A Subset of Immune Cells Contribute to Transplant Rejection (Medicine)

Non-circulating memory T cells, whose main function is to provide local protection against re-infection, contribute to chronic transplant rejection, University of Pittsburgh School of Medicine researchers reveal in a paper published today in Science Immunology.

The scientists show that these “tissue-resident memory T cells” are harmful in situations where antigens that the cells recognize are present in the body for a long time, such as in cases of an organ or tissue transplant. This finding is an important step toward improving therapies to help prevent organ rejection in transplant recipients.

Martin Oberbarnscheidt, M.D., Ph.D., assistant professor of surgery, University of Pittsburgh © Martin Oberbarnscheidt

“Tissue-resident memory T cells serve an important surveillance function,” said co-senior author Martin Oberbarnscheidt, M.D., Ph.D., assistant professor of surgery at Pitt. “If these cells encounter the same pathogen more than once, they can help quickly eliminate it. But studying these cells in transplants gives us a unique opportunity to look into what happens when the antigen persists—a new organ transplant is a big piece of tissue which, unlike an infection, stays in the body for a long time.”

Immunologists and transplant surgeons have long been aware that T cells—a subset of immune cells central to the development of acquired immunity—play a critical role in acute rejection of a transplanted organ. But until now, the role of resident memory T cells in transplant rejection was overlooked.

Khodor Abou-Daya, M.D., research assistant professor, Department of Surgery, University of Pittsburgh © Khodor Abou-Daya

“Resident memory T cells turn from being protective against an infection into a problem in a transplant setting as they fight off a life-saving organ,” said lead author Khodor Abou-Daya, M.D., research assistant professor in Pitt’s Department of Surgery. “It’s an elephant in the room—T cells are present at a chronic stage of the kidney transplant rejection, but no one knew if these cells were functional.”

Using a mouse model of kidney transplantation, the researchers showed that, over time, activated T cells that infiltrate a transplanted organ morph into resident memory T cells. 

They discovered that if they surgically conjoin blood circulation of two mice, both of which received identical kidney transplants, memory T cells formed in transplanted organs don’t travel from one mouse to the other. Similarly, if a transplanted kidney was then removed and re-transplanted again to yet another mouse, resident memory T cells stayed in the transplanted kidney and didn’t disseminate anywhere else in the recipient’s body, establishing that these cells reside in the tissue permanently. 

It also is remarkable that, despite the presence of the ubiquitous antigen, these tissue-resident memory T cells didn’t become “exhausted,” as commonly happens to these T cells during chronic infections and in tumors. Instead, the cells remained functional, proliferating and producing signals that sustained a prolonged immune response. Moreover, their formation precipitated kidney graft rejection.

“There is an assumption that T cells in transplanted organs or tissues are exhausted and dysfunctional and may not contribute significantly to tissue rejection,” said Abou-Daya. “Our work shows that tissue-resident memory T cells are functional and destructive.”

Specifically targeting these cells could improve clinical transplant outcomes while preserving the immune system’s ability to fight off infections, reducing the side effects of current systemic immunosuppressive therapies.

Other authors on the manuscript include Rayan Rammal, M.D., of the American University of Beirut, Lebanon; Roger Tieu, Daqiang Zhao, M.D., Faruk Sacirbegovic, Ph.D., Amanda Williams, M.S., and Warren Shlomchik, M.D., all of Pitt. Fadi Lakkis, M.D., of Pitt, is a co-senior author.

This work was supported by the National Institutes of Health (grants AI049466, AI145881, HL143349, AI074490, DK124925, GM008208, 1S10OD011925-01 and 1S10OD019942-01). It also was supported by the Ben J. Lipps Fellowship from the American Society of Nephrology and the Thomas E. Starzl Postdoctoral Fellowship in Transplantation Biology

Featured image: Transplanted kidney stained with a blue dye shows signs of inflammation.  © Martin Oberbarnscheidt

Reference: Khodor I. Abou-Daya, Roger Tieu, Daqiang Zhao, Rayan Rammal, Faruk Sacirbegovic, Amanda L. Williams, Warren D. Shlomchik, Martin H. Oberbarnscheidt, Fadi G. Lakkis, “Resident memory T cells form during persistent antigen exposure leading to allograft rejection”, Science Immunology  19 Mar 2021: Vol. 6, Issue 57, eabc8122 DOI: 10.1126/sciimmunol.abc8122

Provided by University of Pittsburgh

New Technology ‘Retrains’ Cells To Repair Damaged Brain Tissue In Mice After Stroke (Neuroscience)

Most stroke victims don’t receive treatment fast enough to prevent brain damage. Scientists at The Ohio State University Wexner Medical CenterCollege of Engineering and College of Medicine have developed technology to “retrain” cells to help repair damaged brain tissue. It’s an advancement that may someday help patients regain speech, cognition and motor function, even when administered days after an ischemic stroke. 

Engineering and medical researchers use a process created by Ohio State called tissue nanotransfection (TNT) to introduce genetic material into cells. This allows them to reprogram skin cells to become something different – in this case vascular cells – to help fix damaged brain tissue.  

Study findings published online today in the journal Science Advances. 

In this mouse study, cells were ‘pre-conditioned’ with specific genes and injected into the stroke-affected brains, where they promoted the formation of new blood vessels via reprogramming and the repair of damaged brain tissue.  

“We can rewrite the genetic code of skin cells so that they can become blood vessel cells,” said Daniel Gallego-Perez, an assistant professor of biomedical engineering and surgery at Ohio State who is leading the research. “When they’re deployed into the brain, they’re able to grow new, healthy vascular tissue to restore normal blood supply and aid in the repair of damaged brain tissue.”

Researchers studied the process in mice and found that those treated with this innovative cell therapy regained 90% of their motor function. MRI scans showed damaged areas of the brain were repaired within a few weeks. 

“We found that the mice have a higher recovery because the cells that are being injected into the affected area also release healing signals in the form of vesicles that help in the recovery of damaged brain tissue” said Natalia Higuita Castro, assistant professor of biomedical engineering and surgery at Ohio State and a co-lead author on the study. 

Every 40 seconds, someone in the United States suffers a stroke. It’s the second-leading cause of death worldwide, and those who survive often have irreversible brain damage resulting in paralysis, speech impairment and loss of motor function. No treatments exist to address the lasting and debilitating damage to brain tissue caused by stroke. 

Although medical advancements have allowed doctors to clear clots in the brain faster and improve outcomes, this is only effective if done within a few hours of the stroke, before the brain tissue dies. About 80% of ischemic stroke patients don’t receive the clot-busting therapy in time to prevent permanent deficits to their speech, cognition and motor function. 

“The thought was that once brain tissue dies, that was it,” said Dr. Shahid Nimjee, a neurosurgeon at Ohio State Wexner Medical Center, a member of Ohio State’s Neurological Institute and co-author of the study. “We’re now learning that there could be opportunities to regenerate cells to restore brain function.” 

Researchers continue to study this approach, and they’re also exploring other potential uses for this technology to treat brain disorders such as Alzheimer’s and autoimmune diseases. 

The research team spans across the Ohio State campus in the departments of biomedical engineering, neurosurgery, biology, nutrition, neuroscience, neurology and surgery; along with the biomedical science graduate program. The team also includes scientists at the Georgia Institute of Technology in Atlanta, National University of Colombia in Bogota, Columbia and Indiana University School of Medicine in Indianapolis. 

This study is funded by grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering.

Featured image: From left, researchers Luke Lemmerman and Daniel Gallego-Perez helped develop a new cell therapy that may lead to unprecedented recovery for stroke victims. © Wexner Medical Center

Reference: Luke R. Lemmerman, Maria H. H. Balch et al., “Nanotransfection-based vasculogenic cell reprogramming drives functional recovery in a mouse model of ischemic stroke”, Science Advances  19 Mar 2021: Vol. 7, no. 12, eabd4735 DOI: 10.1126/sciadv.abd4735

Provided by Wexner Medical Center

Astronomers Discovered 4 New Hot Jupiters from the Next Generation Transit Survey (Planetary Science)

Rosanna H. Tilbrook and colleagues reported the discovery of four new hot Jupiters: NGTS-15b, NGTS-16b, NGTS-17b, and NGTS-18b. All four planets are short-period (𝑃 < 5d) planets orbiting G-type main sequence stars, with radii and masses between 1.10 − 1.30 𝑅𝐽 (1.10-1.30 times that of the radius of Jupiter) and 0.41 − 0.76 𝑀𝐽 (0.41–0.76 times that of the mass of Jupiter).

Each planet was originally identified from photometry from the Next Generation Transit Survey (NGTS), and was confirmed through follow-up observations carried out at the South African Astronomical Observatory (SAAO) with the 1.0 m and Lesedi telescopes, and radial velocity measurements made with the HARPS, CORALIE and FEROS spectrographs. Additional photometry from the Transiting Exoplanet Survey Satellite (TESS) was also acquired for three of the four targets.

Global fits to these data were produced using the open-source astronomy software package ALLESFITTER, and yielded masses, radii, and orbital periods consistent with hot Jupiter planets (see Table 1). Spectral analysis via iSPEC and SED fitting via ARIADNE revealed the properties of the host stars in each system, which were all found to be main-sequence G-type stars (see Tables 2, 3, 4, and 5).

Table 1: Planetary properties for each system from ALLESFITTER © Tilbrook et al.
Table 2. Stellar Properties for NGTS-15. For the values from ariadne, we include a second systematic error from the difference between the average best-fit value and the maximum value from the individual stellar atmosphere models. © Tilbrook et al.
Table 3. Stellar Properties for NGTS-16. © Tilbrook et al.
Table 4. Stellar Properties for NGTS-17. © Tilbrook et al.
Table 5. Stellar Properties for NGTS-18. © Tilbrook et al.

By considering the host star luminosities and the planets’ small orbital separations (0.039 − 0.052 AU), they found that all four hot Jupiters are highly irradiated and therefore occupy a region of parameter space in which planetary inflation mechanisms become effective. Comparison with statistical studies and a consideration of the planets’ high incident fluxes reveals that NGTS-16b, NGTS-17b, and NGTS-18b are indeed likely inflated, although some disparities arise upon analysis with current Bayesian inflationary models. While, they were unable to draw any firm conclusions on the nature of inflation for NGTS-15b due to the poorly constrained age for this system resulting in a broad range of non-inflated radius values.

“We found that two of the planets are likely inflated when compared with non-inflationary models, and it is reasonable to assume that NGTS-18b, although consistent with both inflated and non-inflated solutions, is also inflated due to its high incident flux. We were unable to draw any firm conclusions on the nature of inflation for NGTS-15b due to the poorly constrained age for this system resulting in a broad range of non-inflated radius values.”

— told Rosanna Tilbrook, first author of the study

Figure 1. Exoplanets from the Exoplanet Orbit Database with masses between 0.37 ↦ 0.97 𝑀𝐽 . They overplot the model (solid black line) from Sestovic et al. (2018) with the associated standard deviation in 𝑅 (dotted black line) for hot Jupiter inflation in this mass regime. The hot Jupiters presented in their paper are plotted as stars with coloured outlines. © Tilbrook et al.

Furthermore, they note some disparity between the radii derived from global modelling and those predicted by the inflationary forward model of Sestovic et al. (2018), although all four planets were found to fit within the general hot Jupiter population (see Featured image & Figure 1). They suggested that the inclusion of both new hot Jupiter data and additional hyperparameters which describe latent parameters, such as system age, into the Bayesian model may refine the relations further.

Featured image: Exoplanets with confirmed masses and radii (grey points) from the NASA Exoplanet Archive (https://exoplanetarchive.ipac.caltech.edu/). The background and the dotted black contour lines highlight the point density per grid element of their sample. The hot Jupiters presented in this paper are plotted with error bars, and can be seen to lie comfortably within the general population of hot Jupiters. NGTS-15b to NGTS-18b are labeled with coloured circles on the plot with associated uncertainties. © Tilbrook et al.

Reference: Rosanna H. Tilbrook, Matthew R. Burleigh, Jean C. Costes, Samuel Gill, Louise D. Nielsen, José I. Vines, Didier Queloz, Simon T. Hodgkin, Hannah L. Worters, Michael R. Goad, Jack S. Acton, Beth A. Henderson, David J. Armstrong, David R. Anderson, Daniel Bayliss, François Bouchy, Joshua T. Briegal, Edward M. Bryant, Sarah L. Casewell, Alexander Chaushev, Benjamin F. Cooke, Philipp Eigmüller, Edward Gillen, Maximilian N. Günther, Aleisha Hogan, James S. Jenkins, Monika Lendl, James McCormac, Maximiliano Moyano, Liam Raynard, Alexis M. S. Smith, Stéphane Udry, Christopher A. Watson, Richard G. West, Peter J. Wheatley, Hannes Breytenbach, Ramotholo R. Sefako, Jessymol K. Thomas, Douglas R. Alves, “NGTS 15b, 16b, 17b and 18b: four hot Jupiters from the Next Generation Transit Survey”, pp. 1-17, ArXiv, 18 March 2021. https://arxiv.org/abs/2103.10302

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How RNA Editing Affects the Immune System? (Biology)

CU Cancer Center researchers investigate the role of ADAR1 in cancer regulation.

Three University of Colorado Cancer Center researchers are part of a team that recently published a paper offering new insight into how the immune system relates to cancer. Quentin Vicens, PhD, Jeffrey Kieft, PhD, and Beat Vögeli, PhD, are authors on the paper, which looks at how an enzyme called ADAR1 operates in pathways associated with cancer.

“In a cell, ADAR1 edits native RNA — or self-RNA — so that the cell recognizes it as its own. It’s a key protection against autoimmune disorders,” Kieft says. “But if a virus infects, viral RNA isn’t edited by ADAR1, so the cell can recognize that and react. The cell knows it has foreign RNA, and it activates immune responses to fight off that infection.”

The binding mechanism of ADAR1

For their paper published last month in the journal Nature Communications, Kieft, Vögeli, Vicens, and the rest of the team — including Parker Nichols, a graduate student in the Structural Biology and Biochemistry program in the CU School of Medicine who works jointly in the Kieft and Vögeli labs — looked at where specifically the ADAR1 binds to RNA to perform the editing process. They already knew a domain of ADAR1 known as Z-alpha binds to a form of RNA called Z-RNA, but they found that Z-alpha ADAR1 can bind to other RNA forms as well.

“The team asked, ‘How are all these locations in RNA being recognized by Z-alpha if they supposedly don’t form Z-RNA?’” Kieft says. “One of the take-home messages is that other forms of RNA can bind to Z-alpha ADAR1 and can even partially form Z-RNA. That was a surprise because it shows that RNA can form this specific Z structure in places we didn’t recognize before.”

Problems caused by over-editing

The team is now proposing a model for how Z-alpha ADAR1 is able to bind to different types of RNA. It’s an important finding in cancer research because of the role of ADAR1 in cancer regulation. A normally functioning immune system oftentimes can detect cancerous cells as being dangerous and then eliminate them, but if there’s too much ADAR1 editing happening, a cell could be tamping down the immune response in an effort to protect itself.

“In a lot of cancers, there is upregulation of ADAR1; it is doing more than it should,” Kieft says. “The excess ADAR1 presumably is leading to more RNA editing than is normal. This is going to misregulate things,affecting specific regions of RNA or types of RNA. The excess editing is going to throw off the normal immune response, but it probably has a lot of other affects in the cell as well. Cancer is a disease where gene regulation has gone awry, so if an important regulatory pathway like editing by ADAR has gone haywire, that can contribute to the cancer.”

Applications beyond cancer

Knowing all the targets of ADAR1 in a cell is also a step toward more effective therapies, Kieft says. If researchers understand the pathways, they may be able to find a way to disrupt the overactive editing process and boost the immune response. It’s a finding applicable to many other diseases as well — Vögeli says since the paper was published, the researchers have heard from other scientists around the country interested in ADAR1.

“We have gotten a lot of feedback on the paper,” he says. “There is a lot of interest in this field right now, and other people are interested in how they could use our structural information.”

Vögeli and Vicens are now organizing a meeting focused on ADAR1 function and putting together special issues of the journals Molecules and International Journal of Molecular Sciences.

Vicens says the research project also illustrates the importance of collaborative work and being open to new directions. “I basically brought a new project and direction to the Kieft lab when I joined,” Vicens says. “Both labs were open to supporting it intellectually and financially, and the resultant team effort enabled research that would not otherwise have been done.”

Reference: Nichols, P.J., Bevers, S., Henen, M. et al. Recognition of non-CpG repeats in Alu and ribosomal RNAs by the Z-RNA binding domain of ADAR1 induces A-Z junctions. Nat Commun 12, 793 (2021). https://doi.org/10.1038/s41467-021-21039-0

Provided by University of Colorado Anschutz Medical Campus

Solving ‘Barren Plateaus’ is The Key to Quantum Machine Learning (Quantum)

New theorems put quantum machine learning on rigorous footing and identify the key issue that will determine whether it will provide quantum speedup

The work solves a key problem of useability for quantum machine learning. We rigorously proved the conditions under which certain architectures of variational quantum algorithms will or will not have barren plateaus as they are scaled up.- Marco Cerezo

Many machine learning algorithms on quantum computers suffer from the dreaded “barren plateau” of unsolvability, where they run into dead ends on optimization problems. This challenge had been relatively unstudied—until now. Rigorous theoretical work has established theorems that guarantee whether a given machine learning algorithm will work as it scales up on larger computers.

“The work solves a key problem of useability for quantum machine learning. We rigorously proved the conditions under which certain architectures of variational quantum algorithms will or will not have barren plateaus as they are scaled up,” said Marco Cerezo, lead author on the paper published in Nature Communications today by a Los Alamos National Laboratory team. Cerezo is a post doc researching quantum information theory at Los Alamos. “With our theorems, you can guarantee that the architecture will be scalable to quantum computers with a large number of qubits.”

“Usually the approach has been to run an optimization and see if it works, and that was leading to fatigue among researchers in the field,” said Patrick Coles, a coauthor of the study. Establishing mathematical theorems and deriving first principles takes the guesswork out of developing algorithms.

The Los Alamos team used the common hybrid approach for variational quantum algorithms, training and optimizing the parameters on a classical computer and evaluating the algorithm’s cost function, or the measure of the algorithm’s success, on a quantum computer.

Machine learning algorithms translate an optimization task—say, finding the shortest route for a traveling salesperson through several cities—into a cost function, said coauthor Lukasz Cincio. That’s a mathematical description of a function that will be minimized. The function reaches its minimum value only if you solve the problem.

Most quantum variational algorithms initiate their search randomly and evaluate the cost function globally across every qubit, which often leads to a barren plateau.

“We were able to prove that, if you choose a cost function that looks locally at each individual qubit, then we guarantee that the scaling won’t result in an impossibly steep curve of time versus system size, and therefore can be trained,” Coles said.

A quantum variational algorithm sets up a problem-solving landscape where the peaks represent the high energy points of the system, or problem, and the valleys are the low energy values. The answer lies in the deepest valley. That’s the ground state, represented by the minimized cost function. To find the solution, the algorithm trains itself about the landscape, thereby navigating to the low spot.

“People have been proposing quantum neural networks and benchmarking them by doing small-scale simulations of 10s (or fewer) few qubits,” Cerezo said. “The trouble is, you won’t see the barren plateau with a small number of qubits, but when you try to scale up to more qubits, it appears. Then the algorithm has to be reworked for a larger quantum computer.”

A barren plateau is a trainability problem that occurs in machine learning optimization algorithms when the problem-solving space turns flat as the algorithm is run. In that situation, the algorithm can’t find the downward slope in what appears to be a featureless landscape and there’s no clear path to the energy minimum. Lacking landscape features, the machine learning can’t train itself to find the solution.

“If you have a barren plateau, all hope of quantum speedup or quantum advantage is lost,” Cerezo said.

The Los Alamos team’s breakthrough takes an important step toward quantum advantage, when a quantum computer performs a task that would take infinitely long on a classical computer. Achieving quantum advantage hinges in the short term on scaling up variational quantum algorithms. These algorithms have the potential so solve practical problems when quantum computers of 100 qubits or more become available—hopefully soon. Quantum computers currently max out at 65 qubits. A qubit is the basic unit of information in a quantum computer, as bits are in a classical digital computer.

“The hottest topic in noisy intermediate-scale quantum computers is variational quantum algorithms, or quantum machine learning and quantum neural networks,” Coles said. “They have been proposed for applications from solving the structure of a molecule in chemistry to simulating the dynamics of atoms and molecules and factoring numbers.”

The paper: “Cost function dependent barren plateaus in shallow parametrized quantum circuits,” Nature Communications, by M. Cerezo, Akira Sone, Tyler Volkoff, Lukasz Cincio, and Patrick J. Coles. DOI: 10.1038/s41467-021-21728-w

Funding: Los Alamos National Laboratory’s Laboratory Directed Research and Development (LDRD), the Center for Nonlinear Studies at Los Alamos, the ASC Beyond Moore’s Law project at Los Alamos, and the U.S. Department of Energy (DOE), Office of Science, Office of Advanced Scientific Computing Research.

Featured image: A barren plateau is a trainability problem that occurs in machine learning optimization algorithms when the problem-solving space turns flat as the algorithm is run. Researchers at Los Alamos National Laboratory have developed theorems to prove that any given algorithm will avoid a barren plateau as it scales up to run on a quantum computer. © LANL

Provided by Los Alamos National Laboratory

How Gamblers Plan Their Actions to Maximize Rewards? (Psychology)

A study from biological psychology shows that habitual gamblers use different strategies than controls when it comes to reward learning. This difference could be related to changes in the dopamine system that affect strategic action planning.

Gamblers rely less on exploring new but potentially better strategies and more on proven courses of action that have worked in the past in their pursuit of maximum reward. The neurotransmitter dopamine in the brain could play an important role here. This is what a study from Biological Psychology at the Faculty of Human Sciences conducted by Professor Dr. Jan Peters and Dr. Antonius Wiehler shown. The study was published under the title “Attenuated directed exploration during reinforcement learning in gambling disorder” in the journal Journal of Neuroscience of the Society for Neuroscience.

Gambling disorder affects slightly less than one percent of the population – often men – and is similar to substance use disorders. Scientists suspect that this disorder, like other addiction disorders, is associated with a change in the dopamine system. The brain’s reward system releases the neurotransmitter dopamine while gambling. Since dopamine is important for planning and controlling actions, among other things, this could also have an impact on strategic learning processes.
“One of the reasons why the gambling disorder is of great scientific interest is that it is a dependency disorder that is not associated with a specific substance,” says Professor Dr. Jan Peters, one of the leaders of the study. The psychologists examined how gamblers plan their actions to maximize rewards – how their reinforcement learning works. In the study, the study participants had to weigh up whether they would rather choose already tried or new options in order to gain as much as possible. At the same time, the scientists used functional magnetic resonance imaging to measure the activity in brain regions that are important for processing reward stimuli and for planning action. 

Twenty-three regular gamblers and twenty-three control persons (all male) performed a so-called “four-armed bandit task”. The name of this type of decision-making investigation task refers to slot machines, also colloquially known as “one-armed bandit”. In each round, test persons decide between four options (“four-armed bandit”, in this case four colored squares), the winnings of which slowly change. Various strategies can play a role here. For example, you can choose the option that last produced the highest profit. However, you can also choose the option whose profit prospects are the least certain. The gain in information is maximal here. 

Both groups won roughly the same amount of money and demonstrated targeted exploration. However, this was significantly less pronounced in the group of gamblers than in the group of control subjects. These results show that while reward learning, gamblers are less likely to adapt to changing environments. At the neural level, gamblers showed changes in a network of brain regions that had been linked to targeted exploration in previous studies.

In an earlier study by the Cologne-based scientists, a pharmacological increase in dopamine levels in healthy volunteers had a very similar effect on behavior. “Although this suggests that dopamine could also play a role in the reduction in targeted exploration in gamblers, this relationship still needs to be investigated directly in future studies,” explains Dr. Antonius Wiehler.

Further research must also clarify whether the observed changes in decision-making behavior among gamblers are a risk factor for or a consequence of regular gambling.

Reference: A. Wiehler, K. Chakroun and J. Peters, “Attenuated Directed Exploration during Reinforcement Learning in Gambling Disorder”, Journal of Neuroscience 17 March 2021, 41 (11) 2512-2522; DOI: https://doi.org/10.1523/JNEUROSCI.1607-20.2021

Provided by University of Cologne

Living A Stress-free Life May Have Benefits, But Also A Downside (Psychology)

Stress is a universal human experience that almost everyone deals with from time to time. But a new study found that not only do some people report feeling no stress at all, but that there may be downsides to not experiencing stress.

The researchers found that people who reported experiencing no stressors were more likely to experience better daily well-being and fewer chronic health conditions. However, they were also more likely to have lower cognitive function, as well.

David M. Almeida, professor of human development and family studies at Penn State, said the study suggests that small, daily stressors could potentially benefit the brain, despite being an inconvenience.

“It’s possible that experiencing stressors creates opportunities for you to solve a problem, for example, maybe fixing your computer that has suddenly broken down before an important Zoom meeting,” Almeida said. “So experiencing these stressors may not be pleasant but they may force you to solve a problem, and this might actually be good for cognitive functioning, especially as we grow older.”

According to the researchers, a large number of previous studies have linked stress with a greater risk for many negative outcomes, like chronic illness or worse emotional wellbeing. But Almeida said that while it may make sense to believe that the less stress someone experiences the more healthy they will be, he said little research has explored that assumption.

“The assumption has always been that stress is bad,” Almeida said. “I took a step back and thought, what about the people who report never having stress? My previous work has focused on people who have higher versus lower levels of stress, but I’d never questioned what it looks like if people experience no stress. Are they the healthiest of all?”

The researchers used data from 2,711 participants for the study. Prior to the start of the study, the participants completed a short cognition test. Then, the participants were interviewed each night for eight consecutive nights, and answered questions about their mood, chronic conditions they may have, their physical symptoms — such as headaches, coughs or sore throats — and what they did during that day.

The participants also reported the number of stressors — like disagreements with friends and family or a problem at work — and the number of positive experiences, such as sharing a laugh with someone at home or work, they had experienced in the previous 24 hours.

After analyzing the data, the researchers found that there did appear to be benefits for those who reported no stressors throughout the study, about 10 percent of the participants. These participants were less likely to have chronic health conditions and experience better moods throughout the day.

However, those who reported no stressors also performed lower on the cognition test, with the difference equaling more than eight years of aging. Additionally, they were also less likely to report giving or receiving emotional support, as well as less likely to experience positive things happening throughout the day.

“I think there’s an assumption that negative events and positive events are these polar opposites, but in reality they’re correlated,” Almeida said. “But really, I think experiencing small daily stressors like having an argument with somebody or having your computer break down or maybe being stuck in traffic, I think they might be a marker for someone who has a busy and maybe full life. Having some stress is just an indicator that you are engaged in life.”

Almeida said the findings — recently published in the journal Emotion — suggest that it may not be as important to avoid stress as it is to change how you respond to stress.

“Stressors are events that create challenges in our lives,” Almeida said. “And I think experiencing stressors is part of life. There could be potential benefits to that. I think what’s important is how people respond to stressors. Respond to a stressor by being upset and worried is more unhealthy than the number of stressors you encounter.”

Susan T. Charles, University of California, Irvine; Jacqueline Mogle, Penn State; and Hye Won Chai, Penn State, also participated in this work.

Reference: Charles, S. T., Mogle, J., Chai, H. W., & Almeida, D. M. (2021). The mixed benefits of a stressor-free life. Emotion. Advance online publication. https://doi.apa.org/doiLanding?doi=10.1037%2Femo0000958 https://doi.org/10.1037/emo0000958

Provided by Penn State

New Antibiotic Clears Multi-drug Resistant Gonorrhea in Mice in Single Dose (Medicine)

A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study led by researchers at Penn State and Emory University. The compound targets a molecular pathway found in bacteria but not humans and could lead to new treatments for gonorrhea and infections from other bacteria, such as tuberculosis and MRSA.

The research team, which also includes scientists from the biopharmaceutical company Microbiotix, the Uniformed Services University, and Florida State, published their results in a paper appearing March 19 in the journal Nature Communications.

Gonorrhea infects more than 500 thousand people in the United States each year, and several strains of the bacteria that causes the disease, Neisseria gonorrhoeae, are resistant to multiple antibiotics in use today. For this reason, the Centers for Disease Control and Prevention (CDC) lists multi-drug resistant gonorrhea as one of the five most dangerous urgent threats today.

“Many current antibiotics target the process of translation — when proteins are made based on information in genetic material — within the bacteria,” said Ken Keiler, professor of biochemistry and molecular biology at Penn State and an author of the paper. “Over the last decade, we have been investigating a family of compounds that instead inhibit the trans-translation pathway in bacteria, which bacteria use to fix certain kinds of errors during protein synthesis. In this paper, we provide a proof-of-concept that inhibiting the trans-translation pathway can effectively clear multi-drug resistant gonorrhea in animals.”

The researchers previously identified a promising trans-translation inhibitor that clears gonorrhea infection in lab cultures but is ineffective in animals because the compound breaks down. In this study, members of the research team at Microbiotix strategically altered the compound to identify which portions of its structure were necessary to inhibit the pathway and which could be changed to improve its stability.

“Our iterative optimization campaign evaluated over 500 versions of the compound to assess their potency, toxicity, and other pharmacological properties,” said Zachary Aron, director of chemistry at Microbiotix and an author of the paper. “We determined that the central region of the compound plays a critical role in blocking the trans-translation pathway, however modifications at the periphery could be altered to modulate its pharmacological properties. By altering a functional group to sidestep the primary mechanism of metabolism, we can create versions of the compound that are much more stable in animals.”

Members of the research team at the Uniformed Services University then tested one of these modified compounds, MBX-4132, in mice. Their experiments utilized the gonorrhea strain WHO-X, an extremely virulent pathogen that is resistant to almost all approved antibiotics. A single oral dose of the compound completely cleared the infection in 80% of mice within six days, and the bacterial load in the remaining 20% was dramatically reduced.

“Developing a single dose therapy for gonorrhea is incredibly important,” said Keiler. “In some cases, bacteria can develop resistance to a drug when additional doses are skipped, for example when a patient starts to feel better and stops taking antibiotics. With a single dose therapy, a patient could complete the treatment during a visit to their health provider.”

To better determine how the compound inhibits the trans-translation pathway, members of the research team at Emory University and Florida State University used cryo-electron microscopy (cryo-EM) to produce high-resolution images of the compound as it binds to the bacterial ribosome — the macromolecule where proteins are synthesized.

A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study. The compound, MBX-4132, binds to the bacterial ribosome and, in so doing, displaces a region of a protein (bL27, purple) that is critical to the trans-translation pathway in bacteria. IMAGE: DUNHAM LAB, EMORY UNIVERSITY

“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” said Christine Dunham, associate professor of biochemistry at Emory University and an author of the paper. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”

The research team plans to further optimize the compound before pursuing preclinical trials.

“This type of compound is actually a broad-spectrum inhibitor,” said Keiler. “It is effective against most Gram-positive bacteria — including tuberculosis and difficult-to-treat staph infections (MRSA) — and some Gram-negative bacteria and could be a promising candidate for future treatments. In this study, we lay the groundwork for using this type of compound and demonstrate that inhibiting the trans-translation pathway in bacteria is a viable antibiotic strategy.”

In addition to Keiler, Aron and Dunham, the research team includes John Alumasa, Mynthia Cabrera and Divya Hosangadi at Penn State; Matthew Torhan, Jay Barbor, Steven Cardinale, Steven Kwasny, Lucas Morin, Michelle Butler, Timothy Opperman and Terry Bowlin at Microbiotix; Atousa Mehrani and Scott Stagg at Florida State; Eric Hoffer and Pooja Srinivas at Emory University; and Kristie Connolly and Ann Jerse at the Uniformed Services University.

This research was supported by the National Institutes of Health.

Featured image: A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study.Image: Alissa Eckert/Centers for Disease Control and Prevention

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Happiness Can Be Learned (Psychology)

A new study coordinated by the University of Trento shows the beneficial effects of an intensive program on happiness

The results showed that several psychological well-being measures gradually increased within participants from the beginning to the end of the course. That was especially true for life satisfaction, perceived well-being, self-awareness and emotional self-regulation. The participants in the study also reported a significant decrease in anxiety, perceived stress, negative thoughts, rumination and anger tendencies. The researchers observed, simultaneously, improvements in the positive aspects and a reduction of negative emotions, both in the short term and longitudinally throughout the program.

Nicola De Pisapia, researcher of the Department of Psychology and Cognitive Sciences of the University of Trento and scientific coordinator, explained the fundamental principles of the study: “The training that we proposed to the participants was inspired by the idea – present in both Western and Eastern philosophical traditions – that happiness is inextricably linked to the development of inner equilibrium, a kinder and more open perspective of self, others, and the world, towards a better understanding of the human mind and brain. In this training process we need on the one hand the theoretical study of philosophy and science, and on the other meditation practices”.

The study was conducted over nine months (with seven theoretical/practical weekends and two meditation retreats) at the Lama Tzong Khapa Institute of Tibetan culture in Pomaia (Italy). For the theoretical part, the participants attended a series of presentations and watched some video courses, and took part in open discussions on topics of psychology, neuroscience, the history of Western thought and the philosophy of life of Buddhism. The scientific topics included neuroplasticity, the brain circuits of attention and mind wandering, stress and anxiety, pain and pleasure, positive and negative emotions, desire and addiction, the sense of self, empathy and compassion. For the practical part, a series of exercises were proposed, taken from different, Buddhist and Western, contemplative traditions (for example, meditation on the breath, analytical meditation, personal journal).

In recent years, excluding the “recipes” that mistake happiness for hedonism, and the New Age obsession with positive thinking, research has shown that meditation practices have important benefits for the mind, while studies on happiness and wisdom have been scarce. De Pisapia therefore concluded: ” I believe that in times like these, full of changes and uncertainties, it is fundamental to scientifically study how Western and Eastern philosophical traditions, together with the most recent discoveries on the mind and the brain, can be integrated with contemplative practices in secular way. The goal is to give healthy people the opportunity to work on themselves to develop authentic happiness, not hedonism or superficial happiness. With this study we wanted to take a small step in this direction”.

Featured image: Nicola de Pisapia, assistant professor ate the Department of Psychology and Cognitive Science, University of Trento ©UniTrento ph. Alessio Coser

Reference: Clara Rastelli, Lucia Calabrese et al., “The Art of Happiness: An Explorative Study of a Contemplative Program for Subjective Well-being”, Front. Psychol., 11 February 2021 | https://doi.org/10.3389/fpsyg.2021.600982

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