Culture

A global science collaboration using data from NASA's Neutron star Interior Composition Explorer (NICER) telescope on the International Space Station has discovered X-ray surges accompanying radio bursts from the pulsar in the Crab Nebula. The finding shows that these bursts, called giant radio pulses, release far more energy than previously suspected.

A pulsar is a type of rapidly spinning neutron star, the crushed, city-sized core of a star that exploded as a supernova. A young, isolated neutron star can spin dozens of times each second, and its whirling magnetic field powers beams of radio waves, visible light, X-rays, and gamma rays. If these beams sweep past Earth, astronomers observe clock-like pulses of emission and classify the object as a pulsar.

"Out of more than 2,800 pulsars cataloged, the Crab pulsar is one of only a few that emit giant radio pulses, which occur sporadically and can be hundreds to thousands of times brighter than the regular pulses," said lead scientist Teruaki Enoto at the RIKEN Cluster for Pioneering Research in Wako, Saitama prefecture, Japan. "After decades of observations, only the Crab has been shown to enhance its giant radio pulses with emission from other parts of the spectrum."

The new study, which will appear in the April 9 edition of Science and is now available online, analyzed the largest amount of simultaneous X-ray and radio data ever collected from a pulsar. It extends the observed energy range associated with this enhancement phenomenon by thousands of times.

Located about 6,500 light-years away in the constellation Taurus, the Crab Nebula and its pulsar formed in a supernova whose light reached Earth in July 1054. The neutron star spins 30 times each second, and at X-ray and radio wavelengths it is among the brightest pulsars in the sky.

Between August 2017 and August 2019, Enoto and his colleagues used NICER to repeatedly observe the Crab pulsar in X-rays with energies up to 10,000 electron volts, or thousands of times that of visible light. While NICER was watching, the team also studied the object using at least one of two ground-based radio telescopes in Japan - the 34-meter dish at the Kashima Space Technology Center and the 64-meter dish at the Japan Aerospace Exploration Agency's Usuda Deep Space Center, both operating at a frequency of 2 gigahertz.

he combined dataset effectively gave the researchers nearly a day and a half of simultaneous X-ray and radio coverage. All told, they captured activity across 3.7 million pulsar rotations and netted some 26,000 giant radio pulses.

Giant pulses erupt quickly, spiking in millionths of a second, and occur unpredictably. However, when they occur, they coincide with the regular clockwork pulsations.

NICER records the arrival time of every X-ray it detects to within 100 nanoseconds, but the telescope's timing precision isn't its only advantage for this study.

"NICER's capacity for observing bright X-ray sources is nearly four times greater than the combined brightness of both the pulsar and its nebula," said Zaven Arzoumanian, the project's science lead at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "So these observations were largely unaffected by pileup - where a detector counts two or more X-rays as a single event - and other issues that have complicated earlier analyses."

Enoto's team combined all of the X-ray data that coincided with giant radio pulses, revealing an X-ray boost of about 4% that occurred in synch with them. It's remarkably similar to the 3% rise in visible light also associated with the phenomenon, discovered in 2003. Compared to the brightness difference between the Crab's regular and giant pulses, these changes are remarkably small and provide a challenge for theoretical models to explain.

The enhancements suggest that giant pulses are a manifestation of underlying processes that produce emission spanning the electromagnetic spectrum, from radio to X-rays. And because X-rays pack millions of times the punch of radio waves, even a modest increase represents a large energy contribution. The researchers conclude that the total emitted energy associated with a giant pulse is dozens to hundreds of times higher than previously estimated from the radio and optical data alone.

"We still don't understand how or where pulsars produce their complex and wide-ranging emission, and it's gratifying to have contributed another piece to the multiwavelength puzzle of these fascinating objects," Enoto said.

SALT LAKE CITY - A letter published today by Huntsman Cancer Institute (HCI) at the University of Utah (U of U) in the New England Journal of Medicine reports that melanoma mortality among Utahns outpaced that of the rest of the United States during the period from 1975 to 2013. Melanoma death rates have been decreasing in recent years both in Utah and the United States, a trend likely attributable to new, more effective treatments, like immunotherapy. However, melanoma remains the deadliest type of skin cancer, and the incidence of melanoma diagnoses in Utahns is higher than in any other state.

The research was conducted in response to recent published data showing that for most of the 1990s and 2000s, melanoma mortality in the United States remained constant, while incidence increased six-fold. Increasing incidence without a corresponding increase in mortality suggests a potentially worrying trend of overdiagnosis--that is, when patients with benign conditions are incorrectly diagnosed as having cancer. In the case of melanoma, overdiagnosis may result from increased scrutiny, where repeated skin exams lead to increasing numbers of biopsies and a higher chance of finding a lesion that would not have been detected otherwise, and which might not be likely to progress to a harmful cancer.

Given Utah's status as the state with the highest incidence of melanoma, the HCI team set out to evaluate the melanoma diagnosis and death rate data in Utah. After review and analysis of data by biostatistician Kim Herget from the Utah Cancer Registry, a National Cancer Institute Survival, Epidemiology, and End Results (SEER) database, the researchers found that in contrast to the rest of the United States, melanoma mortality in Utah increased by 0.8% per year through the entire period from 1975 through 2013. While melanoma deaths in Utah are decreasing in recent years, Utah's melanoma death rate remains higher than that observed in the rest of the United States.

"Although we agree that overdiagnosis of melanoma is a growing problem, the sustained increase in melanoma mortality in Utah suggests that at least some fraction of the increasing incidence is real and cannot be attributed solely to overdiagnosis," said Doug Grossman, MD, PhD, who co-leads the HCI melanoma and skin cancer center at HCI and serves as professor of dermatology at the U of U. "Our research underscores an increased risk for Utahns, and so we must remain vigilant about melanoma. For doctors, this means regular conversations with patients about their skin health and family history. For patients, this means practicing sun-safe behaviors like diligent sunscreen use, wearing sun-protective clothing, and monitoring their skin at home on a monthly basis to reduce risk of skin cancer and optimize early detection."

The researchers anticipate future studies to determine whether this trend in Utahns is a result of increased ultraviolet exposure in a largely fair-skinned population living in a sunny, high-altitude climate or is associated with other environmental or genetic factors.

LOS ALAMOS, N.M., April 8, 2021-While attention has been focused on the Perseverance rover that landed on Mars last month, its predecessor Curiosity continues to explore the base of Mount Sharp on the red planet and is still making discoveries. Research published today in the journal Geology shows that Mars had drier and wetter eras before drying up completely about 3 billion years ago.

"A primary goal of the Curiosity mission was to study the transition between the habitable environment of the past, to the dry and cold climate that Mars has now. These rock layers recorded that change in great detail," said Roger Wiens, a coauthor on the paper and scientist at Los Alamos National Laboratory, where he is on the ChemCam team. ChemCam is the rock-vaporizing laser that sits on the mast of the Curiosity rover and analyzes the chemical composition of martian rocks.

William Rapin, a researcher with the French National Centre for Scientific Research (CNRS), led the study

Using the long-range camera on ChemCam to make detailed observations of the steep terrain of Mount Sharp, a team including Wiens and other researchers at Los Alamos discovered that the Martian climate alternated between dry and wetter periods before it went completely dry. Spacecraft in orbit around Mars had previously provided clues about the mineral composition of the slopes of Mount Sharp. Now, ChemCam has successfully made detailed observations of the sedimentary beds from the planet's surface, revealing the conditions under which they formed.

Moving up through the terrain, Curiosity observed that the types of bed change drastically. Lying above the lake-deposited clays that form the base of Mount Sharp, sandstone layers show structures indicating their formation from wind-formed dunes, suggesting long, dry climate episodes. Higher up still, thin alternating brittle and resistant beds are typical of river floodplain deposits, marking the return of wetter conditions.

These changes in terrain show that the climate of Mars underwent several large-scale fluctuations between wetter and dryer periods, until the generally arid conditions observed today took hold. During its extended mission, Curiosity is scheduled to climb the foothills of Mount Sharp and drill into its various beds for a closer look at these fascinating materials.

The ChemCam laser instrument uses an infrared-colored laser beam, which heats rock fragments to around 18,000 degrees Fahrenheit (10,000 degrees Celsius), vaporizing them. The plasma produced by this process allows scientists to analyze the chemical and mineral composition of the rocks, which convey important information about the geological history of Mars. The instrument also has a high-resolution camera. ChemCam is commanded alternately from Los Alamos in New Mexico and the French Space Agency in Toulouse, as a partnership between Los Alamos National Laboratory and the IRAP research center. Every week, the operations change hands between the two places. Together, the ChemCam team has published over 100 scientific papers on its discoveries from more than 850,000 laser zaps.

PHILADELPHIA (April 8, 2021) - Many factors, including need, affect healthcare use. Strategies geared to enhancing the provision and access to healthcare must consider the various mechanisms that contribute to healthcare need and use. Until now, the mechanism of violence and its impact on both health and healthcare use has not been investigated.

A new study from the University of Pennsylvania School of Nursing (Penn Nursing) is one of the first to examine the association between violence exposure and healthcare service utilization in Mexico. Results are published in the International Journal of Health Equity.

Widespread violence in Mexico can impact health through various channels. The study explores how violence relates to service utilization changes as a possible mechanism that may impact short- and long-term health. "Violence is a pervasive problem in developing nations such as Mexico and its consequences for service utilization are important to understand," says Laura X. Vargas, PhD, MSW, MPA, Vice-Provost post-doctoral fellow at the Penn Injury Science Center at Penn Nursing and lead author of the study.

Given the prolonged period of escalating violence in Mexico, policymakers should consider whether broader investments in health prevention, primary care, and mental health might effectively buffer some of the long-term (perhaps costlier) impacts of violence on the health of society, the researchers suggest. "One way to do that, for example, is by making trauma-informed health services widely available at the primary care level to improve health outcomes in communities exposed to violence," says Therese S. Richmond, PhD, RN, FAAN, Andrea B. Laporte Professor of Nursing and Associate Dean for Research & Innovation at Penn Nursing, one of the co-authors of the article.

Ion channels play an indispensable role in cellular physiology, and understanding the physical features that affect ion channel functions is a matter of considerable interest to biologists. Given that mechanosensitivity is an intrinsic feature of cells, the complex set of mechanical stresses acting on a cell at any time represents an important consideration in the field of cellular physiology. In fact, stretching forces created by mechanical stress are sometimes necessary to activate ion channels. As Professor Masayuki Iwamoto and Professor Shigetoshi Oiki of the University of Fukui explain, "Mechanical stresses change the level of cell membrane tension, and stretch-activated ion channels in the membrane mediate tension-related electrical transduction".

Recent experiments have shown that tension sensitivity is a property of ion channels other than those historically classified as "mechanosensitive" channels, and biophysicists are coming to see tension sensitivity as an intrinsic property of ion channels in general. However, efforts to elucidate the physiological relevance and molecular mechanisms of such tension sensitivity depend on the establishment of experimental methods that allow experimenters to evaluate dynamic changes in membrane tension in real time.

To meet this growing need, Professors Iwamoto and Oiki focused their efforts on developing a novel time-lapse system for measuring membrane tension. In their experiments, they formed a bilayer by docking two monolayer-lined water bubbles and evaluated tension using the Young-Laplace principle to measure intra-bubble pressures lower than 100 pascals. This novel experimental method has the advantage of relying on a straightforward model system consisting of purified channels and a simple lipid bilayer. This model allows experimenters to avoid the unmanageable complexity of real cell membranes, which feature a wide variety of ion channels and accessory proteins. The experimental setup permits real-time monitoring of membrane tension.

The KcsA ion channel is the prototypical ion channel used to understand ion channel structure-function relationships. The channel functions in the bilayer, and this is an important advantage given the rapid variability in membrane tension that occurs during actual cellular activity while recording the dynamic responsiveness of the KcsA ion channel. These experiments revealed a novel mode of action for tension sensitivity without precedent in the existing literature. Their results appear in a paper recently published in the peer-reviewed journal JACS Au.

Interestingly, the KcsA ion channels exhibited sensitivity to membrane tension and responded quickly to its fluctuations. One notable observation was that the ion channels' responses to increasing membrane tension differed substantially from their responses to decreasing membrane tension. During the stretching phase, the channels started to activate only when the membrane tension reached high levels. In the tension decreasing phase, they remained active for a while even after returning to a low level of tension. This feature is called hysteresis, and it implies that the channel molecules can "memorize" their active state for a short period.

In conclusion, Professors Iwamoto and Oiki have developed a time-lapse system for measuring membrane tension while recording the dynamic responsiveness of a prototypical ion channel. Their findings revealed a process of hysteresis, which they note "extends existing knowledge of the mechanisms of the tension-sensitive channels that play key roles in various cellular activities."

The present study is thus important both as a demonstration of a new method for fundamental ion channel research and as basic research into ion channel mechanisms. The insights into hysteresis as a functional feature of KcsA ion channels could be valuable for drug discovery research.

BIRMINGHAM, Ala. - Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.

For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.

Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF -- tryptophan/any-amino-acid/glycine, known in shorthand as WXG -- is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.

"Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion," said Niederweis, a professor in the UAB Department of Microbiology. "Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria."

TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.

EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

By creating different strains that lacked either EsxE or EsxF, they showed that both proteins were necessary for the translocation of CpnT to the cell surface of M. tuberculosis and for the secretion of TNT into the cytosol of macrophages infected with M. tuberculosis. Furthermore, EsxE and EsxF are surface-accessible proteins on M. tuberculosis as a membrane-associated complex.

To learn more about the mechanism of that translocation, the UAB team made mutants of each Esx protein, where the tryptophan amino acid of the single WXG motif on each protein was replaced by the amino acid alanine. The mutants showed that an intact WXG motif on EsxE and on EsxF were required for efficient CpnT translocation to the outer membrane of M. tuberculosis and subsequent TNT secretion into the cytosol of infected macrophages.

Purification of the water-soluble EsxE and EsxF proteins showed they formed EsxE-EsxF dimers, and five of these dimers assembled into star-shaped structures, as viewed by electron microscopy. Each was about 10 nanometers across, with a 3-nanometer central pore.

Experiments with planar lipid bilayers were key to understanding the molecular function of EsxE-EsxF, as they showed that the EsxE-EsxF pores formed channels through lipid membranes.

Finally, the researchers showed that the WXG motifs were required for pore formation and membrane disruption by the EsxE-EsxF complex, and the motifs mediated assembly of functional EsxE-EsxF oligomers. This now defines a biochemical role for the previously enigmatic WXG motif.

"EsxE and EsxF constitute the first known outer membrane components mediating protein secretion in M. tuberculosis," Niederweis said. "However, it is unlikely that EsxE and EsxF are sufficient for TNT secretion, since an energy source is required in all known bacterial protein secretion systems. Therefore, it is possible that EsxE-EsxF associate with other proteins or protein complexes to achieve CpnT export and TNT secretion."

The UAB researchers propose two models for the transport of CpnT by EsxE and EsxF. In the first, the EsxE-EsxF heterodimers form a pore in the inner membrane, and then form another pore in the outer membrane to create transmembrane channels. "Alternatively," Niederweis said, "the inner membrane channel is extended to span the periplasm via filament formation, and connects to EsxE-EsxF pores in the outer membrane, exposing EsxF on the cell surface. In this model, the putative EsxE-EsxF channel tunnel enables export of the CpnT polypeptide to the outer membrane of M. tuberculosis, and subsequent secretion of TNT and EsxE-EsxF."

Co-authors with Niederweis in the study, "Pore-forming Esx proteins mediate toxin secretion
by Mycobacterium tuberculosis," published in Nature Communications, are Uday Tak and Terje Dokland, UAB Department of Microbiology.

"This work was a remarkable achievement of an outstanding graduate student, Uday Tak, who did almost all of these experiments by himself," Niederweis said. Uday Tak obtained his Ph.D. in November 2020 and is now a postdoctoral fellow at the University of Colorado-Boulder.

With the help of machine-learning techniques, a team of astronomers has discovered a dozen quasars that have been warped by a naturally occurring cosmic "lens" and split into four similar images. Quasars are extremely luminous cores of distant galaxies that are powered by supermassive black holes.

Over the past four decades, astronomers had found about 50 of these "quadruply imaged quasars," or quads for short, which occur when the gravity of a massive galaxy that happens to sit in front of a quasar splits its single image into four. The latest study, which spanned only a year and a half, increases the number of known quads by about 25 percent and demonstrates the power of machine learning to assist astronomers in their search for these cosmic oddities.

"The quads are gold mines for all sorts of questions. They can help determine the expansion rate of the universe, and help address other mysteries, such as dark matter and quasar 'central engines,'" says Daniel Stern, lead author of the new study and a research scientist at the Jet Propulsion Laboratory, which is managed by Caltech for NASA. "They are not just needles in a haystack but Swiss Army knives because they have so many uses."

The findings, to be published in The Astrophysical Journal, were made by combining machine-learning tools with data from several ground- and space-based telescopes, including the European Space Agency's Gaia mission; NASA's Wide-field Infrared Survey Explorer (or WISE); the W. M. Keck Observatory on Maunakea, Hawaii; Caltech's Palomar Observatory; the European Southern Observatory's New Technology Telescope in Chile; and the Gemini South telescope in Chile.

Cosmological Dilemma

In recent years, a discrepancy has emerged over the precise value of the universe's expansion rate, also known as Hubble's constant. Two primary means can be used to determine this number: one relies on measurements of the distance and speed of objects in our local universe, and the other extrapolates the rate from models based on distant radiation left over from the birth of our universe, called the cosmic microwave background. The problem is that the numbers do not match.

"There are potentially systematic errors in the measurements, but that is looking less and less likely," says Stern. "More enticingly, the discrepancy in the values could mean that something about our model of the universe is wrong and there is new physics to discover."

The new quasar quads, which the team gave nicknames such as Wolf's Paw and Dragon Kite, will help in future calculations of Hubble's constant and may illuminate why the two primary measurements are not in alignment. The quasars lie in between the local and distant targets used for the previous calculations, so they give astronomers a way to probe the intermediate range of the universe. A quasar-based determination of Hubble's constant could indicate which of the two values is correct, or, perhaps more interestingly, could show that the constant lies somewhere between the locally determined and distant value, a possible sign of previously unknown physics.

Gravitational Illusions

The multiplication of quasar images and other objects in the cosmos occurs when the gravity of a foreground object, such as a galaxy, bends and magnifies the light of objects behind it. The phenomenon, called gravitational lensing, has been seen many times before. Sometimes quasars are lensed into two similar images; less commonly, they are lensed into four.

"Quads are better than the doubly imaged quasars for cosmology studies, such as measuring the distance to objects, because they can be exquisitely well modeled," says co-author George Djorgovski, professor of astronomy and data science at Caltech. "They are relatively clean laboratories for making these cosmological measurements."

In the new study, the researchers used data from WISE, which has relatively coarse resolution, to find likely quasars, and then used the sharp resolution of Gaia to identify which of the WISE quasars were associated with possible quadruply imaged quasars. The researchers then applied machine-learning tools to pick out which candidates were most likely multiply imaged sources and not just different stars sitting close to each other in the sky. Follow-up observations by Keck, Palomar, the New Technology Telescope, and Gemini-South confirmed which of the objects were indeed quadruply imaged quasars lying billions of light-years away.

Humans and Machines Working Together

The first quad found with the help of machine learning, nicknamed Centaurus' Victory, was confirmed during an all-nighter the team spent at Caltech, with collaborators from Belgium, France, and Germany, while using a dedicated computer in Brazil, recalls co-author Alberto Krone-Martins of UC Irvine. The team had been remotely observing their objects using the Keck Observatory.

"Machine learning was key to our study but it is not meant to replace human decisions," explains Krone-Martins. "We continuously train and update the models in an ongoing learning loop, such that humans and the human expertise are an essential part of the loop. When we talk about 'AI' in reference to machine-learning tools like these, it stands for Augmented Intelligence not Artificial Intelligence."

"Alberto not only initially came up with the clever machine-learning algorithms for this project, but it was his idea to use the Gaia data, something that had not been done before for this type of project," says Djorgovski.

"This story is not just about finding interesting gravitational lenses," he says, "but also about how a combination of big data and machine learning can lead to new discoveries."

Cells from healthy individuals with major depressive disorder were found to have higher than expected rates of methylation at specific sites on their DNA, when compared to cells from healthy individuals without MDD, according to a study by a multidisciplinary team of Walter Reed Army Institute of Research and University of California San Francisco scientists, in collaboration with others.

Methylation is a process by which DNA is chemically modified at specific sites, resulting in changes in the expression of certain genes. Methylation of particular sets of genes, called "DNA methylation clocks," typically change in predictable ways as people age, but the rate of these changes varies between people. Methylation patterns in individuals with MDD suggested that their DNA methylation cellular age was, on average, accelerated relative to matched healthy controls.

In the study, published in Translational Psychiatry, blood samples from 49 individuals with MDD were compared to 60 healthy control subjects of the same chronological age using the 'GrimAge' clock--a mathematical algorithm designed to predict an individual's remaining lifespan based on cellular methylation patterns. Individuals with MDD showed a significantly higher GrimAge score, suggesting increased mortality risk compared to healthy individuals of the same chronological age--an average of approximately two years on the GrimAge clock.

The individuals with MDD were unmedicated prior to the study and showed no outward signs of age-related pathology, as they and the healthy controls were screened for physical health before entry into the study. The methylation patterns associated with mortality risk persisted even after accounting for lifestyle factors like smoking and BMI. These findings provide new insight into the increased mortality and morbidity associated with the condition, suggesting that there is an underlying biological mechanism accelerating cellular aging in some MDD sufferers.

"This is shifting the way we understand depression, from a purely mental or psychiatric disease, limited to processes in the brain, to a whole-body disease," said Katerina Protsenko, a medical student at UCSF and lead author of the study. "This should fundamentally alter the way we approach depression and how we think about it--as a part of overall health."

MDD is one of the most prevalent health concerns globally. According to the World health Organization, some 300 million people (4.4% of the population) suffer from some form of depression. MDD is associated with higher incidence and mortality related to increased rates of cardiovascular disease, diabetes, and Alzheimer's disease among sufferers.

"One of the things that's remarkable about depression is that sufferers have unexpectedly higher rates of age-related physical illnesses and early mortality, even after accounting for things like suicide and lifestyle habits," said Dr. Owen Wolkowitz, professor of psychiatry and a member of UCSF's Weill Institute for Neurosciences, co-senior author of the study. "That's always been a mystery, and that's what led us to look for signs of aging at the cellular level."

The researchers say that they don't yet know if depression causes altered methylation in certain individuals, or if depression and methylation are both related to another underlying factor. It is possible that some individuals may have a genetic predisposition to produce specific methylation patterns in response to stressors, but this has not been well-studied. Alterations in methylation patterns have previously been observed in individuals with post-traumatic stress disorder.

"These findings will allow us to better understand the relationships between behavioral health disorders--for example, 60% of PTSD cases are co-morbid with MDD. Elucidating these mechanistic and biochemical underpinnings will improve efforts to develop targeted diagnostic and treatment strategies, ultimately improving patient care," said Dr. Marti Jett, WRAIR chief scientist. Previous research from the group used GrimAge to study men with combat PTSD.

Moving forward, the researchers hope to determine whether pharmacological treatments or therapy may mitigate some methylation changes related to MDD in hopes of normalizing the cellular aging process in affected individuals before it advances. Also, although the "GrimAge" methylation clock has been associated with mortality in other populations, no studies have yet prospectively determined whether this methylation pattern also predicts mortality in MDD.

"As we continue our studies, we hope to find out whether addressing the MDD with anti-depressants or other treatments alters the methylation patterns, which would give us some indication that these patterns are dynamic and can be changed," said Dr. Synthia Mellon, professor in the Department of Obstetrics, Gynecology and the Reproductive Sciences at UCSF and co-senior author of the study.

New Haven, Conn. -- Alzheimer's disease is known for its slow attack on neurons crucial to memory and cognition. But why are these particular neurons in aging brains so susceptible to the disease's ravages, while others remain resilient?

A new study led by researchers at the Yale School of Medicine has found that susceptible neurons in the prefrontal cortex develop a "leak" in calcium storage with advancing age, they report April 8 in the journal Alzheimer's & Dementia, The Journal of the Alzheimer's Association. This disruption of calcium storage in turns leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer's.

These changes occur slowly, building over many years, and can be seen within neurons in the brains of very old monkeys, the researchers report.

"Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition," said corresponding author Amy Arnsten, the Albert E. Kent Professor of Neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.

These vulnerable neurons face another problem. As they age, they tend to lose a key regulator of calcium signaling, a protein called calbindin, which protects neurons from calcium overload, and is abundant in the neurons of younger individuals.

"With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin," said Arnsten.

Neurons in the prefrontal cortex require relatively high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. However, as regulation is lost with increasing age, neurons become susceptible to tau pathology and degeneration. Essentially, neurons "eat" themselves from within.

"Understanding these early pathological changes may provide strategies to slow or prevent disease progression," Arnsten said.

WEST LAFAYETTE, Ind. - New insights into the immune response to SARS-CoV-2 infections could bring better treatments for COVID-19 cases.

An international team of researchers unexpectedly found that a biochemical pathway, known as the immune complement system, is triggered in lung cells by the virus, which might explain why the disease is so difficult to treat. The research is published this week in the journal Science Immunology.

The researchers propose that the pairing of antiviral drugs with drugs that inhibit this process may be more effective. Using an in vitro model using human lung cells, they found that the antiviral drug Remdesivir, in combination with the drug Ruxolitinib, inhibited this complement response.

This is despite recent evidence that trials of using Ruxolitinib alone to treat COVID-19 have not been promising.

To identify possible drug targets, Majid Kazemian, assistant professor in the departments of computer science and biochemistry at Purdue University, said the research team examined more than 1,600 previously FDA-approved drugs with known targets.

"We looked at the genes that are up-regulated by COVID-19 but down-regulated by specific drugs, and Ruxolitinib was the top drug with that property," he said.

Within the last few years, scientists have discovered that the immune complement system - a complex system of small proteins produced by the liver that aids, or complements, the body's antibodies in the fight against blood-borne pathogens - can work inside cells and not just in the bloodstream.

Surprisingly, the study found that this response is triggered in cells of the small structures in the lungs known as alveoli, Kazemian said.

"We observed that SARS-CoV2 infection of these lung cells causes expression of an activated complement system in an unprecedented way," Kazemian said. "This was completely unexpected to us because we were not thinking about activation of this system inside the cells, or at least not lung cells. We typically think of the complement source as the liver."

Claudia Kemper, senior investigator and chief of the Complement and Inflammation Research Section of the National Institutes of Health, was among the first to characterize novel roles of the complement system in the immune system. She agreed these latest findings are surprising.

"The complement system is traditionally considered a liver-derived and blood-circulating sentinel system that protects the host against infections by bacteria, fungi and viruses," she said. "It is unexpected that in the setting of a SARS-CoV2 infection, this system rather turns against the host and contributes to the detrimental tissue inflammation observed in severe COVID-19. We need to think about modulation of this intracellular, local, complement when combating COVID-19."

Dr. Ben Afzali, an Earl Stadtman Investigator of the National Institute of Health's National Institute of Diabetes and Digestive and Kidney Diseases, said there are now indications that this has implications for difficulties in treating COVID-19.

"These findings provide important evidence showing not only that complement-related genes are amongst the most significant pathways induced by SARS-CoV2 in infected cells, but also that activation of complement occurs inside of lung epithelial cells, i.e., locally where infection is present," he said.

"This may explain why targeting the complement system outside of cells and in the circulation has, in general, been disappointing in COVID-19. We should probably consider using inhibitors of complement gene transcription or complement protein activation that are cell permeable and act intracellularly instead."

Afzali cautions that appropriate clinical trials should be conducted to establish whether a combination treatment provides a survival benefit.

"The second finding that I think is important is that the data suggest potential benefit for patients with severe COVID-19 from combinatorial use of an antiviral agent together with an agent that broadly targets complement production or activation within infected cells," he said. "These data are promising, but it is important to acknowledge that we carried out the drug treatment experiments in cell lines infected with SARS-CoV2. So, in and of themselves they should not be used to direct treatment of patients."

Kemper added that the unexpected findings bring more questions.

"A currently unexplored and possibly therapeutically interesting aspect of our observations is also whether the virus utilizes local complement generation and activation to its benefit, for example, for the processes underlying cell infection and replication," she said.

About Purdue University

Purdue University is a top public research institution developing practical solutions to today's toughest challenges. Ranked the No. 5 Most Innovative University in the United States by U.S. News & World Report, Purdue delivers world-changing research and out-of-this-world discovery. Committed to hands-on and online, real-world learning, Purdue offers a transformative education to all. Committed to affordability and accessibility, Purdue has frozen tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue never stops in the persistent pursuit of the next giant leap at https://purdue.edu/.

Journal

Science Immunology

DOI

10.1126/sciimmunol.abg0833

When most Americans imagine an archaeologist, they picture someone who looks like Indiana Jones. Or, perhaps, Lara Croft, from the Tomb Raider game. White, usually male but occasionally female, digging up the spoils of a vanished culture in colonized lands.

Depictions of archaeologists in popular culture mirror reality. Many scholars have noted the experts institutions recognize as authorities to discuss or represent the past are overwhelmingly white and mostly male. Archaeology has also been a tool colonizing countries use to consolidate and justify their domination. As a new open-access paper in American Antiquity points out, the first doctoral degree in archaeology was not granted to a Black woman until 1980.

First author Ayana Omilade Flewellen, an assistant professor of anthropology at UC Riverside and co-founder of the Society of Black Archaeologists, is working to change this by investigating antiblackness within the discipline, increasing the visibility of Black archaeologists and changing how archaeologists are portrayed in the media, and developing strategies to get more Black students to study archaeology.

"Public-facing avenues for history-making have historically excluded Black and Brown people," Flewellen said. "It has been white, extracting value from and not in dialogue with surrounding communities. How can we be part of history making? How can we get more excluded communities engaged in this work?"

The paper urges archaeologists and history professionals to work closely with people who are grappling with racism in public monuments and institutional names in the wake of last year's uprising following the killing of George Floyd. The authors argue that by working with "broad publics who are actively dictating what should be preserved and what should not the field can begin to redress the harm it has perpetuated."

"The past is messy," Flewellen said. "And archaeologists, we're in the dirt."

The authors assert that professionals of color who deal with history, whether as archaeologists, historians, museum curators, or other heritage experts, are often accused of bias in topics related to slavery, racism, or genocide. Their scholarly or public-facing work is often said to lack objectivity or express excessive emotion. The work of white scholars, writing on the same topics, is considered objective and taken more seriously.

"People question the objectivity of Black scholars but everyone, including white scholars, always has our own biases," Flewellen said. "But embracing these biases by working closely with communities, including Indigenous and Asian, usually excluded from history making allows us to have a more human image of the past."

For example, the authors suggest monuments damaged by protestors could be preserved and displayed alongside exhibits contextualizing the damage as part of a broader history that includes the oppression and struggle for equality of Black, Brown and Indigenous peoples in America. Defacing or destroying monuments could be seen not as an attempt to erase history but rather, as part of an active process of making history.

Recognizing acts of Black resistance against such monuments and other markers of white supremacy makes for a more objective, inclusive, and human telling of history, the authors argue. It also shifts attention from a preoccupation with preservation toward critical examination of the histories scholars choose to see, excavate, and steward.

The paper also addresses the challenges of bringing more Black college students into archaeology, which, in America, is usually housed in anthropology departments.

"Many Black students don't even have access," Flewellen said. "Historically Black colleges and universities don't usually have anthropology majors, and there are financial barriers as well. Field schools, necessary to complete training, are expensive, and because there are so few Black archaeologists, it's also hard for Black students to find mentors."

The authors argue Black archaeology, a specialization shaped by Black Feminist theory focusing on Africa and the African Disapora, can help bring more Black people, especially women, into archaeology and work against racism in the discipline.

"An antiracist archaeology is committed to forging sustainable and nurturing connections among archaeologists of all backgrounds, as well as with communities impacted by archaeological work, community organizers and activists, and those working with smaller historical societies that are also fighting to preserve local histories," the authors write.

The paper emerged from a forum last summer and calls on universities to:

Hire and advance more minority faculty and staff through tenure and promotion and into senior-level roles, respectively.

Make the process of obtaining tenure and merit reviews more transparent.

Admit more minority students and offer more scholarships to help them achieve a degree.

Train faculty and graduate students to integrate antiracist pedagogy in their classes.

Rethink curricula and syllabi to incorporate a greater diversity of voices and perspectives.

Reduce and respond to incidents of macro and microaggressions on campus, such as overtly racist abuse and small everyday insults that make for a hostile environment for students of color.

Hire counseling center staff members who are competent to address the psychological stress of minority students.

Many Mario Kart enthusiasts are familiar with the rush of racing down Rainbow Road, barely squeaking around a corner, and catching a power-up from one of the floating square icons on the screen—or, less ideally, slipping on a banana peel laid by another racer and flying off the side of the road into oblivion. This heated competition between multiple players, who use a variety of game tokens and tools to speed ahead or thwart their competitors, is part of what makes the classic Nintendo racing game that has been around since the early 1990s so appealing.

"It's been fun since I was a kid, it's fun for my kids, in part because anyone can play it," says Andrew Bell, a Boston University College of Arts & Sciences assistant professor of earth and environment. But as a researcher studying economic principles, Bell also sees Mario Kart as much more than just a racing game.

In a recent paper, Bell argues that the principles of Mario Kart—especially the parts of it that make it so addictive and fun for players—can serve as a helpful guide to create more equitable social and economic programs that would better serve farmers in low-resource, rural regions of the developing world. That's because, even when you're doing horribly in Mario Kart—flying off the side of Rainbow Road, for example—the game is designed to keep you in the race.

"Farming is an awful thing to have to do if you don't want to be a farmer," Bell says. "You have to be an entrepreneur, you have to be an agronomist, put in a bunch of labor...and in so many parts of the world people are farmers because their parents are farmers and those are the assets and options they had." This is a common story that Bell has come across many times during research trips to Pakistan, Bangladesh, Cambodia, Malawi, and other countries in southern Africa, and is what largely inspired him to focus his research on policies that could aid in development.

In his new paper, Bell argues that policies that directly provide assistance to farmers in the world's poorest developing regions could help reduce poverty overall, while increasing sustainable and environmentally friendly practices. Bell says the idea is a lot like the way that Mario Kart gives players falling behind in the race the best power-ups, designed to bump them towards the front of the pack and keep them in the race. Meanwhile, faster players in the front don't get these same boosts, and instead typically get weaker powers, such as banana peels to trip up a racer behind them or an ink splat to disrupt the other players' screens. This boosting principle is called "rubber banding," and it's what keeps the game fun and interesting, Bell says, since there is always a chance for you to get ahead.

"And that's exactly what we want to do in development," he says. "And it is really, really difficult to do."

In the video game world, rubber banding is simple, since there are no real-world obstacles. But in the real world, the concept of rubber banding to extend financial resources to agricultural families and communities who need it the most is extremely complicated.

Those opportunities might look like this, Bell says: governments could set up a program so that a third party—such as a hydropower company—would pay farmers to adopt agricultural practices to help prevent erosion, so that the company can build a dam to provide electricity. It is a complicated transaction that has worked under very specific circumstances, Bell says, but systems like this—known as Payments for Ecosystem Services (PES)—have been successful in benefitting both the farmers and the environment. A major challenge is finding private companies that are willing to pay for ecosystem services, and connecting them with farmers who are willing to change their agricultural practices. The good news about rubber banding, though, is that the more people participate in such economic programs, the more other people will join in as well; a concept Bell calls "crowding in," in his analysis.

Bell says the biggest obstacle to overcome in most of the world's developing places is figuring out how to route assistance to people in need in the first place—because, until recently, many of the people were essentially living off the grid.

"It's hard to know who is in the back [of the pack]," Bell says.

But Bell says the ability to reach people in the lowest-resource areas has improved in the last decade or so, largely thanks to the adoption of mobile phones. (In another recent paper, Bell and his collaborators found that smartphones can also play a role in understanding and addressing food insecurity.) Now, mobile devices help local governments and organizations identify people searching for more prosperous livelihoods beyond the challenging practice of agriculture and reach out to those people with economic opportunities.

Bell says further expanding access to mobile devices in poor regions of the world would also allow the gap between the richest and poorest families to be better calculated, and could also help measure the success of newly implemented policies and programs.

"Mario Kart's rubber banding ethos is to target those in the back with the items that best help them to close their gap—their own 'golden mushrooms,'" Bell wrote in the paper, referring to the power-up that gives lagging racers powerful speed bursts. Improving environmental stewardship while alleviating poverty requires that researchers and decision-makers consider from the outset, "within their unique context and challenge at-large, what the golden mushroom might be."

A horse's gut microbiome communicates with its host by sending chemical signals to its cells, which has the effect of helping the horse to extend its energy output, finds a new study published in Frontiers in Molecular Biosciences. This exciting discovery paves the way for dietary supplements that could enhance equine athletic performance.

"We are one of the first to demonstrate that certain types of equine gut bacteria produce chemical signals that communicate with the mitochondria in the horse's cells that regulate and generate energy," says Eric Barrey, author of this study and the Integrative Biology and Equine Genetics team leader at the National Research Institute for Agriculture, Food and Environment, France. "We believe that metabolites - small molecules created by breaking down bigger molecules for food or growth - produced by these bacteria have the effect of delaying low blood sugar and inflammation in the cells, which in turn extends the horse's athletic performance."

Links to disease

Mitochondria, which can be briefly described as the energy provider of cells, have been shown in recent studies to be interdependent with gut bacteria. In fact, many diseases associated with mitochondrial dysfunction in humans, such as Parkinson's and Crohn's have been linked to changes in the gut microbiome in many previous studies.

"Studying horses is a good way to assess the link between gut bacteria and mitochondria, because the level of exercise, and thereby mitochondrial function, performed by a horse during an endurance race is similar to that of a human marathon runner," explains Dr Nuria Mach, first author of this paper, also based at the National Research Institute for Agriculture, Food and Environment, France.

She continues, "For this study we gained permission for veterinary doctors to take blood samples from 20 healthy horses of similar age and performance level, at the start and end of the International Endurance Competition of Fontainebleau, an 8-hour horse race in France. These samples provided information about the chemical signals and expression of specific genes, which is the process by which DNA is converted into instructions for making proteins or other molecules. To understand the composition of the horse's gut bacteria metabolites, we obtained fecal samples at the start of the race."

The researchers found that certain bacteria in the gut were linked to the expression of genes by the mitochondria in the cells. Furthermore, the genes that were expressed, or "turned on", were linked to activities in the cell that helped it to adapt to energetic metabolism.

Evolutionary explanation

"Interestingly, mitochondria have a bacterial origin - it is thought they formed a symbiotic relationship with other components to form the first cell. This may explain why mitochondria have this line of communication with gut bacteria," says Barrey.

Mach concludes, "Improving our understanding of the intercommunication between the horse and the gut microbiome could help enhance their individual performance, as well as the method by which they are trained and dietary composition intake. Manipulating the gut microbiota with probiotic supplements as well as prebiotics, to feed the good bacteria, could be a way for increasing the health and balance of the microbiome and horses, to better sustain endurance exercise."

PISCATAWAY, NJ - Adolescents who frequently see billboard or storefront advertisements for recreational cannabis are more likely to use the drug weekly and to have symptoms of a cannabis use disorder, according to a new study in the Journal of Studies on Alcohol and Drugs.

Despite use being illegal for those below age 21 even in states that have approved recreational marijuana, "legalization may alter the ways that youth use cannabis," write the study authors, led by Pamela J. Trangenstein, Ph.D., M.P.H., of the University of North Carolina at Chapel Hill.

An increasing number of states have legalized or are considering legalizing recreational marijuana, and public concern over the risks of cannabis use has declined in recent years, Trangenstein and colleagues note. However, research continues to find cannabis use associated with negative outcomes. These include neuropsychiatric conditions, automobile crashes and substance use disorders.

And marijuana use among teens may be more problematic than in adults. "As the 2019 Surgeon General's Report warned, cannabinoid receptors are crucial for brain development, which is why cannabis use during adolescence carries special risk," the authors write.

To conduct their research, Trangenstein and colleagues used ads on social media sites and apps to recruit 172 teens, ages 15 to 19, who lived in states with legal recreational marijuana and who had used the drug at least once.

Participants answered questions about their use of marijuana and their exposure to its marketing. The latter included seeing advertisements on billboards and storefronts as well as Instagram and Facebook, if they owned or were likely to buy cannabis-branded merchandise (e.g., hats, sunglasses or t-shirts with cannabis logos or other images) and if they reported having a favorite brand or strain of cannabis or related paraphernalia, such as rolling papers.

Compared with those who never saw billboard or storefront ads, those who said they saw them "most of the time" or "always" had seven times the odds of frequent cannabis use and nearly six times the odds of having symptoms of cannabis use disorder. Having a favorite brand was linked to three times the odds of frequent use and symptoms of cannabis use disorder compared with those who did not have a preferred brand.

Further, those who owned or were likely to own cannabis-branded merchandise had 23 times the odds of frequent use as those who did not own and did not plan to own such merchandise.

Unexpectedly, though, teens who occasionally saw cannabis ads on Instagram were 85% less likely to use marijuana frequently compared with those who never saw such promotions. Those who saw them frequently were 93% less likely to use frequently. To explain these unexpected results, the authors reasoned that the teens could be seeing more user-generated content on Instagram than Facebook. Further, Instagram's image-centric style may not contain the text descriptions that teens need to understand new products.

Trangenstein and colleagues note that, although research into cannabis marketing is in its infancy, studies on alcohol and tobacco advertising indicate that "associations between ads and use may not stop at experimentation--ad exposure may facilitate progression toward problematic use, and their association may even be causal."

As states open up access to recreational marijuana for adults, the researchers say, the collateral effect on youth should not be ignored. "[S]tates and other localities with legalized cannabis should exercise special caution regarding forms of marketing that promote brand identification and engagement with youth," they conclude.

A new clinical trial from King's College London's Institute of Psychiatry, Psychology, & Neuroscience, in collaboration with Oxford University, Oxford Health NHS Foundation Trust, Sussex University, and Sussex Partnership NHS Foundation Trust has established an innovative therapy as an effective means of treating paranoid thoughts in people experiencing psychosis.

In research published in JAMA Psychiatry today, participants of the SlowMo therapy trial had eight face-to-face therapy sessions with support from an interactive web platform and app. The app, designed in collaboration with people experiencing psychosis and the Royal College of Art, is used outside the clinic to help individuals feel safer in daily life.

Paranoia is fuelled by "fast thinking"; a thinking style that is driven by instinct and gut feelings. Slowing down can help. SlowMo starts by supporting people to notice their fast thoughts, visualised as grey, fast-spinning bubbles. People learn to slow down for a moment using tips and personalised safer thoughts.

Professor Philippa Garety, Lead Researcher at SlowMo from King's IoPPN said, "In this trial, we have demonstrated that helping people to slow down their thinking, which is a simple idea, but very difficult to achieve unaided, reduces paranoia in everyday life, and improves quality of life and wellbeing. This has been made possible by devising a brief therapy which uses a powerful combination of therapy sessions and a personalised app. It is at least as effective as longer, more complex psychological treatments for paranoia, which are generally more challenging to deliver and frequently not available in clinical services. The results of this trial have been hugely exciting, and they point a way forwards to harnessing digital technology in the service of developing more effective treatments in the future."

362 people from three NHS Foundation Trusts took part in the trial, with half being provided with SlowMo therapy and their usual care, while the other half continued to receive their usual care. Over the course of six months, patients were measured on a number of outcomes, including their ability to slow down thinking. At the end of the trial, the group who had received SlowMo showed reduced levels of paranoia and worry, no longer meeting the threshold for persecutory beliefs and reported significant improvements to their wellbeing and quality of life.

Sam, who lives with psychosis and took part in the study said, "The focus on fast and slow thinking really helped. The eye catching, helpful bubbles taught me that I can end the cycle of worry, and I do not need to think speedily and start panicking. I have got that now for life. Now all my worries are lessened by SlowMo and I have freedom and peace that I did not have before."
The trial was made possible with funding from the National Institute for Health Research and the Medical Research Council (Efficacy and Mechanism Evaluation). The team now have funding to develop SlowMo so that it can be tested in routine NHS services.

Dr Amy Hardy, Digital Lead at SlowMo from King's IoPPN said "It can be difficult for people to make use of traditional therapies, and we are delighted that the trial showed the SlowMo design overcame common barriers to engagement and effectiveness. It had high rates of use and satisfaction, and worked equally well for a wide range of people. We are now working on developing SlowMo so that this accessible therapy will be widely available in the NHS".