different cells in tumors utilize fuel was an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes.”

Hot and cold

Through several different approaches, including single-cell gene expression analyses, large-scale protein surveys and high-resolution imaging, the team identified numerous diet-related changes to metabolic pathways of both cancer and immune cells in the tumor microenvironment.

Of particular interest was PHD3, a protein that in normal cells has been shown to act as a brake on excessive fat metabolism. Cancer cells in an obese environment had significantly lower expression of PHD3 compared to in a normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this diminished a tumor’s ability to take up fat in obese mice. It also restored the availability of key free fatty acids in the tumor microenvironment.

Increased PHD3 expression largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew slower in obese mice compared to tumors with low PHD3. This was a direct result of increased CD8+ T cell activity. In obese mice lacking CD8+ T cells, tumor growth was unaffected by differences in PHD3 expression.

The team also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically “cold” tumors, defined by fewer numbers of immune cells. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the authors said.

“CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T,” Sharpe said. “These approaches need T cells to have sufficient energy to kill cancer cells, but at the same time we don’t want tumors to have fuel to grow. We now have amazingly comprehensive data for studying this dynamic and determining mechanisms that prevent T cells from functioning as they should.”

More broadly, the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes, the authors said. While it’s too early to tell if PHD3 is the best therapeutic target, the findings open the door for new strategies to combat cancer through its metabolic vulnerabilities, they said.

“We’re interested in identifying pathways that we could use as potential targets to prevent cancer growth and to increase immune antitumor function,” Haigis said. “Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity and the crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more pathways to be explored.”

Provided by Harvard Medical School

New Compound Related to Psychedelic Ibogaine Could Treat Addiction, Depression (Psychiatry)

A non-hallucinogenic version of the psychedelic drug ibogaine, with potential for treating addiction, depression and other psychiatric disorders, has been developed by researchers at the University of California, Davis. A paper describing the work is published Dec. 9 in Nature.

“Psychedelics are some of the most powerful drugs we know of that affect the brain,” said David Olson, assistant professor of chemistry at UC Davis and senior author on the paper. “It’s unbelievable how little we know about them.”

Ibogaine is extracted from the plant Tabernanthe iboga. There are anecdotal reports that it can have powerful anti-addiction effects such as reducing drug cravings and preventing relapse. But there are also serious side-effects, including hallucinations and cardiac toxicity, and the drug is a Schedule 1 controlled substance under U.S. law.

Olson’s laboratory at UC Davis is one of a few in the U.S. licensed to work with Schedule 1 substances. They set out to create a synthetic analog of ibogaine which retained therapeutic properties without the undesired effects of the psychedelic compound. Olson’s team worked through a series of similar compounds by swapping out parts of the ibogaine molecule. They engineered a new, synthetic molecule which they named tabernanthalog or TBG.

Models of anxiety, depression and addiction

Unlike ibogaine, the new molecule is water-soluble and can be synthesized in a single step. Experiments with cell cultures and zebrafish show that it is less toxic than ibogaine, which can cause heart attacks and has been responsible for several deaths.

TBG increased formation of new dendrites (branches) in rat nerve cells, and of new spines on those dendrites. That’s similar to the effect of drugs like ketamine, LSD, MDMA and DMT (the active component in the plant extract ayahuasca) on connections between nerve cells.

TBG did not, however, cause a head twitch response in mice, which is known to correlate with hallucinations in humans.

A series of experiments in rodent models of depression and addiction show that the new drug has promising positive effects. These animal models—conducted in accordance with NIH regulations and reviewed and approved by Institutional Animal Care and Use Committees—remain vital to investigating complex psychiatric disorders.

Mice trained to drink alcohol cut back their consumption after a single dose of TBG. Rats were trained to associate a light and tone with pressing a lever to get a dose of heroin. When the opiate is taken away, the rats develop signs of withdrawal and press the lever again when given the light and sound cues. Treating the rats with TBG had a long-lasting effect on opiate relapse.

Olson thinks that TBG works by changing the structure of neurons in key brain circuits involved in depression, anxiety, post-traumatic stress disorder and addiction.

“We’ve been focused on treating one psychiatric disease at a time, but we know that these illnesses overlap,” Olson said. “It might be possible to treat multiple diseases with the same drug.”

Indeed, psychedelic therapies have been attracting new interest in recent years. But taking patients on individual ‘trips’ is time consuming and costly, requiring hours of close medical supervision apart from the possible negative effects.

“We need a drug that people can keep in their medicine cabinet and this is a significant step in that direction,” Olson said.

Reference: Cameron, L.P., Tombari, R.J., Lu, J. et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature (2020). https://www.nature.com/articles/s41586-020-3008-z https://doi.org/10.1038/s41586-020-3008-z

Provided by UC Davis

Scientists Discover a Cellular and Molecular Mechanism That Promotes Vascular Arterialization (Cardiology / Medicine)

Research carried out by scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) advances the understanding of the biology of blood vessels, and points the way to the design of new therapeutic strategies to induce vascularization and more effective blood perfusion of injured or ischemic tissues.

Confocal microscopy projection image of a mouse heart in which a multispectral genetic mosaic was induced in coronary vessels. This novel genetic and imaging technology was used to label and fate map individual coronary endothelial cells containing distinct genetic mutations. These mutations either impair or promote cell-cycle progression, determining the arterial or venous fate of endothelial cells. To form arteries, cells need to lower their metabolism and exit the cell-cycle (G0). Credit: CNIC

The study, led by Rui Benedito and published in Nature, reveals a new cellular and molecular mechanism essential for the development of arteries from blood capillaries, a process called arterialization. Activation of this mechanism could improve the recovery of heart function after transient or long term reduction in heart blood flow.

Until now, vascular arterialization was believed to depend on the differentiation and specification of a progenitor cell into an arterial cell, a process thought to require transcriptional activation and DNA remodeling. The new discovery shows that arterialization involves instead the timely suppression of metabolism and the cell cycle, and that this event is both necessary and sufficient to trigger the differentiation and development of arteries.

In the past 20 years, scientists have discovered several cellular and molecular mechanisms that are essential for the formation and differentiation of arteries and veins. The first blood vessels to develop in any growing organ are immature and form an undifferentiated and rudimentary vascular network called a precursor vascular plexus. This network is formed from endothelial cells and is relatively inefficient at transporting blood. It can be likened to a road network built for local traffic but lacking a system of larger connecting highways.

The formation of a hierarchical vascular system composed of larger conduction arteries and veins is therefore essential for the efficient transport of blood to and from tissues. “The incorrect development of this system causes premature embryonic death or potentially fatal diseases linked to vascular malformations that can cause stroke, poor oxygen supply or inadequate tissue perfusion,” explained the study authors.

Initiation of correct arterial specification requires the activation of two genetic pathways: the VEGF and the Notch signaling pathway. “Notch is a molecular signaling pathway that directly regulates the transcription of an immense array of genes that alter a cell’s biology. When Notch is not activated in endothelial cells, arterial specification and development fails, remaining only capillary and venous endothelial cells,” said Rui Benedito.

This led to the view that arteries are built through the induction of a highly conserved, Notch-dependent program of genetic change in a subset of endothelial cells. This genetic program was thought to be essential for the capacity of endothelial cells to differentiate, migrate, and form arteries.

Using sophisticated mouse models, cell imaging and fate mapping tools, Rui Benedito’s group has now discovered that cells with distinct Notch signaling levels are biased towards a particular fate, but not genetically pre-determined, as they can adopt distinct arteriovenous fates if placed in the appropriate biophysical context.

First author Wen Luo found that the main function of VEGF and Notch in arterializing endothelial cells is to inhibit Myc, suppressing its ability to promote cell proliferation and metabolism. The study shows that Myc inhibition is necessary and sufficient to induce an effective bias towards arterialization.

The results also have important implications for the use of drugs to boost angiogenesis in ischemic cardiovascular disease. The study suggests that pro-angiogenic drugs that stimulate general blood vessel proliferation will suppress arterialization. “One of our future goals will be to identify new ways to supress proliferation signals exclusively in pre-arterial cells, thereby promoting effective arterialization without negatively interfering with the induction of capillary angiogenesis,” said Rui Benedito.

From a translational standpoint, the authors conclude that the ability to modulate arterial or venous identity of blood vessels is of great interest for the treatment of coronary artery disease and myocardial infarction. The results obtained could lead to novel therapeutic approaches to induce effective arterialization in ischemic cardiovascular disease.

Reference: Luo, W., Garcia-Gonzalez, I., Fernández-Chacón, M. et al. Arterialization requires the timely suppression of cell growth. Nature (2020). https://www.nature.com/articles/s41586-020-3018-x https://doi.org/10.1038/s41586-020-3018-x

Provided by Centro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.)

Targeting T Cell Protein Could Prevent Type 1 Diabetes, Study Suggests (Medicine)

Researchers at the University of Utah School of Medicine have identified a new therapeutic target to treat patients with type 1 diabetes. The study, which will be published December 9 in the Journal of Experimental Medicine (JEM), reveals that inhibiting a protein called OCA-B protects mice from type 1 diabetes by limiting the activity of immune cells that would otherwise destroy the pancreas’ insulin-producing β cells.

Pancreatic tissue from a type 1 diabetic mouse (left) shows large numbers of infiltrating immune cells and a reduction in the size of β cell-containing islets of Langerhans (yellow arrows). These symptoms are prevented by deletion of the gene encoding OCA-B (right). Credit: © 2020 Kim et al. Originally published in Journal of Experimental Medicine. 10.1084/jem.20200533

Type 1 diabetes is an autoimmune disease in which the body’s immune system mistakenly attacks pancreatic β cells, cutting off the production of insulin. Patients require life-long insulin therapy to maintain appropriate blood glucose levels. At present, there are no treatments that can prevent the immune system from targeting β cells while preserving its ability to fight infection.

White blood cells called T cells can recognize specific molecules produced by invading bacteria and viruses. When T cells encounter these molecules, known as antigens, they turn on hundreds of genes that allow them to fight the infection. A protein called OCA-B binds to many of these genes and helps ensure that they can easily be reactivated if the T cells reencounter the same antigens at a later date.

In many autoimmune diseases, T cells mistakenly recognize and respond to antigens produced by normal, healthy cells. “Repeated antigen exposure is a common property of autoimmune responses,” explains Dean Tantin, a professor in the Department of Pathology at the University of Utah School of Medicine and a member of the Huntsman Cancer Institute. “We therefore hypothesized that targeting OCA-B would inhibit autoreactive, diabetogenic T cell responses.”

In the new study, Tantin and colleagues found that mice prone to developing type 1 diabetes were protected from the disease if they lacked OCA-B. Potentially autoreactive cytotoxic T cells—which can directly target and kill pancreatic β cells—remained inactive and did not accumulate in the pancreas. Potentially autoreactive helper T cells—which can recruit other immune cells to induce a damaging inflammatory response—accumulated in the pancreas but remained in a non-responsive state.

OCA-B regulates the activity of T cell genes by recruiting an enzyme called Jmjd1a to chemically modify the surrounding chromosomal DNA. Tantin and colleagues designed a small peptide capable of inhibiting the association of OCA-B with Jmjd1a and preventing the reactivation of isolated T cells in the lab. Injecting prediabetic mice with this peptide reduced the activity of autoreactive T cells, lowered pancreatic inflammation, and restored blood glucose levels to normal.

“While the peptide is unlikely to be used in a clinical setting, it offers a proof-of-principle for OCA-B as a therapeutic target for type 1 diabetes, and can be used as a tool for the further development of therapeutics,” Tantin says.

Provided by Rockefeller University Press